(Z)-3,5,4'-Trimethoxystilbene Limits Hepatitis C and Cancer Pathophysiology by Blocking Microtubule Dynamics and Cell-Cycle Progression.
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Chronic hepatitis C virus (HCV) infection causes induction of several tumors/cancer stem cell (CSC) markers and is known to be a major risk factor for development of HCC. Therefore, drugs that simultaneously target viral replication and CSC properties are needed for a risk-free treatment of advanced stage liver diseases, including HCC. Here, we demonstrated that (Z)-3,5,4'-trimethoxystilbene (Z-TMS) exhibits potent antitumor and anti-HCV activities without exhibiting cytotoxicity to human hepatocytes in vitro or in mice livers. Diethylnitrosamine (DEN)/carbon tetrachloride (CCl4) extensively induced expression of DCLK1 (a CSC marker) in the livers of C57BL/6 mice following hepatic injury. Z-TMS exhibited hepatoprotective effects against DEN/CCl4-induced injury by reducing DCLK1 expression and improving histologic outcomes. The drug caused bundling of DCLK1 with microtubules and blocked cell-cycle progression at G2-M phase in hepatoma cells via downregulation of CDK1, induction of p21(cip1/waf1) expression, and inhibition of Akt (Ser(473)) phosphorylation. Z-TMS also inhibited proliferation of erlotinib-resistant lung adenocarcinoma cells (H1975) bearing the T790M EGFR mutation, most likely by promoting autophagy and nuclear fragmentation. In conclusion, Z-TMS appears to be a unique therapeutic agent targeting HCV and concurrently eliminating cells with neoplastic potential during chronic liver diseases, including HCC. It may also be a valuable drug for targeting drug-resistant carcinomas and cancers of the lungs, pancreas, colon, and intestine, in which DCLK1 is involved in tumorigenesis. Cancer Res; 76(16); 4887-96. ©2016 AACR.
College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Charles B
CB
Nguyen
Department of Biology, University of Central Oklahoma, Edmond, Oklahoma.
Hari
H
Kotturi
Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois.
Gulam
G
Waris
College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Center for Cancer Prevention and Drug Development, Hematology-Oncology Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Altaf
A
Mohammed
Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma.
Parthasarathy
P
Chandrakesan
Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma.
Randal
R
May
Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma.
Sripathi
S
Sureban
Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Nathaniel
N
Weygant
Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma.
Dongfeng
D
Qu
College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Center for Cancer Prevention and Drug Development, Hematology-Oncology Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Chinthalapally V
CV
Rao
Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Danny N
DN
Dhanasekaran
Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Michael S
MS
Bronze
Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma. naushad-ali@ouhsc.edu Courtney-houchen@ouhsc.edu.
Courtney W
CW
Houchen
Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma. naushad-ali@ouhsc.edu Courtney-houchen@ouhsc.edu.
Naushad
N
Ali
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000821:virology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D019698:Hepatitis C, Chronic / Q000150:complications / Q000473:pathology*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000187:drug effects*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D013267:Stilbenes / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
C497286:3,4',5-trimethoxystilbene; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D013267:Stilbenes