Giant Phyllodes Tumor in an 82-Year-Old Female Initially Diagnosed a Fibroadenoma: A Case Report
Phyllodes tumors are a rare fibroepithelial neoplasm of the breast occurring in approximately 2.1 in every 1 million women with no clear predilection for women of specific races. They are characterized by spindle-shaped stromal cells with increased stromal cellularity and increased mitotic activity. The histologic characteristics are similar to that of cellular fibroadenomas making them frequently difficult to differentiate on core biopsy. We present a case of an 82-year-old female with a right breast mass which was initially diagnosed as a fibroadenoma in 2009. She was lost to follow-up and presented in 2021 with complaint of a right breast mass for which diagnostic imaging was performed. A diagnostic mammogram demonstrated a macrolobulated mass measuring 14×12×12 cm which corresponded to the palpable abnormality. The patient subsequently underwent simple mastectomy demonstrating a 14 cm mass with a fibroepithelial structure consistent with a borderline phyllodes tumor. The patient received adjuvant radiotherapy to minimize the likelihood of local recurrence. We concluded that reliable preoperative diagnosis and further studies regarding guidelines for adequate tumor margins and indication for adjuvant radiotherapy are crucial for proper surgical planning and follow-up after excision.
Donald Hefelfinger
Harley Hefelfinger
Lydia Hernandez
Cureus
. 2022 Nov 17;14(11):e31598. doi: 10.7759/cureus.31598. eCollection 2022 Nov.
2022
English
WHEN YOU HEAR HOOFBEATS, THINK ZEBRAS: MALIGNANT PHEOCHROMOCYTOMA MASQUERADING AS UNSTABLE ANGINA
A 65 year old man with a history of CAD, hypertension and diabetes presented for abrupt onset crushing chest pain at rest and was admitted for inpatient evaluation of ACS. There were no EKG changes or elevation in cardiac markers. Several hours after being admitted, the patient developed sudden shortness of breath and abdominal pain. CTA chest showed a small acute distal right lower lobe pulmonary embolism. CT abdomen and pelvis showed a 15 cm heterogenous mass of the left adrenal with extensive metastatic lesions in the liver. Serum metanephrines were significantly elevated and subsequent liver biopsy showed adrenal origin. The patient was discharged home with palliative care.
Pheochromocytomas are rare tumors with less than 0.8 per 100,000 person years. Despite an asymptomatic presentation being most common, the classic triad of symptoms including episodic headaches, paroxysmal sweating and tachycardia is present in less than half of cases with rarer manifestations being orthostatic hypotension, cardiomyopathy or pheochromocytoma crisis. Diagnosis is made by measuring serum or urine metanephrines followed by tumor visualization via CT. Treatment is alpha and beta blockade followed by surgical removal. However, 10% of pheochromocytomas are malignant, which are incurable. We present a malignant pheochromocytoma presenting as unstable angina.
Young S; Ahmed A; Saling M
Journal Of The American College Of Cardiology
2021
2021-05-03
Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Case Report
<table width="91" style="border-collapse:collapse;width:68pt;"><colgroup><col width="91" style="width:68pt;" /></colgroup><tbody><tr style="height:15pt;"><td width="91" height="20" class="xl18" style="width:68pt;height:15pt;"><a href="http://doi.org/10.1016/S0735-1097(21)03911-5">http://doi.org/10.1016/S0735-1097(21)03911-5</a></td>
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Recognition Sites for Cancer-Targeting Durg Delivery Systems
Nanoparticles; tumor; ligand; Recognition sites; targeted drug delivery system
BACKGROUND: Target-homing drug delivery systems are now gaining significant traction for use as novel therapeutic approaches in antitumor targeting for cancer therapy. Numerous targeted drug delivery systems have been designed to improve the targeting effects because these systems can display a range of favorable properties. Thus, providing suitable characteristics for clinical applicability of anticancer drugs, such as increasing the solubility, and improving the drug distribution at target sites. The majority of these targeting systems are designed with respect to differences between cancerous and normal tissues, for instance, the low pH of tumor tissues or overexpressed receptors on tumor cell membranes. Because of the growing number of targeting possibilities, it is important to know the tumor-specific recognition strategies for designing novel, targeted, drug delivery systems. Herein, we will identify and summarize literature pertaining to various recognition sites for optimizing the design of targeted drug delivery systems to augment current chemotherapeutic approaches. OBJECTIVE: This review focuses on identification of the recognition sites for developing targeted drug delivery systems for use in cancer therapeutics. METHOD: We have reviewed and compiled cancer-specific recognition sites and their abnormal characteristics within tumor tissues (low pH, high glutathione, targetable receptors, etc.), tumor cells (receptor overexpression or tumor cell membrane changes) and tumor cell organelles (nuclear and endoplasmic reticular dysregulation) utilizing existing scientific literature. Moreover, we have highlighted the design of some targeted drug delivery systems that can be used as homing tools for these recognition sites. RESULTS AND CONCLUSION: Targeted drug delivery systems are a promising therapeutic approach for tumor chemotherapy. Additional research focused on finding novel recognition sites, and subsequent development of targeting moieties for use with drug delivery systems will aid in the evaluation and clinical application of new and improved chemotherapeutics.
Guan Siyu; Zhang Qianqian; Bao Jianwei; Hu Rongfeng; Czech Tori; Tang Jihui
Current Drug Metabolism
2019
2019-10-03
Journal Article
<a href="http://doi.org/10.2174/1389200220666191003161114" target="_blank" rel="noreferrer noopener">10.2174/1389200220666191003161114</a>
PMID: 31580248
Strain Elastography For Prediction Of Breast Cancer Tumor Grades
Acoustics; agreement; breast; breast cancer; breast ultrasound; ductal carcinoma; elasticity; elastography; experience; grade; histologic grade; lesions; Nuclear Medicine & Medical Imaging; prognostic factors; Radiology; sonoelastography; sonography; strain; tumor; Ultrasound
Objectives-The purpose of this study was to determine whether the elasticity imaging/B-mode ratio on strain elastography can predict breast cancer tumor grades. Methods-A retrospective review of patients with breast lesions who underwent strain elastography and had a diagnosis of breast cancer by image-guided or surgical biopsy was performed. The axis of the maximum elastographic dimension was compared to the B-mode dimension to form an elasticity imaging/B-mode ratio. Lesions were categorized according to their pathologic type, including atypical ductal hyperplasia (ADH), mucinous or colloid cancer, ductal carcinoma in situ (DCIS), grade I invasive ductal carcinoma (MC), grade II IDC, grade III DC, invasive lobular carcinoma (ILC), and lymphoma. The mean elasticity imaging/B-mode ratio of each tumor type was calculated. The elasticity imaging/B-mode ratio of the tumor was compared to the tumor type by Kruskal-Wallis and Tukey-Kramer tests (lymphoma and ADH excluded because of small numbers). Results-Tumor grades included lymphoma (n = 3),.ADH (n = 2), mucinous cancer (n = 11), DCIS (n = 19), DC (grades I III; n = 200), and ILC (n = 31). The mean elasticity imaging/B-mode ratio varied with increasing tumor grade. Tumor grades could not have been selected at random from one population (P < .0001, chi(2) test). Invasive lobular carcinoma and grade III DC were statistically different from mucinous or colloid cancer, DCIS, and grade land II IDC. Conclusions-The elasticity imaging/B-mode ratio on strain elastography is related to the tumor grade.
