Dietary Phytochemicals In The Chemoprevention And Treatment Of Hepatocellular Carcinoma: In Vivo Evidence, Molecular Targets, And Clinical Relevance
acid phenethyl ester; altered hepatic foci; black tea; carcinoma; Chemoprevention; dietary; diethylnitrosamine-induced hepatocarcinogenesis; hepatocarcinogenesis; hepatocellular; implanted; liver cancer; liver preneoplastic foci; model; multiorgan carcinogenesis model; nitrosodiethylamine-induced; nude-mice; Oncology; phenobarbital-induced hepatocarcinogenesis; phytochemicals; polyphenols; resistant hepatocyte; treatment
Hepatocellular carcinoma (HCC), one of the most common and lethal cancers, is a growing menace in modern society. Until recently, the majority of detected cases of liver cancer have been found in the developing nations of Asia and Africa; however, its occurrence has significantly increased in the United States. HCC occurs due to several etiologies, such as alcoholism, dietary carcinogens, iron overload, viral hepatitis, as well as several hepatic chronic diseases. In view of the limited treatment options, such as surgery and transplantation, a critical need exists to examine alternative approaches. The use of phytochemicals obtained from dietary sources provides a novel and fascinating preventive and therapeutic approach against HCC. Dietary phytochemicals possess potent antioxidant and anti-inflammatory properties which are extremely critical to combat the significant oxidative stress and inflammation implicated in liver cancer. An impressive number of phytochemicals have shown considerable promise as candidates for the prevention and treatment of HCC. In this article, we systematically review the in vivo pre-clinical evidence documenting the chemopreventive and therapeutic potential of several important dietary phytochemicals in HCC. This review critically examines the molecular mechanisms of the pharmacological effects of the aforementioned animal studies. Clinical and epidemiological studies are also highlighted in this review. Emerging issues such as bioavailability, dose optimization, targeted drug delivery, role of botanical extracts and synergy are also discussed. Finally, current challenges, limitations, future directions, innovative concepts and novel hypotheses for the use of dietary phytochemicals in the chemoprevention and amelioration of human HCC are presented.
Bishayee A; Thoppil R J; Waghray A; Kruse J A; Novotny N A; Darvesh A S
Current Cancer Drug Targets
2012
2012-11
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.2174/156800912803987896" target="_blank" rel="noreferrer noopener">10.2174/156800912803987896</a>
Black Currant Phytoconstituents Exert Chemoprevention Of Diethylnitrosamine-initiated Hepatocarcinogenesis By Suppression Of The Inflammatory Response
Biochemistry & Molecular Biology; cancer-cell proliferation; Chemoprevention; cyclooxygenase-2; cyclooxygenase-2 inhibitors; gamma-glutamyl-transferase; heat-shock proteins; heat-shock proteins; hepatocarcinogenesis; human hepatocellular-carcinoma; Inflammation; liver cancer; molecular chaperones; nf-kappa-b; nuclear factor-B; Oncology; ribes-nigrum; signaling; united-states
Black currant fruits containing high amounts of anthocyanins are known to possess potent antioxidant and anti-inflammatory properties. We have previously reported that anthocyanin-rich black currant skin extract (BCSE) inhibits diethylnitrosamine (DENA)-initiated hepatocarcinogenesis in rats although the underlying mechanisms are not fully understood. Our present study investigates the anti-inflammatory mechanisms of BCSE during DENA rat liver carcinogenesis. Dietary BCSE (100 or 500mg/kg) treatment for 22wk afforded a striking inhibition of DENA-induced hepatic gamma-glutamyl transpeptidase-positive preneoplastic foci in a dose-responsive fashion. There was a significant increase in hepatic expression of heat shock proteins (HSP70 and HSP90), cyclooxygenase-2, and nuclear factor-B (NF-B) in DENA-exposed rat livers. Dietary BCSE dose-dependently abrogated all these elevated inflammatory markers. The possible cardiotoxicity of BCSE was assessed by monitoring cardiac functions using transthoracic echocardiography. BCSE-mediated anti-inflammatory effects during rat liver carcinogenesis have been achieved without any cardiotoxicity. Our results provide convincing evidence, for the very first time, that suppression of the inflammatory cascade through modulation of the NF-B signaling pathway could be implicated, at least in part, in the chemopreventive effects of black currant bioactive phytoconstituents against experimental hepatocarcinogenesis. These results coupled with an excellent safety profile of BCSE support the development of black currant phytochemicals for the chemoprevention of inflammation-driven hepatocellular cancer. (c) 2011 Wiley Periodicals, Inc.
