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

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.

Resveratrol suppresses the growth and metastatic potential of cervical cancer by inhibiting STAT3Tyr705 phosphorylation

“…Inhibition of STAT3 signaling plays a critical role in RES-induced suppression of several cancer types. RES inhibits STAT3 Tyr705 phosphorylation in ovarian cancer, 20,21 pancreatic cancer, 22 head and neck tumor, 23 osteosarcoma, 24 colorectal cancer, 25 colon cancer, [22][23][24][25][26] and STAT3 S727 phosphorylation in head and neck tumor and colorectal cancer. 23,25 Similarly, STAT3 signaling is a critical target of RES to induce apoptosis of SiHa and HeLa cells.…”

Resveratrol Suppresses the Growth and Metastatic Potential of Cervical Cancer through Inhibiting STAT3Tyr705 Phosphorylation

“…Studies have shown that resveratrol inhibits IL-6induced transcriptional activity of STAT3 in human prostate cancer LNCaP-FGC cells (18), and STAT3 axis in primary glioblastoma tumor initiating cells (19). Inhibition of STAT3 signaling plays a critical role in resveratrol-induced suppression of several types of cancer, including ovarian cancer (20,21), pancreatic cancer cells (22), head and neck tumor cells (23), osteosarcoma (24), colorectal cancer (25), colon cancer (26). In these types of cancers, it has been shown that resveratrol inhibits STAT3 Tyr705 phosphorylation (22)(23)(24)(25)(26) and STAT3 S727 phosphorylation (23,25).…”

“…Inhibition of STAT3 signaling plays a critical role in resveratrol-induced suppression of several types of cancer, including ovarian cancer (20,21), pancreatic cancer cells (22), head and neck tumor cells (23), osteosarcoma (24), colorectal cancer (25), colon cancer (26). In these types of cancers, it has been shown that resveratrol inhibits STAT3 Tyr705 phosphorylation (22)(23)(24)(25)(26) and STAT3 S727 phosphorylation (23,25). Zhang et al showed that STAT3 signaling is more critical for cervical cancer cells and is the major target of resveratrol because selective inhibition of STAT3 rather than Wnt or Notch activation commits SiHa and Hela cells to apoptosis (27).…”

Targeting Cancer with Phytochemicals via Their Fine Tuning of the Cell Survival Signaling Pathways

“…Research on apoptosis and autophagy caused by phytochemicals seems to be mostly polarized on certain types of cancer, i.e., breast, prostate and colon cancer and more frequently involving curcumin, flavonoids, and resveratrol [ 116 ]. Curcumin and resveratrol also induce apoptosis via the same survival pathways targeted by several flavonoids, e.g., PI3K/Akt [ 117 , 118 ], MAPK/JAK2/STAT3 [ 119 , 120 ], p38MAPK/ERK1/2/JNK [ 121 , 122 ], Wnt/β-catenin [ 123 , 124 ], NF-κB [ 125 , 126 ]. Besides these major pathways, phytochemicals are able to induce apoptosis in cancer cells, targeting many further signaling and biochemical mechanisms.…”