Grajo J R; Barr R G
Journal of Ultrasound in Medicine
2014
2014-01
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.7863/ultra.33.1.129" target="_blank" rel="noreferrer noopener">10.7863/ultra.33.1.129</a>
Ultrastructural Aspects Of Autoschizis: A New Cancer Cell Death Induced By The Synergistic Action Of Ascorbate/menadione On Human Bladder Carcinoma Cells
2-methyl-1; 4-naphthoquinone; antitumor-activity; apoptosis; autoschizis; bladder tumor; cell death; combined vitamin-c; cultured-mammalian-cells; growth-invitro; induced oxidative stress; Microscopy; necrosis; Pathology; scanning electron-microscopy; T24 ultrastructure; tumor; vitamins
Gilloteaux J; Jamison J M; Arnold D; Taper H S; Summers J L
Ultrastructural Pathology
2001
2001-05
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1080/019131201300343810" target="_blank" rel="noreferrer noopener">10.1080/019131201300343810</a>
Cancer Cell Necrosis By Autoschizis: Synergism Of Antitumor Activity Of Vitamin C : Vitamin K-3 On Human Bladder Carcinoma T24 Cells
apoptosis; bladder; cancer; combinations; cultured-mammalian-cells; cytoskeleton; death; features; induced oxidative stress; Instruments & Instrumentation; mechanism; Microscopy; necrosis; potentiation; tumor; ultrastructure; vitamins
Gilloteaux J; Jamison J M; Arnold D; Ervin E; Eckroat L; Docherty J J; Neal D; Summers J L
Scanning
1998
1998-11
Journal Article or Conference Abstract Publication
n/a
Stimulus-dependent Phosphorylation Of Profilin-1 In Angiogenesis
actin polymerization; angiogenesis; cancer; Cell Biology; chemotaxis; endothelial-cell migration; growth-factor; motility; pathway; tumor; tyrosine kinases; vegf
Fan Y; Arif A; Gong Y Q; Jia J; Eswarappa S M; Willard B; Horowitz A; Graham L M; Penn M S; Fox P L
Nature Cell Biology
2012
2012-10
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1038/ncb2580" target="_blank" rel="noreferrer noopener">10.1038/ncb2580</a>
Denosumab in Osteoporosis and Oncology
Prostate cancer; breast-cancer; osteoporosis; Pharmacology & Pharmacy; postmenopausal women; breast-cancer; bone-mineral density; tumor; metastases; ligand; biochemical markers; bisphosphonate therapy; bone metastases; denosumab; monoclonal antibody; multiple; myeloma; necrosis factor; phase-ii; RANKL; solid tumor; turnover; zoledronic acid
OBJECTIVE: To review the pharmacology, pharmacokinetics, pharmacodynamics, safety, efficacy, and use of denosumab in osteoporosis, breast cancer, prostate cancer, and multiple myeloma. DATA SOURCES: Studies and abstracts were identified through MEDLINE and International Pharmaceutical Abstracts (1966-July 2009). Key search terms include denosumab, AMG-162, and receptor activator of nuclear factor-kappa B ligand system. Information available in abstract form was retrieved from major oncology and bone metabolism meetings. Additional data were obtained from the manufacturer. STUDY SELECTION AND DATA EXTRACTION: All available studies in humans were included except for studies in rheumatoid arthritis and giant cell tumor of the bone. DATA SYNTHESIS: In patients with osteoporosis, denosumab significantly reduces bone resorption and fractures. Studies of denosumab in the prevention and treatment of osteoporosis have demonstrated significantly increased bone mineral density and reduced bone turnover markers. Studies of denosumab versus placebo in the treatment of osteoporosis have demonstrated reductions in vertebral, hip, and nonvertebral fractures. In oncology, positive results from clinical trials in patients receiving endocrine therapy for breast and prostate cancer demonstrated decreases in bone loss and skeletal-related events. Denosumab seems to be at least as effective in reducing bone turnover markers as intravenous bisphosphonates in the oncology setting. The most common adverse effects in patients with osteoporosis were arthralgia, nasopharyngitis, back pain, and headache. The most common adverse effects in patients with cancer were infection, pain in the extremities, arthralgia, bone pain, fatigue, and pain. Serious adverse effects include infections requiring hospitalization. CONCLUSIONS: Denosumab has documented efficacy and safety in patients with osteoporosis, breast cancer, and prostate cancer. Additional clinical trial data are needed to more completely establish the effectiveness of denosumab in the treatment of osteoporosis and neoplastic disease as well as its cost-effectiveness and long-term safety.
Burkiewicz J S; Scarpace S L; Bruce S P
Annals of Pharmacotherapy
2009
2009-09
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1345/aph.1M102" target="_blank" rel="noreferrer noopener">10.1345/aph.1M102</a>
The in vitro antitumor activity of vitamins C and K-3 against ovarian carcinoma
alternative medicine use; aspects; autoschizis; cancer-chemotherapy; cell-lines; double-blind; k-3 combinations; mitomycin-c; Oncology; ovarian-cancer; phase-ii trial; pretreatment; tumor; ultrastructural; vitamin C; vitamin K-3
Background: The objective was to evaluate the cytotoxic effect and mechanism of action of vitamins C (VC) and K-3 (VK3) on ovarian carcinoma. Materials and Methods: Cytotoxicity assays were performed on ovarian cancer cell lines with VC, VK3 or a VC/VK3 combination. FIC index was employed to evaluate synergism. Flow cytometry was accomplished at 90% cytotoxic doses. Light, transmission electron microscopy and DNA isolation were performed. Results: Antitumor activity was exhibited by both VC, VK3 and VC/VK3. VC/VK3 demonstrated synergistic activity. VC/VK3 may induce a G(1) block in the cell cycle. Combined vitamin treatment resulted in cells that maintain apparently intact nuclei while extruding pieces of organelle-free cytoplasm. Degradation of chromosomal DNA was observed. Conclusion: Cell death (autoschizis) displayed characteristics of both apoptosis and necrosis. The cytotoxic effects observed may enable vitamins C and K-3 to play an adjuvant role in the treatment of ovarian cancer.
Von Gruenigen V E; Jamison J M; Gilloteaux J; Lorimer H E; Summers M; Pollard R R; Gwin C A; Summers J L
Anticancer Research
2003
2003-07
Journal Article
n/a
BENIGN MICROCYSTIC ADENOMA OF THE PANCREAS PRESENTING AS FEVER OF UNKNOWN ORIGIN
enigmatic; fever; pancreas; Surgery; tumor
A 68-year-old man with fever of undetermined origin (FUO) was admitted to the hospital. At laparotomy, a large multilobulated benign microcystic adenoma of the pancreas was removed. Fever resolved spontaneously after surgery. Although a wide range of diseases may cause fever, a standard definition of FUO remains to be established. The patient in this case demonstrated a definite relationship between a benign pancreatic tumor and FUO, the first such case described in the literature. However, the exact mechanism of fever production is unclear.
Spirtos G; Dallis D J; Qadri A M; Watanakunakorn C
Complications in Surgery
1991
1991-10
Journal Article
n/a
CONSISTENT CHROMOSOME-ABNORMALITIES IN SQUAMOUS-CELL CARCINOMA OF THE VULVA
bowenoid papulosis; cancer; colorectal carcinomas; dna; gene; Genetics & Heredity; identification; neoplasia; Oncology; prostate; tumor; tumorigenic expression; wilms
Six squamous cell carcinomas of the vulva (SCV) were karyotyped in short-term culture and in early passages as established cell lines. Each tumor was cytogenetically distinct, contained multiple chromosome rearrangements, and was karyotypically stable in culture. Heterogeneity within individual tumors was manifested by the presence of more than one clonal population, but the clones within each tumor were closely related to one another. Seven consistent chromosome abnormalities found in five of the six tumors were: losses of 3p14-cen, 8pter-p11, 22q13.1-q13.2, and the short arm of the inactive X; chromosome gains involving 3q25-qter and 11q21; and rearrangement breakpoints at 5cen-q12. Ten additional chromosome changes were observed in four of the six SCVs, and together, 22 changes occurred in at least three of the tumors. Two specific losses, 10q23-q25 and 18q22-q23, were present in all four tumors that exhibited biologically aggressive behavior in vivo, but these losses were not found in the tumors of the two long-term survivors. These findings indicate that: 1) SCVs are genetically complex, but homogeneous; 2) loss of 18q22-q23 and loss of 10q23-q25 may be associated with a poor prognosis; and 3) development and progression of SCV appear to result from cumulative effects of altered gene dosage at multiple, consistent loci.
Worsham M J; Vandyke D L; Grenman S E; Grenman R; Hopkins M P; Roberts J A; Gasser K M; Schwartz D R; Carey T E
Genes Chromosomes & Cancer
1991
1991-11
Journal Article
<a href="http://doi.org/10.1002/gcc.2870030604" target="_blank" rel="noreferrer noopener">10.1002/gcc.2870030604</a>
Inhibition of the development of metastases by dietary vitamin C : K-3 combination
ascorbate; ascorbic-acid; cancer-chemotherapy; growth-invitro; k-3 combinations; lung; lymph node; menadione; metastases; mouse liver; n-nitrosomorpholine; oxidative stress; Pharmacology & Pharmacy; prostatic-carcinoma cells; Research & Experimental Medicine; synergistic antitumor-activity; tumor; ultrastructural aspects; vitamin CK3
The tumor growth-inhibiting and chemo-potentiating effects of vitamin C and K(3)combinations have been demonstrated both in vitro and in vivo. The purpose of this study was to investigate the influence of orally administered vitamin C and K-3 on the metastasis of mouse liver tumor (T.L.T.) cells implanted in C3H mice. Adult male C3H mice were given water containing vitamin C and K3 (15 g/0.15 g dissolved in 1000 ml) beginning 2 weeks before tumor transplantation until the end of the experiment. T.L.T. cells (106) were implanted intramuscularly in the right thigh of mice. All mice were sacrificed 42 days after tumor transplantation. Primary tumor, lungs, lymph nodes and other organs or tissues suspected of harboring metastases were macroscopically examined. Samples of primary tumors, their local lymph nodes, lungs and main organs such as liver, kidneys, spleen were taken for histological examination. Forty-two percent of control mice exhibited lung metastases and 27% possessed metastases in local lymph nodes whereas 24% of vitamin-treated mice exhibited lung metastases and 10% possessed local lymph nodes metastases. The total number of lung metastases was 19 in control group and 10 in vitamin C and K-3-treated mice. Histopathological examination of the metastatic tumors from the vitamin-treated mice revealed the presence of many tumor cells undergoing autoschizic cell death. These results demonstrate that oral vitamin C and K3 significantly inhibited the metastases of T.L.T. tumors in C3H mice. At least a portion of this inhibition was due to tumor cell death by autoschizis. (C) 2004 Published by Elsevier Inc.
