RRC ID 51738
Author Harada K, Ferdous T, Harada T, Ueyama Y.
Title Metformin in combination with 5-fluorouracil suppresses tumor growth by inhibiting the Warburg effect in human oral squamous cell carcinoma.
Journal Int. J. Oncol.
Abstract Cancer cells show enhanced glucose consumption and lactate production even in the presence of abundant oxygen, a phenomenon known as the Warburg effect, which is related to tumor proliferation, progression and drug-resistance in cancers. Hypoxia-inducible factor-1 (HIF-1) and several members of Phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway positively contribute to the Warburg effect, whereas AMP activated protein Kinase (AMPK) acts as a negative regulator. Targeting the regulator molecules of Warburg effect might be a useful strategy to effectively kill cancer cells. Metformin was reported to be effective against various cancers as it inhibits cell proliferation by activating AMPK, and inhibiting mTOR and HIF-1α. Several studies suggested the efficacy of metformin with 5-fluorouracil (5-FU) against esophageal and colon cancer. In this study, we evaluated the efficacy of metformin and 5-FU combined therapy against human oral squamous cell carcinoma (OSCC) in vitro and in vivo. MTT assay and TUNEL assay revealed that metformin (4 mg/ml) and 5-FU (2.5 µg/ml) combination treatment effectively inhibited cell growth and induced apoptosis in OSCC cell lines (HSC2, HSC3 and HSC4) compared to either agent alone. Lactate colorimetric assay detected decreased level of lactate in the supernatants of metformin and 5-FU treated cells compared to cells treated with metformin or 5-FU. Western blot analysis showed marked downregulation of HIF-1α and mTOR expression, and upregulation of AMPKα in cells treated with metformin and 5-FU combination treatment. Combination therapy with metformin (200 mg/kg, i.p.) and 5-FU (10 mg/kg, i.p.) for 4 weeks (5 days/week) effectively reduced HSC2 tumor growth (77.6%) compared to metformin (59.9%) or 5-FU (52%) alone in nude mice. These findings suggest that metformin and 5-FU combined therapy could exert strong antitumor effect against OSCC through the inhibition of Warburg phenomenon in tumor cells.
Volume 49(1)
Pages 276-84
Published 2016-7
DOI 10.3892/ijo.2016.3523
PMID 27210058
MeSH AMP-Activated Protein Kinases / biosynthesis Animals Apoptosis / drug effects Carcinoma, Squamous Cell / drug therapy* Carcinoma, Squamous Cell / genetics Carcinoma, Squamous Cell / pathology Cell Proliferation / drug effects Drug Synergism Fluorouracil / administration & dosage* Gene Expression Regulation, Neoplastic / drug effects Humans Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis Metformin / administration & dosage* Mice Mouth Neoplasms / drug therapy* Mouth Neoplasms / genetics Mouth Neoplasms / pathology Signal Transduction / drug effects TOR Serine-Threonine Kinases / biosynthesis Xenograft Model Antitumor Assays
IF 3.333
Human and Animal Cells HSC-2(RCB1945) HSC-3(RCB1975) HSC-4(RCB1902)