Bishayee A; Thoppil R J; Mandal A; Darvesh A S; Ohanyan V; Meszaros J G; Haznagy-Radnai E; Hohmann J; Bhatia D
Molecular Carcinogenesis
2013
2013-04
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1002/mc.21860" target="_blank" rel="noreferrer noopener">10.1002/mc.21860</a>
Pomegranate Phytoconstituents Blunt The Inflammatory Cascade In A Chemically Induced Rodent Model Of Hepatocellular Carcinogenesis
Biochemistry & Molecular Biology; cancer chemoprevention; Chemoprevention; cyclooxygenase-2; cyclooxygenase-2; factor-kappa-b; gene-expression; heat-shock proteins; hepatocarcinogenesis; human-disease; Inflammation; inhibitors; molecular chaperones; nitric-oxide synthase; Nuclear factor-kappaB; Nutrition & Dietetics; oxidative stress; Pomegranate; punica-granatum l.
Liver cancer, predominantly hepatocellular carcinoma (HCC), represents a complex and fatal malignancy driven primarily by oxidative stress and inflammation. Due to dismal prognosis and limited therapeutic intervention, chemoprevention has emerged as a viable approach to reduce the morbidity and mortality of HCC. Pomegranate fruit is a rich source of phytochemicals endowed with potent antioxidant and anti-inflammatory properties. We previously reported that pomegranate phytochemicals inhibit diethylnitrosamine (DENA)-initiated hepatocarcinogenesis in rats though nuclear factor E2-related factor 2 (Nrf2)-mediated antioxidant mechanisms. Since Nrf2 also acts as a key mediator of the nuclear factor-kappaB (NF-kappa B)-regulated inflammatory pathway, our present study investigated the anti-inflammatory mechanisms of a pomegranate emulsion (PE) during DENA-induced rat hepatocarcinogenesis. Rats were administered with PE (1 or 10 g/kg) 4 weeks before and 18 weeks following DENA initiation. There was a significant increase in hepatic expressions of inducible nitric oxide synthase, 3-nitrotyrosine, heat shock protein 70 and 90, cyclooxygenase-2 and NF-kappa B in DENA-exposed rat livers. PE dose-dependently suppressed all aforementioned elevated inflammatory markers. A conspicuous finding of this study involves lack of cardiotoxicity of PE as assessed by monitoring cardiac function using noninvasive echocardiography. Our results provide substantial evidence that suppression of the inflammatory cascade through modulation of NF-kappa B signaling pathway may represent a novel mechanism of liver tumor inhibitory effects of PE against experimental hepatocarcinogenesis. Data presented here coupled with those of our earlier study underline the importance of simultaneously targeting two interconnected molecular circuits, namely, Nrf2-mediated redox signaling and NF-kappa B-regulated inflammatory pathway, by pomegranate phytoconstituents to achieve chemoprevention of HCC. (C) 2013 Elsevier Inc. All rights reserved.