Taper H S; Jamison J M; Gilloteaux J; Summers J L; Calderon P B
Life Sciences
2004
2004-07
Journal Article
<a href="http://doi.org/10.1016/j.lfs.2004.02.011" target="_blank" rel="noreferrer noopener">10.1016/j.lfs.2004.02.011</a>
Brain-targeted delivery of doxorubicin using glutathione-coated nanoparticles for brain cancers.
Antibiotics; Animals; *Drug Delivery Systems; Rats; Cell Line; Polylactic Acid-Polyglycolic Acid Copolymer; Blood-Brain Barrier/*metabolism; Brain cancer; Brain Neoplasms/drug therapy/metabolism; brain-targeted delivery; doxorubicin; Doxorubicin/*administration & dosage/pharmacokinetics; Drug Carriers/*chemistry/metabolism; Glutathione/*chemistry/metabolism; Lactic Acid/chemistry/metabolism; Nanoparticles/*chemistry/metabolism; PLGA-PEG NP; Polyethylene Glycols/chemistry/metabolism; Polyglycolic Acid/chemistry/metabolism; Tumor; Antineoplastic/*administration & dosage/pharmacokinetics
OBJECTIVES: To prepare and characterize in vitro a novel brain-targeted delivery of doxorubicin using glutathione-coated nanoparticles (NPs) for the treatment of brain cancer. METHODS: Doxorubicin-loaded NPs were prepared by the nanoprecipitation method using PLGA-COOH (dl-lactide-co-glycolide). The NPs were coated with a glutathione-PEG conjugate (PEG-GSH) in order to target delivery to the brain. The NPs were characterized via in vitro studies to determine particle size, drug release, cellular uptake, immunofluorescence study, cytotoxic assay, and in vitro blood-brain barrier (BBB) assay. RESULTS: The NPs showed a particle size suitable for BBB permeation (particle size around 200 nm). The in vitro release profile of the NPs exhibited no initial burst release and showed sustained drug release for up to 96 h. The immunofluorescence study showed the glutathione coating does not interfere with the drug release. Furthermore, in vitro BBB Transwell study showed significantly higher permeation of the doxorubicin-loaded NPs compared with the free doxorubicin solution through the coculture of rat brain endothelial (RBE4) and C6 astrocytoma cells (p \textless 0.05). CONCLUSIONS: We conclude that the initial in vitro characterization of the NPs demonstrates potential in delivering doxorubicin to cancer cells with possible future application in targeting brain cancers in vivo.
Geldenhuys Werner; Wehrung Daniel; Groshev Anastasia; Hirani Anjali; Sutariya Vijaykumar
Pharmaceutical development and technology
2015
2015-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3109/10837450.2014.892130" target="_blank" rel="noreferrer noopener">10.3109/10837450.2014.892130</a>
Brain-targeted delivery of paclitaxel using glutathione-coated nanoparticles for brain cancers.
Humans; Male; Animals; Mice; *Drug Delivery Systems; Rats; Cell Line; Nanoparticles; Permeability; Particle Size; Delayed-Action Preparations; Blood-Brain Barrier/metabolism; Adenosine Triphosphatases/metabolism; Brain Neoplasms/drug therapy; Cell Death/drug effects; Coumarins/administration & dosage/pharmacokinetics; Glioma/drug therapy/pathology; Glutathione/*chemistry; Microtubules/metabolism; Paclitaxel/administration & dosage/*pharmacokinetics/pharmacology; Thiazoles/administration & dosage/pharmacokinetics; Tubulin/metabolism; Inbred C57BL; Tumor; ATP Binding Cassette Transporter; Antineoplastic Agents; Member 1/metabolism; Subfamily B; Phytogenic/administration & dosage/*pharmacokinetics/pharmacology
Paclitaxel is not effective for treatment of brain cancers because it cannot cross the blood-brain barrier (BBB) due to efflux by P-glycoprotein (P-gp). In this work, glutathione-coated poly-(lactide-co-glycolide) (PLGA) nanoparticles (NPs) of paclitaxel were developed for brain targeting for treatment of brain cancers. P-gp ATPase assay was used to evaluate the NP as potential substrates. The NP showed a particle size suitable for BBB permeation (particle size around 200 nm) and higher cellular uptake of the NP was demonstrated in RG2 cells. The
Geldenhuys Werner; Mbimba Thomas; Bui Thong; Harrison Kimberly; Sutariya Vijaykumar
Journal of drug targeting
2011
2011-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3109/1061186X.2011.589435" target="_blank" rel="noreferrer noopener">10.3109/1061186X.2011.589435</a>
Brain-targeted delivery of Tempol-loaded nanoparticles for neurological disorders.
Animals; Rats; Cell Line; Nanoparticles; Polylactic Acid-Polyglycolic Acid Copolymer; Particle Size; Delayed-Action Preparations; Antibodies; Polyethylene Glycols; Blood-Brain Barrier/metabolism; *Lactic Acid; *Polyglycolic Acid; Antioxidants/chemistry/*metabolism; Cross-Linking Reagents/chemistry; Cyclic N-Oxides/chemistry/*metabolism; Free Radical Scavengers/chemistry/*metabolism; Maleimides/chemistry; Spin Labels; Transferrin/*immunology; Tumor; Monoclonal/chemistry/*metabolism
Brain-targeted Tempol-loaded poly-(lactide-co-glycolide) (PLGA) nanoparticles (NPs) conjugated with a transferrin antibody (OX 26) were developed using the nanoprecipitation method. These NPs may have utility in treating neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Central to these diseases is an increased production of reactive oxygen and nitrogen species which may take part in the development of these conditions. As proof of principle, the NPs were loaded with Tempol, a free radical scavenger that has been shown to be protective against oxidative insults. To enhance the delivery of NPs to the central nervous system (CNS), we conjugated the transferrin receptor antibody covalently to PLGA NPs using the
Carroll Richard T; Bhatia Deepak; Geldenhuys Werner; Bhatia Ruchi; Miladore Nicholas; Bishayee Anupam; Sutariya Vijaykumar
Journal of drug targeting
2010
2010-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3109/10611861003639796" target="_blank" rel="noreferrer noopener">10.3109/10611861003639796</a>
Identification of Novel Agents for the Treatment of Brain Metastases of Breast Cancer.
Female; Humans; Animals; Mice; Apoptosis; Cell Line; ADME; Antineoplastic Agents/*therapeutic use; brain cancer; Brain Neoplasms/*drug therapy/pathology/*secondary; Breast Neoplasms/*pathology; chemotherapy; CNS; distribution; drug discovery; Drug resistance; Tumor
BACKGROUND: Brain cancer from metastasized breast cancer has a high mortality rate in women. The treatment of lesions is hampered in large part by the blood-brain barrier (BBB), which prevents adequate distribution of anti-cancer compounds to brain metastases. METHOD: In this study we used a novel screening method to identify candidate molecules that are well-suited to utilizing the BBB choline transporter for distribution into the brain parenchyma. RESULTS: From our screen we identified two compounds, Ch-1 and Ch-2 that were able to reduce the brain tumor burden in a murine mouse model of brain metastasis of breast cancer. These compounds also significantly increased the survival of mice by more than 10 days. Mechanistic studies indicated that Ch-1 is able to prevent the activation of the pro-survival mitogen-activated kinases (MAPKs) by osteoactivin (OA; Glycoprotein nonmetastatic melanoma protein B GPNMB). CONCLUSION: The results from this study show that nutrient transporter virtual screening is a viable novel alternative to traditional drug screening programs to identify anti-cancer compounds for the treatment of brain cancers.
