Melatonin sensitises shikonin-induced cancer cell death mediated by oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway
Mengling Li,
Chengai Wu,
Jibran Sualeh Muhammad,
Dan Yan,
Koichi Tsuneyama,
Hideki Hatta,
Zheng-Guo Cui,
Hidekuni Inadera
Affiliations
Mengling Li
Department of Public Health, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
Chengai Wu
Institute of Orthopaedic Trauma, Xicheng District Xinjiekou East Street on the 31st, Beijing, 100035, China
Jibran Sualeh Muhammad
Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates
Dan Yan
Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
Koichi Tsuneyama
Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
Hideki Hatta
Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
Zheng-Guo Cui
Department of Public Health, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan; Department of Environmental Health, University of Fukui School of Medical Science, University of Fukui, Fukui, 910-1193, Japan; Corresponding author. Department of Environmental Health, University of Fukui School of Medical Science, University of Fukui, Fukui, 910-1193, Japan.
Hidekuni Inadera
Department of Public Health, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan; Corresponding author. Department of Public Health, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
Recent research suggests that melatonin (Mel), an endogenous hormone and natural supplement, possesses anti-proliferative effects and can sensitise cells to anti-cancer therapies. Although shikonin (SHK) also possesses potential anti-cancer properties, the poor solubility and severe systemic toxicity of this compound hinders its clinical usage. In this study, we combined Mel and SHK, a potentially promising chemotherapeutic drug combination, with the aim of reducing the toxicity of SHK and enhancing the overall anti-cancer effects. We demonstrate for the first time that Mel potentiates the cytotoxic effects of SHK on cancer cells by inducing oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway. Particularly, Mel-SHK treatment induced oxidative stress, increased mitochondrial calcium accumulation and reduced the mitochondrial membrane potential in various cancer cells, leading to apoptosis. This drug combination also promoted endoplasmic reticulum (ER) stress, leading to AKT dephosphorylation. In HeLa cells, Mel-SHK treatment reduced SIRT3/SOD2 expression and SOD2 activity, while SIRT3 overexpression dramatically reduced Mel-SHK-induced oxidative stress, ER stress, mitochondrial dysfunction and apoptosis. Hence, we propose the combination of Mel and SHK as a novel candidate chemotherapeutic regimen that targets the SIRT3/SOD2-AKT pathway in cancer.