Bishayee A; Thoppil R J; Darvesh A S; Ohanyan V; Meszaros J G; Bhatia D
Journal of Nutritional Biochemistry
2013
2013-01
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.jnutbio.2012.04.009" target="_blank" rel="noreferrer noopener">10.1016/j.jnutbio.2012.04.009</a>
Chemoprevention Of Hepatocellular Carcinoma With Anthocyanin-rich Black Currant (ribes Nigrum L.) Extract: In Vitro And In Vivo Evidence
Oncology
Bishayee A; Thoppil R J; Darvesh A S; Bhatia D; Hohmann H
Cancer Research
2011
2011-04
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1158/1538-7445.am2011-4607" target="_blank" rel="noreferrer noopener">10.1158/1538-7445.am2011-4607</a>
Chemopreventive Effect Of A Novel Oleanane Triterpenoid In A Chemically Induced Rodent Model Of Breast Cancer
amooranin; apoptosis; breast cancer; carcinogenesis; carcinoma cell-lines; cddo-methyl ester; cell; Chemoprevention; DMBA; growth arrest; mammary; mice; oleanane triterpenoid; Oncology; prevention; proliferation; rat; tumor-growth
Breast cancer represents one of the most frequently diagnosed cancers and predominant causes of death in women worldwide. The value of preventive therapy to limit the devastating impact of breast cancer is well established. Various plant triterpenoids and their synthetic analogs have shown significant promise as potent chemopreventive agents in breast cancer. The current study was initiated to investigate mechanism-based chemopreventive potential of a novel synthetic oleanane triterpenoid (methyl-25-hydroxy-3-oxoolean-12-en-28-oate, AMR-Me) against 7,12-dimethylbenz(a)anthracene (DMBA)-initiated rat mammary carcinogenesis, an experimental rodent tumor model that closely resembles human mammary cancer. Rats were orally administered with AMR-Me (0.8, 1.2 and 1.6 mg/kg) three times per week for 18 weeks. Following two weeks of AMR-Me treatment, mammary carcinogenesis was initiated by oral administration of DMBA (50 mg/kg body weight). At the end of the study (16 weeks following DMBA exposure), AMR-Me exhibited a striking inhibition of DMBA-induced mammary tumor incidence, total tumor burden, average tumor weight and reversed histopathological alterations without toxicity. AMR-Me dose-dependently suppressed abnormal cell proliferation, induced apoptosis, up-regulated pro-apoptotic protein Bax and down-regulated antiapoptotic protein Bcl-2 in mammary tumors. AMR-Me upregulated the transcriptional levels of Bax, Bad, caspase-3, caspase-7 and poly(ADP-ribose) polymerase and down-regulated Bcl-2. These results clearly demonstrate for the first time that novel triterpenoid AMR-Me exerts chemopreventive efficacy in the classical DMBA model of breast cancer by suppressing abnormal cell proliferation and inducing apoptosis mediated through mitochondrial pro-apoptotic mechanisms. AMR-Me could be developed as a chemopreventive drug to reduce the risk of human breast cancer that remains a devastating disease.