Venishetty Vinay K; Geldenhuys Werner J; Terell-Hall Tori B; Griffith Jessica I G; Sondag Gregory R; Safadi Fayez F; Lockman Paul R
Current cancer drug targets
2017
1905-7
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.2174/1568009617666161121123948" target="_blank" rel="noreferrer noopener">10.2174/1568009617666161121123948</a>
A class of genes in the HER2 regulon that is poised for transcription in breast cancer cell lines and expressed in human breast tumors.
Humans; Cell Line; *Gene Expression Regulation; Reverse Transcriptase Polymerase Chain Reaction; *Gene Expression Profiling; Breast Neoplasms/genetics/pathology; Gene Regulatory Networks; Homeodomain Proteins/genetics/metabolism; MCF-7 Cells; Nanog Homeobox Protein; Neoplastic Stem Cells/metabolism; Octamer Transcription Factor-3/genetics/metabolism; Regulon/*genetics; RNA Polymerase II/metabolism; SOXB1 Transcription Factors/genetics/metabolism; Tumor Microenvironment/genetics; Receptor; Blotting; Western; Tumor; Neoplastic; ErbB-2/*genetics/metabolism
HER2-positive breast cancer accounts for 25% of all cases and has a poor prognosis. Although progress has been made in understanding signal transduction, little is known of how HER2 achieves gene regulation. We performed whole genome expression analysis on a HER2(+) and HER2(-) breast cancer cell lines and compared these results to expression in 812 primary tumors stratified by their HER2 expression level. Chip-on-chip with anti-RNA polymerase II was compared among breast cancer cell lines to identify genes that are potentially activated by HER2. The expression levels of these HER2-dependent POL II binding genes were determined for the 812 HER2+/- breast cancer tissues. Genes differentially expressed between HER2+/- cell lines were generally regulated in the same direction as in breast cancer tissues. We identified genes that had POLII binding in HER2(+) cell lines, but without significant gene expression. Of 737 such genes "poised" for expression in cell lines, 113 genes were significantly differentially expressed in breast tumors in a HER2-dependent manner. Pathway analysis of these 113 genes revealed that a large group of genes were associated with stem cell and progenitor cell control as indicated by networks centered on NANOG, SOX2, OCT3/4. HER2 directs POL II binding to a large number of genes in breast cancer cells. A "poised" class of genes in HER2(+) cell lines with POLII binding and low RNA expression but is differentially expressed in primary tumors, strongly suggests a role of the microenvironment and further suggests a role for stem cells proliferation in HER2-regulated breast cancer tissue.
Rahmatpanah Farah B; Jia Zhenyu; Chen Xin; Char Jessica E; Men Bozhao; Franke Anna-Clara; Jones Frank E; McClelland Michael; Mercola Dan
Oncotarget
2015
2015-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.18632/oncotarget.2676" target="_blank" rel="noreferrer noopener">10.18632/oncotarget.2676</a>
MiR-21 enhances melanoma invasiveness via inhibition of tissue inhibitor of metalloproteinases 3 expression: in vivo effects of MiR-21 inhibitor.
Humans; Gene Expression Regulation; Cell Line; MicroRNAs/*genetics/metabolism; Cell Movement/genetics; Cell Proliferation/genetics; Melanoma/*genetics/metabolism/pathology; Neoplasm Invasiveness/*genetics/pathology; Skin Neoplasms/*genetics/metabolism/pathology; Tissue Inhibitor of Metalloproteinase-3/*genetics/metabolism; RNA; Tumor; Neoplastic; Small Interfering
Metastatic melanoma is the most aggressive form of this cancer. It is important to understand factors that increase or decrease metastatic activity in order to more effectively research and implement treatments for melanoma. Increased cell invasion through the extracellular matrix is required for metastasis and is enhanced by matrix metalloproteinases (MMPs). Tissue inhibitor of metalloproteinases 3 (TIMP3) inhibits MMP activity. It was previously shown by our group that miR-21, a potential regulator of TIMP3, is over-expressed in cutaneous melanoma. It was therefore hypothesized that increased levels of miR-21 expression would lead to decreased expression of TIMP3 and thereby enhance the invasiveness of melanoma cells. miR-21 over-expression in the melanoma cell lines WM1552c, WM793b, A375 and MEL 39 was accomplished via transfection with pre-miR-21. Immunoblot analysis of miR-21-overexpressing cell lines revealed reduced expression of TIMP3 as compared to controls. This in turn led to a significant increase in the invasiveness of the radial growth phase cell line WM1552c and the vertical growth phase cell line WM793b (p \textless 0.05), but not in the metastatic cell lines A375 or MEL 39. The proliferation and migration of miR-21 over-expressing cell lines was not affected. Reduced expression of TIMP3 was achieved by siRNA knockdown and significantly enhanced invasion of melanoma cell lines, mimicking the effects of miR-21 over-expression. Treatment of tumor cells with a linked nucleic acid antagomir to miR-21 inhibited tumor growth and increased tumor expression of TIMP3 in vivo in 01B74 Athymic NCr-nu/nu mice. Intra-tumoral injections of anti-miR-21 produced similar effects. This data shows that increased expression of miR-21 enhanced the invasive potential of melanoma cell lines through TIMP3 inhibition. Therefore, inhibition of miR-21 in melanoma may reduce melanoma invasiveness.
Martin del Campo Sara E; Latchana Nicholas; Levine Kala M; Grignol Valerie P; Fairchild Ene T; Jaime-Ramirez Alena Cristina; Dao Thao-Vi; Karpa Volodymyr I; Carson Mary; Ganju Akaansha; Chan Anthony N; Carson William E 3rd
PloS one
2015
2015
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1371/journal.pone.0115919" target="_blank" rel="noreferrer noopener">10.1371/journal.pone.0115919</a>
TGFbeta1, TNFalpha, and insulin signaling crosstalk in regulation of the rat cholesterol 7alpha-hydroxylase gene expression.
*Gene Expression Regulation; Animals; Cell Line; Cholesterol 7-alpha-Hydroxylase/*genetics; Enzymologic; Forkhead Transcription Factors/physiology; Humans; Insulin/*physiology; Male; Nerve Tissue Proteins/physiology; Rats; Signal Transduction; Smad3 Protein/antagonists & inhibitors/pharmacology; Sprague-Dawley; Transforming Growth Factor beta1/*physiology; Tumor; Tumor Necrosis Factor-alpha/*physiology
The TGFbeta1/Smad pathway plays a critical role in cholestasis and liver fibrosis. Previous studies show that TGFbeta1, TNFalpha, and insulin inhibit cholesterol 7alpha-hydroxylase (CYP7A1) gene transcription and bile acid synthesis in human hepatocytes. In this study, we investigated insulin, TGFbeta1, and TNFalpha regulation of rat Cyp7a1 gene transcription. In contrast to inhibition of human CYP7A1 gene transcription, TGFbeta1 stimulates rat Cyp7a1 reporter activity. Smad3, FoxO1, and HNF4alpha synergistically stimulated rat Cyp7a1 gene transcription. Mutations of the Smad3, FoxO1, or HNF4alpha binding site attenuated the rat Cyp7a1 promoter activity. Furthermore, TNFalpha and cJun attenuated TGFbeta1 stimulation of rat Cyp7a1. Insulin or adenovirus-mediated expression of constitutively active AKT1 inhibited FoxO1 and Smad3 synergy. In streptozotocin-induced diabetic rats, Cyp7a1 mRNA expression levels were induced and insulin attenuated CYP7A1 mRNA levels. Chromatin immunoprecipitation assay showed that FoxO1 binding to Cyp7a1 chromatin was increased in diabetic rat livers and insulin reduced FoxO1 binding. These results suggest a mechanistic basis for induction of Cyp7a1 activity and bile acid synthesis in cholestatic rats and in diabetic rats. The crosstalk of insulin, TGFbeta and TNFalpha signaling pathways may regulate bile acid synthesis and lipid homeostasis in diabetes, fatty liver disease, and liver fibrosis.
Li Tiangang; Ma Huiyan; Chiang John Y L
Journal of lipid research
2008
2008-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1194/jlr.M800140-JLR200" target="_blank" rel="noreferrer noopener">10.1194/jlr.M800140-JLR200</a>
Antitumor efficacy and tolerability of systemically administered gallium acetylacetonate-loaded gelucire-stabilized nanoparticles.
