Dithiothreitol enhanced arsenic-trioxide-induced cell apoptosis in cultured oral cancer cells via mitochondrial dysfunction and endoplasmic reticulum stress.
Arsenic is naturally occurring toxic metalloid and drinking As2O3containing water are recognized to be related to increased risk of neurotoxicity, liver injury, blackfoot disease, hypertension, and cancer. On the contrary, As2O3has been an ancient drug used in traditional Chinese medicine with substantial anticancer activities, especially in the treatment of acute promyelocytic leukemia as well as chronic wound healing. However, the cytotoxicity and detail mechanisms of As2O3action in solid cancer cells, such as oral cancer cells, are largely unknown. In this study, we have primarily cultured four pairs of tumor and nontumor cells from the oral cancer patients and treated the cells with As2O3alone or combined with dithiothreitol (DTT). The results showed that 0.5 μM As2O3plus 20 μM DTT caused a significant cell death of oral cancer cells but not the nontumor cells. Also As2O3plus DTT upregulated Bax and Bak, downregulated Bcl-2 and p53, caused a loss of mitochondria membrane potential in oral cancer cells. On the other way, As2O3also triggered endoplasmic reticulum stress and increased the levels of glucose-regulated protein 78, calpain 1 and 2. Our results suggest that DTT could synergistically enhance the effects of As2O3on killing oral cancer cells while nontoxic to the nontumor cells. The combination is promising for clinical practice in oral cancer therapy and worth further investigations. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 17-27, 2017.
Terry Fox Cancer Research Laboratory, China Medical University Hospital, Taichung, Taiwan.
Chia-Wen
CW
Tsai
Terry Fox Cancer Research Laboratory, China Medical University Hospital, Taichung, Taiwan.|Department of Clinical Nutrition, China Medical University Hospital, Taichung, Taiwan.
Mei-Due
MD
Yang
Terry Fox Cancer Research Laboratory, China Medical University Hospital, Taichung, Taiwan.|Department of Intensive Medicine, China Medical University Hospital, Taichung, Taiwan.
Te-Chun
TC
Hsia
Terry Fox Cancer Research Laboratory, China Medical University Hospital, Taichung, Taiwan.|Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
Wen-Shin
WS
Chang
Terry Fox Cancer Research Laboratory, China Medical University Hospital, Taichung, Taiwan.
Chin-Mu
CM
Hsu
Institution of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan.
Yi-Hsien
YH
Hsieh
Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.|Department of Biotechnology, Asia University, Taichung, Taiwan.
Jing-Gung
JG
Chung
Terry Fox Cancer Research Laboratory, China Medical University Hospital, Taichung, Taiwan.|Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.|Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan.
Da-Tian
DT
Bau
D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage; D004229:Dithiothreitol / Q000494:pharmacology*; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D028361:Mitochondrial Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010087:Oxides / Q000633:toxicity*; D013439:Sulfhydryl Reagents / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D013439:Sulfhydryl Reagents; D000077237:Arsenic Trioxide; D004229:Dithiothreitol
apoptosis; arsenic trioxide; dithiothreitol; endoplasmic reticulum stress; oral cancer; traditional Chinese medicine