Canertinib induces ototoxicity in three preclinical models.
Animals; Antineoplastic Agents/*adverse effects/pharmacology; Antitumor; Auditory; Canertinib; Carcinoma; Drug Screening Assays; Ear; Electrophysiology; ERBB; ErbB Receptors/*antagonists & inhibitors; Female; Hair Cells; Hearing Loss/*chemically induced; Hearing/*drug effects; Inbred C57BL; Inbred CBA; Lung Neoplasms/drug therapy; Male; Mice; Morpholines/*adverse effects/pharmacology; Neuregulin-1/metabolism; Non-small cell lung cancer; Non-Small-Cell Lung/drug therapy; NRG1; Ototoxicity; Outer hair cell; Outer/*drug effects; Signal Transduction/drug effects; Zebrafish
Neuregulin-1 (NRG1) ligand and its epidermal growth factor receptor (EGFR)/ERBB family regulate normal cellular proliferation and differentiation in many tissues including the cochlea. Aberrant NRG1 and ERBB signaling cause significant hearing impairment in mice. Dysregulation of the same signaling pathway in humans is involved in certain types of cancers such as breast cancer or non-small cell lung cancer (NSCLC). A new irreversible pan-ERBB inhibitor, canertinib, has been tested in clinical trials for the treatment of refractory NSCLC. Its possible ototoxicity was unknown. In this study, a significant dose-dependent canertinib ototoxicity was observed in a zebrafish model. Canertinib ototoxicity was further confirmed in two mouse models with different genetic backgrounds. The data strongly suggested an evolutionally preserved ERBB molecular mechanism underlying canertinib ototoxicity. Thus, these results imply that clinical monitoring of hearing loss should be considered for clinical testing of canertinib or other pan-ERBB inhibitors.
Tang Jian; Qian Yi; Li Hui; Kopecky Benjamin J; Ding Dalian; Ou Henry C; DeCook Rhonda; Chen Xiaojie; Sun Zhenyu; Kobel Megan; Bao Jianxin
Hearing research
2015
2015-10
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.heares.2015.07.002" target="_blank" rel="noreferrer noopener">10.1016/j.heares.2015.07.002</a>
High-content screen using zebrafish (Danio rerio) embryos identifies a novel kinase activator and inhibitor.
*Cancer; *Compound library; *Kinase; *Notochord; *Phenotypic screen; *Somites; *Zebrafish; Animals; Antineoplastic Agents/chemistry/pharmacology; Antitumor/methods; Benzoic Acid/chemistry/pharmacology; Death-Associated Protein Kinases/metabolism; Drug Discovery/*methods; Drug Screening Assays; Embryo; Enzyme Activation/drug effects; Enzyme Activators/*chemistry/*pharmacology; Neoplasms/drug therapy/enzymology; Nonmammalian/*drug effects/enzymology; Protein Kinase Inhibitors/*chemistry/*pharmacology; Protein-Serine-Threonine Kinases/antagonists & inhibitors/metabolism; Zebrafish Proteins/antagonists & inhibitors/metabolism; Zebrafish/*embryology
In this report we utilized zebrafish (Danio rerio) embryos in a phenotypical high-content screen (HCS) to identify novel leads in a cancer drug discovery program. We initially validated our HCS model using the flavin adenosine dinucleotide (FAD) containing endoplasmic reticulum (ER) enzyme, endoplasmic reticulum oxidoreductase (ERO1) inhibitor EN460. EN460 showed a dose response effect on the embryos with a dose of 10muM being significantly lethal during early embryonic development. The HCS campaign which employed a small library identified a promising lead compound, a naphthyl-benzoic acid derivative coined compound 1 which had significant dosage and temporally dependent effects on notochord and muscle development in zebrafish embryos. Screening a 369 kinase member panel we show that compound 1 is a PIM3 kinase inhibitor (IC50=4.078muM) and surprisingly a DAPK1 kinase agonist/activator (EC50=39.525muM). To our knowledge this is the first example of a small molecule activating DAPK1 kinase. We provide a putative model for increased phosphate transfer in the ATP binding domain when compound 1 is virtually docked with DAPK1. Our data indicate that observable phenotypical changes can be used in future zebrafish screens to identify compounds acting via similar molecular signaling pathways.
Geldenhuys Werner J; Bergeron Sadie A; Mullins Jackie E; Aljammal Rowaa; Gaasch Briah L; Chen Wei-Chi; Yun June; Hazlehurst Lori A
Bioorganic & medicinal chemistry letters
2017
2017-05
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/10.1016/j.bmcl.2017.02.068" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2017.02.068</a>
Resveratrol suppresses oxidative stress and inflammatory response in diethylnitrosamine-initiated rat hepatocarcinogenesis.