Bishayee A; Mandal A; Thoppil R J; Darvesh A S; Bhatia D
International Journal of Cancer
2013
2013-09
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1002/ijc.28108" target="_blank" rel="noreferrer noopener">10.1002/ijc.28108</a>
Dietary Phytochemicals In The Chemoprevention And Treatment Of Hepatocellular Carcinoma: In Vivo Evidence, Molecular Targets, And Clinical Relevance
acid phenethyl ester; altered hepatic foci; black tea; carcinoma; chemoprevention; dietary; diethylnitrosamine-induced hepatocarcinogenesis; hepatocarcinogenesis; hepatocellular; implanted; liver cancer; liver preneoplastic foci; model; multiorgan carcinogenesis model; nitrosodiethylamine-induced; nude-mice; Oncology; phenobarbital-induced hepatocarcinogenesis; phytochemicals; polyphenols; resistant hepatocyte; treatment
Bishayee A; Thoppil R J; Waghray A; Kruse J A; Novotny N A; Darvesh A S
Current Cancer Drug Targets
2012
2012-11
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.2174/156800912803987896" target="_blank" rel="noreferrer noopener">10.2174/156800912803987896</a>
Black Currant Phytoconstituents Exert Chemoprevention Of Diethylnitrosamine-initiated Hepatocarcinogenesis By Suppression Of The Inflammatory Response
Biochemistry & Molecular Biology; cancer-cell proliferation; chemoprevention; cyclooxygenase-2; cyclooxygenase-2 inhibitors; gamma-glutamyl-transferase; heat-shock proteins; heat-shock proteins; hepatocarcinogenesis; human hepatocellular-carcinoma; inflammation; liver cancer; molecular chaperones; nf-kappa-b; nuclear factor-B; Oncology; ribes-nigrum; signaling; united-states
Bishayee A; Thoppil R J; Mandal A; Darvesh A S; Ohanyan V; Meszaros J G; Haznagy-Radnai E; Hohmann J; Bhatia D
Molecular Carcinogenesis
2013
2013-04
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1002/mc.21860" target="_blank" rel="noreferrer noopener">10.1002/mc.21860</a>
Pomegranate Phytoconstituents Blunt The Inflammatory Cascade In A Chemically Induced Rodent Model Of Hepatocellular Carcinogenesis
Biochemistry & Molecular Biology; cancer chemoprevention; chemoprevention; cyclooxygenase-2; cyclooxygenase-2; factor-kappa-b; gene-expression; heat-shock proteins; hepatocarcinogenesis; human-disease; inflammation; inhibitors; molecular chaperones; nitric-oxide synthase; Nuclear factor-kappaB; Nutrition & Dietetics; oxidative stress; Pomegranate; punica-granatum l.
Bishayee A; Thoppil R J; Darvesh A S; Ohanyan V; Meszaros J G; Bhatia D
Journal of Nutritional Biochemistry
2013
2013-01
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.jnutbio.2012.04.009" target="_blank" rel="noreferrer noopener">10.1016/j.jnutbio.2012.04.009</a>
Chemoprevention Of Hepatocellular Carcinoma With Anthocyanin-rich Black Currant (ribes Nigrum L.) Extract: In Vitro And In Vivo Evidence
Oncology
Bishayee A; Thoppil R J; Darvesh A S; Bhatia D; Hohmann H
Cancer Research
2011
2011-04
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1158/1538-7445.am2011-4607" target="_blank" rel="noreferrer noopener">10.1158/1538-7445.am2011-4607</a>
Chemopreventive Effect Of A Novel Oleanane Triterpenoid In A Chemically Induced Rodent Model Of Breast Cancer
amooranin; apoptosis; breast cancer; carcinogenesis; carcinoma cell-lines; cddo-methyl ester; cell; chemoprevention; DMBA; growth arrest; mammary; mice; Oleanane triterpenoid; Oncology; prevention; proliferation; rat; tumor-growth
Bishayee A; Mandal A; Thoppil R J; Darvesh A S; Bhatia D
International Journal of Cancer
2013
2013-09
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1002/ijc.28108" target="_blank" rel="noreferrer noopener">10.1002/ijc.28108</a>
Anthocyanin-rich black currant (Ribes nigrum L.) extract affords chemoprevention against diethylnitrosamine-induced hepatocellular carcinogenesis in rats.
Male; Animals; Rats; Chemoprevention; Phenobarbital; Plants; Biochemical Phenomena; Nitrosamines; Preventive Cardiovascular Nurses Association; Proteins – Metabolism; Cell Physiology – Drug Effects; Liver Neoplasms – Metabolism; Liver Neoplasms – Pathology; Antineoplastic Agents – Therapeutic Use; Liver Neoplasms – Prevention and Control; Liver – Pathology; Plant Extracts – Therapeutic Use; Apoptosis – Drug Effects; Liver Neoplasms – Chemically Induced
Bishayee A; Mbimba T; Thoppil R J; Háznagy-Radnai E; Sipos P; Darvesh A S; Folkesson H G; Hohmann J
Journal of Nutritional Biochemistry
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/10.1016/j.jnutbio.2010.09.001" target="_blank" rel="noreferrer noopener">10.1016/j.jnutbio.2010.09.001</a>
Markers associated with sex differences in methamphetamine-induced striatal dopamine neurotoxicity.
