Combination of resveratrol and 5-flurouracil enhanced anti-telomerase activity and apoptosis by inhibiting STAT3 and Akt signaling pathways in human colorectal cancer cells
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Seyung S. Chung1,3, Pranabananda Dutta1, David Austin1, Piwen Wang1,3, Adam Awad1 and Jaydutt V. Vadgama1,2,3
1Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA
2Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA, USA
3David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
Seyung S. Chung, email: email@example.com
Jaydutt V. Vadgama, email: firstname.lastname@example.org
Keywords: resveratrol; telomerase; combination treatment; colorectal cancer; STAT3
Received: January 26, 2018 Accepted: August 02, 2018 Published: August 31, 2018
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.
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