Animals; Antioxidants/*pharmacology/therapeutic use; Antitumor; Carcinogens/toxicity; Chemical and Drug Induced Liver Injury/*etiology/metabolism/pathology; Diethylnitrosamine/toxicity; Dose-Response Relationship; Drug; Drug Screening Assays; Enzyme Induction/drug effects; Experimental/chemically induced/metabolism/pathology/*prevention & control; Female; Hyperplasia; Inflammation/*prevention & control; Lipid Peroxidation/drug effects; Liver Neoplasms; Liver/drug effects/metabolism/pathology; Messenger/biosynthesis/genetics; NF-E2-Related Factor 2/biosynthesis/genetics; Nitric Oxide Synthase Type II/biosynthesis/genetics; Oxidative Stress/*drug effects; Phenobarbital/toxicity; Precancerous Conditions/*chemically induced/metabolism/pathology; Rats; Resveratrol; RNA; Sprague-Dawley; Stilbenes/*pharmacology/therapeutic use; Tyrosine/analogs & derivatives/analysis
Hepatocellular carcinoma (HCC), one of the most frequent and deadliest cancers, has been increasing considerably in the United States. In the absence of a proven effective therapy for HCC, novel chemopreventive strategies are urgently needed to lower the current morbidity and mortality of HCC. Recently, we have reported that resveratrol, a compound present in grapes and red wine, significantly prevents diethylnitrosamine (DENA)-induced liver tumorigenesis in rats, although the mechanism of action is not completely understood. In the present study, we have examined the underlying mechanisms of resveratrol chemoprevention of hepatocarcinogenesis by investigating the effects of resveratrol on oxidative damage and inflammatory markers during DENA-initiated rat liver carcinogenesis. There was a significant increase in hepatic lipid peroxidation and protein oxidation in carcinogen control animals compared with their normal counterparts at the end of the study (20 weeks). Elevated expressions of inducible nitric oxide synthase and 3-nitrotyrosine were noticed in the livers of the same animals. Dietary resveratrol (50-300 mg/kg) administered throughout the study reversed all the aforementioned markers in a dose-responsive fashion in rats challenged with DENA. Resveratrol also elevated the protein and mRNA expression of hepatic nuclear factor E2-related factor 2 (Nrf2). Results of the present investigation provide evidence that attenuation of oxidative stress and suppression of inflammatory response mediated by Nrf2 could be implicated, at least in part, in the chemopreventive effects of this dietary agent against chemically induced hepatic tumorigenesis in rats. The outcome of this study may benefit the development of resveratrol in the prevention and intervention of human HCC.
Bishayee Anupam; Barnes Kendra F; Bhatia Deepak; Darvesh Altaf S; Carroll Richard T
Cancer prevention research (Philadelphia, Pa.)
2010
2010-06
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/10.1158/1940-6207.CAPR-09-0171" target="_blank" rel="noreferrer noopener">10.1158/1940-6207.CAPR-09-0171</a>
Resveratrol-mediated chemoprevention of diethylnitrosamine-initiated hepatocarcinogenesis: inhibition of cell proliferation and induction of apoptosis.
Animal; Animals; Anticarcinogenic Agents/*antagonists & inhibitors/pharmacology; Antitumor; Apoptosis/*drug effects; Body Weight/drug effects; Cell Proliferation/drug effects; Diethylnitrosamine; Disease Models; Dose-Response Relationship; Drinking/drug effects; Drug; Drug Screening Assays; Eating/drug effects; Experimental/chemically induced/pathology/*prevention & control; Female; Immunohistochemistry; Liver Neoplasms; Organ Size/drug effects; Phenobarbital; Proto-Oncogene Proteins c-bcl-2/biosynthesis; Rats; Resveratrol; Sprague-Dawley; Stilbenes/*pharmacology
Hepatocellular carcinoma (HCC) is one of the most common cancers and lethal diseases. In view of the limited treatment and a grave prognosis of liver cancer, preventive control has been emphasized. Resveratrol, a polyphenol found in grape skins, peanuts, berries and red wine, has been shown to possess potent growth inhibitory effects against various human cancer cells. Although resveratrol has been found to exhibit chemopreventive actions in experimentally induced skin, breast, colon and esophagus rodent tumors, chemopreventive potential of this dietary constituent has not been explored well against experimental liver cancer. We evaluated the inhibitory effect of resveratrol using a two-stage model of rat hepatocarcinogenesis in Sprague-Dawley rats. Initiation was performed by a single intraperitoneal injection of diethylnitrosamine (DENA, 200 mg/kg), followed by promotion with phenobarbital (0.05%) in drinking water. The rats had free access to food supplemented with resveratrol equivalent to 50, 100 or 300 mg/kg body weight/day. Resveratrol treatment was started 4 weeks prior to the initiation and continued for 20 weeks. Resveratrol dose-dependently reduced the incidence, total number and multiplicity of visible hepatocyte nodules. Mean nodular volume and nodular volume as percentage of liver volume were also inhibited upon resveratrol treatment. Histopathological examination of liver tissue confirmed the protective effect of resveratrol. Immunohistochemical detection of cell proliferation and assay of apoptosis indicated a decrease in cell proliferation and increase of apoptotic cells in the livers of resveratrol-supplemented rats. Resveratrol also induced the expression of pro-apoptotic protein Bax, reduced anti-apoptotic Bcl-2 expression, with a concurrent increase in Bax/Bcl-2 ratio with respect to DENA control. The present study provides evidence, for the first time, that resveratrol exerts a significant chemopreventive effect on DENA-initiated hepatocarcinogenesis through inhibition of cell proliferation and induction of apoptosis. Resveratrol-induced apoptogenic signal during rat liver carcinogenesis may be mediated through the downregulation of Bcl-2 and upregulation of Bax expression. Due to a favorable toxicity profile, resveratrol can potentially be developed as a chemopreventive drug against human HCC.
Bishayee Anupam; Dhir Neetika
Chemico-biological interactions
2009
2009-05
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/10.1016/j.cbi.2008.11.015" target="_blank" rel="noreferrer noopener">10.1016/j.cbi.2008.11.015</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>