*Lethal Dose 50; Adenocarcinoma/*drug therapy/pathology; Animals; Antineoplastic Agents/administration & dosage/pharmacokinetics/toxicity; Cell Line; Dose-Response Relationship; Drug; Drug Stability; Drug Tolerance; Gallium/*administration & dosage/pharmacokinetics/*toxicity; Humans; Metabolic Clearance Rate; Mice; Nanocapsules/*administration & dosage/chemistry/*toxicity; Nude; Organ Specificity; Tissue Distribution; Treatment Outcome; Triglycerides/chemistry; Tumor
The widespread clinical success with most gallium compounds in cancer therapy is markedly hampered by lack of tumor specific accumulation, poor tumor permeability and undesirable toxicity to healthy tissues. The aim of this work was to investigate for the first time antitumor mechanism of a new gallium compound (gallium acetylacetonate; GaAcAc) while assessing effectiveness of gelucire-stabilized nanoparticles (NPs) for potential application in gallium-based lung cancer therapy. NPs loaded with GaAcAc (Ga-NPs) were prepared using mixtures of cetyl alcohol with Gelucire 44/14 (Ga-NP-1) or Gelucire 53/13 (Ga-NP-2) as matrix materials. Of special note from this work is the direct evidence of involvement of microtubule disruption in antitumor effects of GaAcAc on human lung adenocarcinoma (A549). In-vivo tolerability studies were based on plasma ALT, creatinine levels and histopathological examination of tissues. The superior in-vivo antitumor efficacy of Ga-NPs over GaAcAc was depicted in marked reduction of tumor weight and tumor volume as well as histological assessment of excised tumors. Compared to free GaAcAc, Ga-NPs showed a 3-fold increase in tumor-to-blood gallium concentrations with minimized overall exposure to healthy tissues. Overall, enhancement of antitumor effects of GaAcAc by gelucire-stabilized NPs coupled with reduced exposure of healthy tissues to gallium would likely ensure desired therapeutic outcomes and safety of gallium-based cancer treatment.
Wehrung Daniel; Bi Lipeng; Geldenhuys Werner J; Oyewumi Moses O
Journal of biomedical nanotechnology
2013
2013-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1166/jbn.2013.1598" target="_blank" rel="noreferrer noopener">10.1166/jbn.2013.1598</a>
Antitumor effect of novel gallium compounds and efficacy of nanoparticle-mediated gallium delivery in lung cancer.
Antineoplastic Agents/*administration & dosage/chemistry/pharmacokinetics; Biocompatible Materials/administration & dosage/chemistry/pharmacokinetics; Cell Line; Cell Survival/drug effects; Coordination Complexes/*administration & dosage/chemistry/pharmacokinetics; Drug Carriers/administration & dosage/chemistry; Drug Stability; Endocytosis/drug effects; Gallium/*administration & dosage/chemistry/pharmacokinetics; Hemolysis/drug effects; Humans; Lung Neoplasms/*drug therapy/metabolism; Materials Testing; Membrane Potential; Mitochondrial/drug effects; Nanoparticles/*administration & dosage/chemistry; Particle Size; Platelet Aggregation/drug effects; Reactive Oxygen Species/metabolism; Transferrin/chemistry/pharmacology; Tumor
The widespread application of gallium (Ga) in cancer therapy has been greatly hampered by lack of specificity resulting in poor tumor accumulation and retention. To address the challenge, two lipophilic gallium (III) compounds (gallium hexanedione; GaH and gallium acetylacetonate; GaAcAc) were synthesized and antitumor studies were conducted in human lung adenocarcinoma (A549) cells. Nanoparticles (NPs) containing various concentrations of the Ga compounds were prepared using a binary mixture of Gelucire 44/14 and cetyl alcohol as matrix materials. NPs were characterized based on size, morphology, stability and biocompatibility. Antitumor effects of free or NP-loaded Ga compounds were investigated based on cell viability, production of reactive oxygen species and reduction of mitochondrial potential. Compared to free Ga compounds, cytotoxicity of NP-loaded Ga (5-150 microg/ml) was less dependent on concentration and incubation time (exposure) with A549 cells. NP-mediated delivery (5-150 microg Ga/ml) enhanced antitumor effects of Ga compounds and the effect was pronounced at: (i) shorter incubation times; and (ii) at low concentrations of gallium (approximately 50 microg/ml) (p \textless 0.0006). Additional studies showed that
Wehrung Daniel; Oyewumi Moses O
Journal of biomedical nanotechnology
2012
2012-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1166/jbn.2012.1361" target="_blank" rel="noreferrer noopener">10.1166/jbn.2012.1361</a>
LEAPS Vaccine Incorporating HER-2/neu Epitope Elicits Protection That Prevents and Limits Tumor Growth and Spread of Breast Cancer in a Mouse Model.
*Cancer Vaccines/genetics/immunology/therapeutic use; Animal; Animals; Breast Neoplasms/genetics/immunology/prevention & control/therapy; CD8-Positive T-Lymphocytes/immunology; Cell Line; Cytotoxic/immunology; Disease Models; Disease Progression; Epitopes; erbB-2; Experimental/immunology/pathology/*prevention & control/*therapy; Female; Genes; Immunoglobulin G/blood; Inbred BALB C; Mammary Neoplasms; Mice; Neoplasm Metastasis/prevention & control; Proof of Concept Study; T-Lymphocyte/immunology; T-Lymphocytes; Tumor
The prototype J-LEAPS T cell vaccine for HER-2/neu breast cancer (J-HER) consists of the murine HER-2/neu66-74 H-2(d) CD8 T cell epitope covalently attached through a triglycine linker to the J-immune cell binding ligand (ICBL) (human beta2 microglobulin38-50 peptide). The J-ICBL was chosen for its potential to promote Th1/Tc1 responses. In this proof-of-concept study, the ability of J-HER to prevent or treat cancer was tested in the TUBO cell-challenged BALB/c mouse model for HER-2/neu-expressing tumors. The J-HER vaccine was administered as an emulsion in Montanide ISA-51 without the need for a more potent adjuvant. When administered as a prophylactic vaccination before tumor challenge, J-HER protected against tumor development for at least 48 days. Despite eliciting protection, antibody production in J-HER-immunized, TUBO-challenged mice was less than that in unimmunized mice. More importantly, therapeutic administration of
Rosenthal Ken S; Stone Sarah; Koski Gary; Zimmerman Daniel H
Journal of immunology research
2017
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1155/2017/3613505" target="_blank" rel="noreferrer noopener">10.1155/2017/3613505</a>
Mechanism of vitamin D receptor inhibition of cholesterol 7alpha-hydroxylase gene transcription in human hepatocytes.
Base Sequence; Calcitriol/drug effects/genetics/*physiology; Cell Line; Cells; Cholesterol 7-alpha-Hydroxylase/*genetics; Cultured; DNA Primers; Electrophoretic Mobility Shift Assay; Gene Knockdown Techniques; Genetic/*physiology; Hepatocytes/*drug effects/enzymology; Humans; Immunoprecipitation; Lithocholic Acid/pharmacology; Messenger/genetics; Polymerase Chain Reaction; Receptors; RNA; Small Interfering; Transcription; Tumor; Two-Hybrid System Techniques
Lithocholic acid (LCA) is a potent endogenous vitamin D receptor (VDR) ligand. In cholestasis, LCA levels increase in the liver and intestine. The objective of this study is to test the hypothesis that VDR plays a role in inhibiting cholesterol 7alpha-hydroxylase (CYP7A1) gene expression and bile acid synthesis in human hepatocytes. Immunoblot analysis has detected VDR proteins in the nucleus of the human hepatoma cell line HepG2 and human primary hepatocytes. 1alpha, 25-Dihydroxy-vitamin D(3) or LCA acetate-activated VDR inhibited CYP7A1 mRNA expression and bile acid synthesis, whereas small interfering RNA to VDR completely abrogated VDR inhibition of CYP7A1 mRNA expression in HepG2 cells. Electrophoretic mobility shift assay and mutagenesis analyses have identified the negative VDR response elements that bind VDR/retinoid X receptor alpha in the human CYP7A1 promoter. Mammalian two-hybrid, coimmunoprecipitation, glutathione
Han Shuxin; Chiang John Y L
Drug metabolism and disposition: the biological fate of chemicals
2009
2009-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1124/dmd.108.025155" target="_blank" rel="noreferrer noopener">10.1124/dmd.108.025155</a>
Rifampicin induction of CYP3A4 requires pregnane X receptor cross talk with hepatocyte nuclear factor 4alpha and coactivators, and suppression of small heterodimer partner gene expression.
