Combination of resveratrol and 5-flurouracil enhanced anti-telomerase activity and apoptosis by inhibiting STAT3 and Akt signaling pathways in human colorectal cancer cells

Abstract

// Seyung S. Chung 1, 3 , Pranabananda Dutta 1 , David Austin 1 , Piwen Wang 1, 3 , Adam Awad 1 and Jaydutt V. Vadgama 1, 2, 3 1 Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA 2 Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA, USA 3 David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA Correspondence to: Seyung S. Chung, email: seyungchung@cdrewu.edu Jaydutt V. Vadgama, email: jayvadgama@cdrewu.edu Keywords: resveratrol; telomerase; combination treatment; colorectal cancer; STAT3 Received: January 26, 2018      Accepted: August 02, 2018      Published: August 31, 2018 ABSTRACT Colorectal cancer is one of the leading causes for mortalities worldwide. The most common cause of colorectal cancer mortality is hepatic metastasis. There has been a limited advancement in the targeted-therapies for metastatic colorectal cancer. Conventional chemotherapeutic agent 5-fluorouracil has been used for various cancer treatments including colorectal cancer. Development of drug resistance and severe toxicity are major hurdles for its use in clinical setting. Resveratrol is a natural polyphenolic compound which has protective effects against aging-related diseases. In this study, we have tested whether combined treatments of resveratrol and 5-FU enhanced inhibitory effects against colorectal cancer cell growth. We herein showed that resveratrol and 5-FU combination treatments caused the anti-cancer activities by simultaneously inhibiting STAT3 and Akt signaling pathways. Resveratrol treatment induced S-phase specific cell cycle arrest, and when combined with 5-FU, it showed further increase in colorectal cancer cell apoptosis. Combined treatments of resveratrol and 5-FU inhibited epithelial-mesenchymal transition. Notably, resveratrol showed anti-inflammatory effects by downregulating inflammatory biomarkers, pSTAT3 and pNFκB. Resveratrol and 5-FU treatments inhibited STAT3 phosphorylation and its binding to the promoter region of human telomerase reverse transcriptase (hTERT). Our data provide the first evidence that resveratrol can enhance anti-telomeric and pro-apoptotic potentials of 5-FU in colorectal cancer, hence lead to re-sensitization to chemotherapy.