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Oncol Rep. 2014 Sep;32(3):1057-63. doi: 10.3892/or.2014.3289. Epub 2014 Jun 25.

Vitamin C enhances anticancer activity in methotrexate‑treated Hep3B hepatocellular carcinoma cells.

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Department of Emergency Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei 231, Taiwan, R.O.C.
Division of Allergy-Immunology-Rheumatology, Department of Internal Medicine, Saint Mary's Hospital Luodong, Yilan 265, Taiwan, R.O.C.
Department of Nutrition, Master Program of Biomedical Nutrition, Hungkuang University, Shalu, Taichung 433, Taiwan, R.O.C.
Department of Food Science and Biotechnology, National Chung Hsing University, Taichung 402, Taiwan, R.O.C.
Graduate Institute of Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan, R.O.C.


Methotrexate (MTX) has been widely used for rheumatoid arthritis therapy for a long time. MTX is also used as an anticancer drug for various tumors. However, many studies have shown that high-dose MTX treatment for cancer therapy may cause liver and renal damage. Alhough the mechanisms involved in MTX-induced liver and renal damage require further research, many studies have indicated that MTX-induced cytotoxicity is associated with increases in oxidative stress and caspase activation. In order to reduce MTX-induced side-effects and increase anticancer efficiency, currently, combination treatments of low-dose MTX and other anticancer drugs are considered and applied for various tumor treatments. The present study showed that MTX induces increases in H2O2 levels and caspase-9/-3 activation leading to cell death in hepatocellular carcinoma Hep3B cells. Importantly, this study is the first to demonstrate that vitamin C can efficiently aid low-dose MTX in inducing cell death in Hep3B cells. Therefore, the present study provides a possible powerful therapeutic method for tumors using a combined treatment of vitamin C and low-dose MTX.

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