Antibiotics; Antitubercular/*pharmacology; Blotting; Cell Line; Chromatin/metabolism; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System/*biosynthesis; Cytoplasmic and Nuclear/*biosynthesis/*drug effects/genetics; Electrophoretic Mobility Shift Assay; Enzyme Induction/drug effects; Glutathione Transferase/metabolism; Hepatocyte Nuclear Factor 4/genetics/*metabolism; Hepatocytes/drug effects/metabolism; Humans; Immunoprecipitation; Messenger/biosynthesis; Plasmids/genetics; Pregnane X Receptor; Receptor Cross-Talk/drug effects; Receptors; Reverse Transcriptase Polymerase Chain Reaction; Rifampin/*pharmacology; RNA; Steroid/*drug effects/genetics; Transfection; Tumor; Western
Bile acids and drugs activate pregnane X receptor (PXR) to induce CYP3A4, which is the predominant cytochrome P450 enzyme expressed in the liver and intestine and plays a critical role in detoxifying bile acids and drugs, and protecting against cholestasis. The aim of this study is to investigate the molecular mechanism of PXR cross talk with other nuclear receptors and coactivators in regulating human CYP3A4 gene transcription. Rifampicin dose dependently induced the CYP3A4 but inhibited small heterodimer partner (SHP) mRNA expression levels in primary human hepatocytes. Rifampicin strongly stimulated PXR and hepatocyte nuclear factor 4alpha (HNF4alpha) interaction, and CYP3A4 reporter activity, which was further stimulated by peroxisome proliferators-activated receptorgamma co-activator 1alpha (PGC-1alpha) and steroid receptor coactivator-1 (SRC-1) but inhibited by SHP. Mutation of the putative HNF4alpha binding site in the distal xenobiotic responsive element module did not affect CYP3A4 basal promoter activity and synergistic stimulation by PXR and HNF4alpha. Chromatin immunoprecipitation assays revealed that rifampicin-activated PXR recruited HNF4alpha and SRC-1 to the CYP3A4 chromatin. On the other hand, SHP reduced PXR recruitment of HNF4alpha and SRC-1 to the CYP3A4 chromatin. The human SHP promoter was stimulated by HNF4alpha and PGC-1alpha. Upon activation by rifampicin, PXR inhibited SHP promoter activity. Results suggest that PXR strongly induces CYP3A4 gene transcription by interacting with HNF4alpha, SRC-1, and PGC-1alpha. PXR concomitantly inhibits SHP gene transcription and maximizes the PXR induction of the CYP3A4 gene in human livers. Drugs targeted to PXR may be developed for treating cholestatic liver diseases induced by bile acids and drugs.
Li Tiangang; Chiang John Y L
Drug metabolism and disposition: the biological fate of chemicals
2006
2006-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1124/dmd.105.007575" target="_blank" rel="noreferrer noopener">10.1124/dmd.105.007575</a>
A novel role of transforming growth factor beta1 in transcriptional repression of human cholesterol 7alpha-hydroxylase gene.
Bile Acids and Salts/metabolism; Carcinoma; Cell Line; Cells; Cholesterol 7-alpha-Hydroxylase/*genetics/*metabolism; Cultured; Enzyme Inhibitors/pharmacology; Genetic/drug effects/*physiology; Hepatocellular/*metabolism/pathology; Hepatocyte Nuclear Factor 4/metabolism; Hepatocytes/drug effects/*metabolism/pathology; Humans; Hydroxamic Acids/pharmacology; Liver Neoplasms/*metabolism/pathology; Messenger/metabolism; RNA; Signal Transduction/physiology; Smad3 Protein/metabolism; Transcription; Transforming Growth Factor beta1/*metabolism; Tumor
BACKGROUND & AIMS: Inhibition of cholesterol 7alpha-hydroxylase (CYP7A1) by bile acids and inflammatory cytokines provides an important mechanism to protect hepatocytes from bile acid toxicity during cholestasis. Transforming growth factor beta1 (TGFbeta1) released by hepatic stellate cells during chronic liver injury plays a critical role in liver inflammation and fibrogenesis. The objective of this study is to investigate the role of TGFbeta1 in hepatic bile acid synthesis. METHODS: mRNA expressions in primary human hepatocytes and HepG2 cells were measured by quantitative real-time polymerase chain reaction. Reporter assay, glutathione-S-transferase pull-down assay, adenovirus-mediated gene transduction, and chromatin immunoprecipitation assay were used to study the mechanism of TGFbeta1 regulation of CYP7A1 gene transcription. RESULTS: TGFbeta1 inhibited the mRNA expression of CYP7A1 and bile acid synthesis in HepG2 cells and primary human hepatocytes. Mothers against decapentaplegic homolog (Smad3) inhibited both CYP7A1 promoter activity and mRNA expression by inhibiting
Li Tiangang; Chiang John Y L
Gastroenterology
2007
2007-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1053/j.gastro.2007.08.042" target="_blank" rel="noreferrer noopener">10.1053/j.gastro.2007.08.042</a>
Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy.
Animals; Calcium Signaling/genetics; Carcinoma; Cell Line; Cell Proliferation/drug effects; Cisplatin/administration & dosage; Endothelium; Gene Expression Regulation; Humans; Leucine/administration & dosage/analogs & derivatives; Lewis Lung/drug therapy/*genetics/pathology; Mice; Neoplastic/drug effects; Neovascularization; Pathologic/drug therapy/*genetics/pathology; Sulfonamides/administration & dosage; TRPV Cation Channels/agonists/biosynthesis/*genetics; Tumor; Vascular Endothelial Growth Factor A/genetics; Vascular/drug effects/*pathology
Tumor vessels are characterized by abnormal morphology and hyperpermeability that together cause inefficient delivery of chemotherapeutic agents. Although vascular endothelial growth factor has been established as a critical regulator of tumor angiogenesis, the role of mechanical signaling in the regulation of tumor vasculature or tumor endothelial cell (TEC) function is not known. Here we show that the mechanosensitive ion channel transient receptor potential vanilloid 4 (TRPV4) regulates tumor angiogenesis and tumor vessel maturation via modulation of TEC mechanosensitivity. We found that TECs exhibit reduced TRPV4 expression and function, which is correlated with aberrant mechanosensitivity towards extracellular matrix stiffness, increased migration and abnormal angiogenesis by TEC. Further, syngeneic tumor experiments revealed that the absence of TRPV4 induced increased vascular density, vessel diameter and reduced pericyte coverage resulting in enhanced tumor growth in TRPV4 knockout mice. Importantly, overexpression or pharmacological activation of TRPV4 restored aberrant TEC mechanosensitivity, migration and normalized abnormal angiogenesis in vitro by modulating Rho activity. Finally, a small molecule activator of TRPV4, GSK1016790A, in combination with anticancer drug cisplatin, significantly reduced tumor growth in wild-type mice by inducing vessel maturation. Our findings demonstrate TRPV4 channels to be critical regulators of tumor angiogenesis and represent a novel target for anti-angiogenic and vascular normalization therapies.
Adapala R K; Thoppil R J; Ghosh K; Cappelli H C; Dudley A C; Paruchuri S; Keshamouni V; Klagsbrun M; Meszaros J G; Chilian W M; Ingber D E; Thodeti C K
Oncogene
2016
2016-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1038/onc.2015.83" target="_blank" rel="noreferrer noopener">10.1038/onc.2015.83</a>
Leukotriene D4 and prostaglandin E2 signals synergize and potentiate vascular inflammation in a mast cell-dependent manner through cysteinyl leukotriene receptor 1 and E-prostanoid receptor 3.
Animals; c-fos; Capillary Permeability; Cell Line; CysLT(1)R; Dinoprostone/*immunology; E-prostanoid receptor 3; Edema/immunology; EP3 Subtype/*immunology; extracellular signal-regulated kinase; Humans; Inbred BALB C; Inbred C57BL; Inflammation/immunology; leukotriene D(4); Leukotriene D4/*immunology; Leukotriene/*immunology; macrophage inflammatory protein 1beta; Mast cells; Mast Cells/*immunology; Mice; prostaglandin D(2); Prostaglandin E; prostaglandin E(2); protein kinase G; Receptors; Transgenic; Tumor
BACKGROUND: Although arachidonic acid metabolites, cysteinyl leukotrienes (cys-LTs; leukotriene [LT] C4, LTD4, and LTE4), and prostaglandin (PG) E2 are generated at the site of inflammation, it is not known whether crosstalk exists between these 2 classes of inflammatory mediators. OBJECTIVE: We sought to determine the role of LTD4-PGE2 crosstalk in inducing vascular inflammation in vivo, identify effector cells, and ascertain specific receptors and pathways involved in vitro. METHODS: Vascular (ear) inflammation was assessed by injecting agonists into mouse ears, followed by measuring ear thickness and histology, calcium influx with Fura-2, phosphorylation and expression of signaling molecules by means of immunoblotting, PGD2 and macrophage inflammatory protein 1beta generation by using ELISA, and expression of transcripts by using RT-PCR. Candidate receptors and signaling molecules were identified by using antagonists and inhibitors and confirmed by using small interfering RNA. RESULTS: LTD4 plus PGE2 potentiated vascular permeability and edema, gearing the system toward proinflammation in wild-type mice but not in Kit(W-sh) mice. Furthermore, LTD4 plus PGE2, through cysteinyl leukotriene receptor 1 (CysLT1R) and E-prostanoid receptor (EP) 3, enhanced extracellular signal-regulated kinase (Erk) and c-fos phosphorylation, inflammatory gene expression, macrophage inflammatory protein 1beta secretion, COX-2 upregulation, and PGD2 generation in mast cells. Additionally, we uncovered that this synergism is mediated through Gi, protein kinase G, and Erk signaling. LTD4 plus PGE2-potentiated effects are partially sensitive to CysLT1R or EP3 antagonists but completely abolished by simultaneous treatment both in vitro and in vivo. CONCLUSIONS: Our results unravel a unique
Kondeti Vinay; Al-Azzam Nosayba; Duah Ernest; Thodeti Charles K; Boyce Joshua A; Paruchuri Sailaja
The Journal of allergy and clinical immunology
2016
2016-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.jaci.2015.06.030" target="_blank" rel="noreferrer noopener">10.1016/j.jaci.2015.06.030</a>
Formulation and photoirradiation parameters that influenced photoresponsive drug delivery using alkoxylphenacyl-based polycarbonates.
