2. Academic Validation
  3. (Z)-3,5,4'-Trimethoxystilbene Limits Hepatitis C and Cancer Pathophysiology by Blocking Microtubule Dynamics and Cell-Cycle Progression

(Z)-3,5,4'-Trimethoxystilbene Limits Hepatitis C and Cancer Pathophysiology by Blocking Microtubule Dynamics and Cell-Cycle Progression

  • Cancer Res. 2016 Aug 15;76(16):4887-96. doi: 10.1158/0008-5472.CAN-15-2722.
Charles B Nguyen 1,  Hari Kotturi 2,  Gulam Waris 3,  Altaf Mohammed 4,  Parthasarathy Chandrakesan 5,  Randal May 6,  Sripathi Sureban 5,  Nathaniel Weygant 7,  Dongfeng Qu 6,  Chinthalapally V Rao 4,  Danny N Dhanasekaran 8,  Michael S Bronze 7,  Courtney W Houchen 9,  Naushad Ali 9
Affiliations

Affiliations

  • 1 College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
  • 2 Department of Biology, University of Central Oklahoma, Edmond, Oklahoma.
  • 3 Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois.
  • 4 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.
  • 5 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.
  • 6 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.
  • 7 Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
  • 8 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.
  • 9 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. [email protected] [email protected].
PMID: 27287718 DOI: 10.1158/0008-5472.CAN-15-2722
Abstract

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.

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