Body Temperature; Body Weight; Bcl-2 PAI-1; Dopamine Transporter.; GFAP; IGF-1R
Three different approaches were employed to assess various markers associated with sex differences in responses to methamphetamine (MA). Bioassay measures reveal that MA treatment results in significantly greater reductions in body weight and increases in body temperature in male mice. Protein and mRNA determinations show significant increases in Bcl-2 and PAI-1 in male mice, while females show significant increases in GFAP and decreases in IGF-1R following treatment with MA. In mice with a heterozygous mutation of their dopamine transporter (+/- DAT), only female mice show significant differences in dopamine transporter binding and mRNA and associated reductions in striatal dopamine content along with increases in MA-evoked striatal dopamine output. The identification of these sex-dependent differences in markers provides a foundation for more exhaustive evaluation of their impact upon, and treatment of, disorders/neurotoxicity of the nigrostriatal dopaminergic system and the bases for the differences that exist between females and males.
Dluzen D E; McDermott J L; Bourque M; Di Paolo T; Darvesh A S; Buletko A B; Laping N J
Current neuropharmacology
2011
2011-03
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/10.2174/157015911795017399" target="_blank" rel="noreferrer noopener">10.2174/157015911795017399</a>
Relationships among gender, age, time, and temperature in methamphetamine-induced striatal dopaminergic neurotoxicity.
3; 4-Dihydroxyphenylacetic Acid/metabolism; Age Factors; Animals; Body Temperature/drug effects; Central Nervous System Stimulants/*toxicity; Corpus Striatum/*drug effects/metabolism; Dopamine/*metabolism; Female; In Vitro Techniques; Male; Methamphetamine/*toxicity; Mice; Neurotoxicity Syndromes/etiology/*metabolism/physiopathology; Sex Factors; Time Factors
A neurotoxic regimen of methamphetamine (MA-40 mg/kg ip) administered at 0 (control-MA vehicle), 0.5 and 72 h prior to determinations of striatal dopamine (DA) and DOPAC (3,4-dihydroxyphenylacetic acid)/DA ratios were compared among juvenile and adult female and male mice. Adult females and males showed similar depletions in striatal DA at 0.5 h post-MA, but males showed greater DA depletions and DOPAC/DA ratios at 72 h post-MA. Juvenile mice showed neither sex differences, nor any MA neurotoxicity upon striatal DA or DOPAC/DA ratios. Following MA, body temperatures increased in all mice, but increases in adult males were greater than adult females; juveniles showed no sex differences and body temperature increases were similar to that of adult males. MA-evoked DA output was greater in adult compared to juvenile males and a biologically effective regimen of testosterone to juvenile males neither increased MA-evoked DA output nor decreased MA-induced striatal DA like that observed in adult males. These results demonstrate: (1) Unlike adults, juvenile mice show neither a sex difference for MA-induced neurotoxicity or body temperature increases, nor MA neurotoxicity, (2) Initial effects of MA (0.5 h) in adult females and males are similar, but at 72 h post-MA females show no further striatal DA depletion, (3) Increased striatal DA depletion within adult versus juvenile males may be related to initially higher MA-evoked DA responses, and (4) Testosterone fails to convert juvenile males into adults with regard to MA effects.
Dluzen D E; McDermott J L; Darvesh A S
Neuroscience
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/10.1016/j.neuroscience.2010.02.076" target="_blank" rel="noreferrer noopener">10.1016/j.neuroscience.2010.02.076</a>