Animals; Biocompatibility; Cardiotoxicity; Cell Line; Chemistry; Dose-Response Relationship; Doxorubicin; Drug; Drug Delivery Systems/*methods; Heart/drug effects; Humans; Inbred BALB C; Mice; Nanotechnology; Pharmaceutical; Photic Stimulation/*methods; Photoresponsive; Photosensitizing Agents/*chemical synthesis/radiation effects/toxicity; Polycarboxylate Cement/*chemical synthesis/radiation effects/toxicity; Polymer chain scission; Stimuli-responsive; Tumor
Recently, we reported the synthesis and biocompatibility of alkoxylphenacyl-based polycarbonates (APP); a promising new class of polymers that undergo photo-induced chain scission. In the current study, nanoparticles (NPs) were prepared from the APP polymer (APP-NPs) and loaded with doxorubicin (DOX) (DOX-APP-NPs) in order to identify and evaluate formulation and photoirradiation parameters that influence photoresponsive efficacy. Stable and spherical APP-NPs were prepared with diameters between 70-80nm depending on APP concentration (10-40mg/mL). There was a direct relationship between APP concentration and resultant particle size. Drug release studies indicated that exposure to the photo-trigger was capable of altering the rate and extent of DOX released. Photoresponsive DOX release was markedly influenced by the frequency of photoirradiation while the effect of APP concentration was most likely propagated through NP size. DOX released by photoactivation retained its efficacy as assessed by cytotoxicity studies in human lung adenocarcinoma (A549) cells. Studies in BALB/c mice indicated that DOX-APP-NPs induce less cardiotoxicity than DOX alone and that DOX-APP-NPs are not susceptible to dose dumping after photoirradiation.
Wehrung Daniel; Chamsaz Elaheh A; Joy Abraham; Oyewumi Moses O
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
2014
2014-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.ejpb.2014.07.011" target="_blank" rel="noreferrer noopener">10.1016/j.ejpb.2014.07.011</a>
Novel compounds that target lipoprotein lipase and mediate growth arrest in acute lymphoblastic leukemia.
*Acute lymphoblastic leukemia; *Cancer; *Co-culture model; *Lipids; *Lipoprotein lipase; *Metabolism; Amides/chemistry/metabolism/pharmacology; Antineoplastic Agents/*chemistry/metabolism/pharmacology; Binding Sites; Cell Line; Cell Proliferation/drug effects; Coculture Techniques; Dyslipidemias/complications/metabolism/pathology; Humans; Lipoprotein Lipase/antagonists & inhibitors/*metabolism; Mesenchymal Stem Cells/cytology/metabolism; Molecular Docking Simulation; Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications/metabolism/pathology; Protein Binding; Protein Structure; Serum Albumin/chemistry/metabolism; Tertiary; Tumor
Over the past decade, the therapeutic strategies employed to treat B-precursor acute lymphoblastic leukemia (ALL) have been progressively successful in treating the disease. Unfortunately, the treatment associated dyslipidemia, either acute or chronic, is very prevalent and a cause for decreased quality of life in the surviving patients. To overcome this hurdle, we tested a series of cylopropanecarboxamides, a family demonstrated to target lipid metabolism, for their anti-leukemic activity in ALL. Several of the compounds tested showed anti-proliferative activity, with one, compound 22, inhibiting both Philadelphia chromosome negative REH and Philadelphia chromosome positive SupB15 ALL cell division. The novel advantage of these compounds is the potential synergy with standard chemotherapeutic agents, while concomitantly blunting the emergence of dyslipidemia. Thus, the cylopropanecarboxamides represent a novel class of compounds that can be potentially used in combination with the present standard-of-care to limit treatment associated dyslipidemia in ALL patients.
Nair Rajesh R; Geldenhuys Werner J; Piktel Debbie; Sadana Prabodh; Gibson Laura F
Bioorganic & medicinal chemistry letters
2018
2018-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bmcl.2018.03.061" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2018.03.061</a>
Screening and identification of novel compounds with potential anti-proliferative effects on gallium-resistant lung cancer through an AXL kinase pathway.
Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology; Antitumor; AXL; Cell Line; Cell Proliferation/drug effects; Cell Survival/drug effects; Dose-Response Relationship; Drug; Drug Resistance; Drug Screening Assays; Gallium; Gallium-resistance; Gallium/pharmacology; Humans; Lung cancer; Lung Neoplasms/drug therapy/*enzymology/*pathology; Molecular Structure; Naphthalenes/chemistry/*pharmacology; Neoplasm/drug effects; Proto-Oncogene Proteins/*antagonists & inhibitors/metabolism; Pyrazoles/chemistry/*pharmacology; Quinolines/chemistry/*pharmacology; Receptor Protein-Tyrosine Kinases/*antagonists & inhibitors/metabolism; Structure-Activity Relationship; Tetrazoles/chemistry/*pharmacology; Tumor; Virtual screening
The clinical application of gallium compounds as anticancer agents is hampered by development of resistance. As a potential strategy to overcome the limitation, eight series of compounds were identified through virtual screening of AXL kinase homology model. Anti-proliferative studies were carried using gallium-sensitive (S) and gallium-resistant (R) human lung adenocarcinoma (A549) cells. Compounds 5476423 and 7919469 were identified as leads. The IC50 values from treating
Oyewumi Moses O; Alazizi Adnan; Liva Sophia; Lin Li; Geldenhuys Werner J
Bioorganic & medicinal chemistry letters
2014
2014-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bmcl.2014.07.072" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2014.07.072</a>
Forkhead box transcription factor O1 inhibits cholesterol 7alpha-hydroxylase in human hepatocytes and in high fat diet-fed mice.
Adenoviridae/genetics; Animals; Bile Acids and Salts/biosynthesis; Cell Line; Cell Nucleus/drug effects/metabolism; Cholesterol 7-alpha-Hydroxylase/*antagonists & inhibitors/genetics/metabolism; Dietary Fats/*administration & dosage/*pharmacology; Down-Regulation/drug effects; Enzymologic/drug effects; Feeding Behavior/*drug effects; Forkhead Box Protein O1; Forkhead Transcription Factors/genetics/*metabolism; Gene Expression Regulation; Gene Knockdown Techniques; Gene Transfer Techniques; Hepatocytes/drug effects/*enzymology; Humans; Inbred C57BL; Insulin Resistance; Insulin/metabolism; Male; Messenger/genetics/metabolism; Mice; RNA; RNA Interference/drug effects; Tumor
The conversion of cholesterol to bile acids is the major pathway for cholesterol catabolism. Bile acids are metabolic regulators of triglycerides and glucose metabolism in the liver. This study investigated the roles of FoxO1 in the regulation of cholesterol 7alpha-hydroxylase (CYP7A1) gene expression in primary human hepatocytes. Adenovirus-mediated expression of a phosphorylation defective and constitutively active form of FoxO1 (FoxO1-ADA) inhibited CYP7A1 mRNA expression and bile acid synthesis, while siRNA knockdown of FoxO1 resulted in a approximately 6-fold induction of CYP7A1 mRNA in human hepatocytes. Insulin caused rapid exclusion of FoxO1 from the nucleus and resulted in the induction of CYP7A1 mRNA expression, which was blocked by FoxO1-ADA. In high fat diet-fed mice, CYP7A1 mRNA expression was repressed and inversely correlated to increase hepatic FoxO1 mRNA expression and FoxO1 nuclear retention. In conclusion, our current study provides direct evidence that FoxO1 is a strong repressor of CYP7A1 gene expression and bile acid synthesis. Impaired regulation of FoxO1 may cause down-regulation of CYP7A1 gene expression and contribute to dyslipidemia in insulin resistance.
Li Tiangang; Ma Huiyan; Park Young Joo; Lee Yoon-Kwang; Strom Stephen; Moore David D; Chiang John Y L
Biochimica et biophysica acta
2009
2009-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bbalip.2009.05.004" target="_blank" rel="noreferrer noopener">10.1016/j.bbalip.2009.05.004</a>
Osteoactivin regulates head and neck squamous cell carcinoma invasion by modulating matrix metalloproteases.
*Cell Movement; Carcinoma; Cell Line; cell lines; Enzymologic; extracellular matrix; Gene Expression Regulation; Head and Neck Neoplasms/*enzymology/genetics/pathology; human; Humans; matrix metalloproteinases; Matrix Metalloproteinases; Membrane Glycoproteins/genetics/*metabolism; Messenger/genetics/metabolism; neoplasm invasion; Neoplasm Invasiveness; Neoplastic; RNA; RNA Interference; Secreted/genetics/*metabolism; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Squamous Cell/*enzymology/genetics/pathology; Transfection; Tumor
Nearly 60% of patients with head and neck squamous cell carcinoma (HNSCC) die of metastases or locoregional recurrence. Metastasis is mediated by cancer cell migration and invasion, which are in part dependent on extracellular matrix degradation by matrix metalloproteinases. Osteoactivin (OA) overexpression plays a role in metastases in several malignancies, and has been shown to upregulate matrix metalloproteinase (MMP) expression and activity. To determine how OA modulates MMP expression and activity in HNSCC, and to investigate OA effects on cell invasion, we assessed effects of OA treatment on MMP mRNA and protein expression, as well as gelatinase and caseinolytic activity in HNSCC cell lines. We assessed the effects of OA gene silencing on MMP expression, gelatinase and caseinolytic activity, and cell invasion. OA treatment had differential effects on MMP mRNA expression. OA treatment upregulated MMP-10 expression in UMSCC14a (p = 0.0431) and SCC15 (p \textless 0.0001) cells, but decreased MMP-9 expression in UMSCC14a cells (p = 0.0002). OA gene silencing decreased MMP-10 expression in UMSCC12 cells (p = 0.0001), and MMP-3 (p = 0.0005) and -9 (p = 0.0036) expression in SCC25 cells. In SCC15 and SCC25 cells, OA treatment increased MMP-2 (p = 0.0408) and MMP-9 gelatinase activity (p \textless 0.0001), respectively. OA depletion decreased MMP-2 (p = 0.0023) and -9 (p \textless 0.0001) activity in SCC25 cells. OA treatment increased 70 kDa caseinolytic activity in UMSCC12 cells consistent with tissue type plasminogen activator (p = 0.0078). OA depletion decreased invasive capacity of UMSCC12 cells (p \textless 0.0001). OA's effects on MMP expression in HNSCC are variable, and may promote cancer cell invasion.
Arosarena Oneida A; Barr Eric W; Thorpe Ryan; Yankey Hilary; Tarr Joseph T; Safadi Fayez F
Journal of cellular physiology
2018
2018-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/jcp.25900" target="_blank" rel="noreferrer noopener">10.1002/jcp.25900</a>
Osteoactivin Promotes Migration of Oral Squamous Cell Carcinomas.
*Cell Movement; Carcinoma; Cell Adhesion; Cell Line; Cell Proliferation; Cell Survival; Enzyme Activation; Gene Expression Regulation; Head and Neck Neoplasms/genetics/*metabolism/pathology; Humans; Integrin beta1/metabolism; Membrane Glycoproteins/genetics/*metabolism; Messenger/metabolism; Mitogen-Activated Protein Kinases/metabolism; Mouth Neoplasms/genetics/*metabolism/pathology; Neoplasm Invasiveness; Neoplastic; Protein Binding; RNA; RNA Interference; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Squamous Cell/genetics/*metabolism/pathology; Time Factors; Transfection; Tumor
Nearly 50% of patients with oral squamous cell carcinoma (OSCC) die of metastases or locoregional recurrence. Metastasis is mediated by cancer cell adhesion, migration, and invasion. Osteoactivin (OA) overexpression plays a role in metastases in several malignancies. The aims were to determine how integrin interactions modulate OA-induced OSCC cell migration; and to investigate OA effects on cell survival and proliferation. We confirmed OA mRNA and protein overexpression in OSCC cell lines. We assessed OA's interactions with integrins using adhesion inhibition assays, fluorescent immunocytochemistry and co-immunoprecipitation. We investigated OA-mediated activation of mitogen-activated protein kinases (MAPKs) and cell survival. Integrin inhibition effects on OA-mediated cell migration were determined. We assessed effects of OA knock-down on cell migration and proliferation. OA is overexpressed in OSCC cell lines, and serves as a migration-promoting adhesion molecule. OA co-localized with integrin subunits, and co-immunoprecipitated with the subunits. Integrin blocking antibodies, especially those directed against the beta1 subunit, inhibited cell adhesion (P = 0.03 for SCC15 cells). Adhesion to OA activated MAPKs in UMSCC14a cells and OA treatment promoted survival of SCC15 cells. Integrin-neutralizing antibodies enhanced cell migration with OA in the extracellular matrix. OA knock-down resulted in decreased proliferation of SCC15 and SCC25 cells, but did not inhibit cell migration. OA in the extracellular matrix promotes OSCC cell adhesion and migration, and may be a novel target in the prevention of HNSCC spread. J. Cell. Physiol. 231: 1761-1770, 2016. (c) 2015 Wiley Periodicals, Inc.
Arosarena Oneida A; Dela Cadena Raul A; Denny Michael F; Bryant Evan; Barr Eric W; Thorpe Ryan; Safadi Fayez F
Journal of cellular physiology
2016
2016-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/jcp.25279" target="_blank" rel="noreferrer noopener">10.1002/jcp.25279</a>
Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression.
Butadienes/pharmacology; Carcinoma; Cell Line; Chenodeoxycholic Acid/*pharmacology; Cholesterol 7-alpha-Hydroxylase/*biosynthesis; Cytoplasmic and Nuclear/metabolism/physiology; DNA-Binding Proteins/metabolism; Fibroblast Growth Factor; Fibroblast Growth Factors/drug effects/*physiology; Gene Expression/drug effects; Hepatocellular/metabolism; Hepatocytes/metabolism; Humans; Isoxazoles/pharmacology; Mitogen-Activated Protein Kinase 1/metabolism; Mitogen-Activated Protein Kinase 3/metabolism; Nitriles/pharmacology; Receptor; Receptors; Signal Transduction/drug effects; Transcription Factors/metabolism; Tumor; Type 4/antagonists & inhibitors
UNLABELLED: Mouse fibroblast growth factor 15 (FGF15) and human ortholog FGF19 have been identified as the bile acid-induced intestinal factors that mediate bile acid feedback inhibition of cholesterol 7alpha-hydroxylase gene (C YP7A1) transcription in mouse liver. The mechanism underlying FGF15/FGF19 inhibition of bile acid synthesis in hepatocytes remains unclear. Chenodeoxycholic acid (CDCA) and the farnesoid X receptor (FXR)-specific agonist GW4064 strongly induced FGF19 but inhibited CYP7A1 messenger RNA (mRNA) levels in primary human hepatocytes. FGF19 strongly and rapidly repressed CYP7A1 but not small heterodimer partner (SHP) mRNA levels. Kinase inhibition and phosphorylation assays revealed that the mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/Erk1/2) pathway played a major role in mediating FGF19 inhibition of CYP7A1. However, small interfering RNA (siRNA) knockdown of SHP did not affect FGF19 inhibition of CYP7A1. Interestingly, CDCA stimulated tyrosine phosphorylation of the FGF receptor 4 (FGFR4) in hepatocytes. FGF19 antibody and siRNA specific to FGFR4 abrogated GW4064 inhibition of CYP7A1. These results suggest that bile acid-activated FXR is able to induce FGF19 in hepatocytes to inhibit CYP7A1 by an autocrine/paracrine mechanism. CONCLUSION: The hepatic FGF19/FGFR4/Erk1/2 pathway may inhibit CYP7A1 independent of SHP. In addition to inducing FGF19 in the intestine, bile acids in hepatocytes may activate the liver FGF19/FGFR4 signaling pathway to inhibit bile acid synthesis and prevent accumulation of toxic bile acid in human livers.
Song Kwang-Hoon; Li Tiangang; Owsley Erika; Strom Stephen; Chiang John Y L
Hepatology (Baltimore, Md.)
2009
2009-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/hep.22627" target="_blank" rel="noreferrer noopener">10.1002/hep.22627</a>