Benzyl isothiocyanate promotes apoptosis of oral cancer cells via an acute redox stress-mediated DNA damage response.
Benzyl isothiocyanate (BITC) is a cruciferous vegetable-derived compound with anticancer properties in human cancer cells. However, its anticancer potential and underlying mechanisms remain absent in human oral cancer cells. Results indicate that BITC inhibits growth, promotes G2/M phase arrest and triggers apoptosis of OC2 cells with a minimal toxicity to normal cells. BITC-induced cell death was completely prevented by pretreatment with thiol-containing redox compounds including N-acetyl-l-cysteine (NAC), glutathione (GSH), dithiothreitol, and 2-mercaptoethanol, but not free radical scavengers mito-TEMPO, catalase, apocynin, l-NAME and mannitol. BITC rapidly produced reactive oxygen species and nitric oxide, triggered oxidative DNA damage. BITC effectively decreased the intracellular GSH and GSH/GSSG ratio and redox balance recovery by thiol-containing redox compounds, but not by free radical scavengers. Accordingly, redox stresses-DNA damage response (DDR) activated ATM, Chk2, p53, and p21 and subsequently resulted in G2/M phase arrest by inhibiting Cdc2 and cyclin B1. Notably, BITC-induced apoptosis was associated with reduced Mcl-1 and Bcl-2 expression, diminished mitochondrial membrane potential (ΔΨm), and increased PARP cleavage. These BITC-induced redox stress-mediated DDR and apoptosis could be blocked by NAC and GSH. Therefore, BITC can be a rational drug candidate for oral cancer and acted via a redox-dependent pathway.
Department of Medical Laboratory Science and Biotechnology, School of Medicine and Health Sciences, Fooyin University, Kaohsiung, Taiwan; Aging and Disease Prevention Research Center, Fooyin University, Kaohsiung, Taiwan; Department of Education and Research, Fooyin University Hospital, Pingtung, Taiwan.
Yao-Tsung
YT
Yeh
Yen Nien Biotechnology Co., Ltd., Taiwan.
Yen-Nien
YN
Hsu
Department of Medical Laboratory Science and Biotechnology, School of Medicine and Health Sciences, Fooyin University, Kaohsiung, Taiwan.
Sheng-Yun
SY
Huang
Department of Medical Laboratory Science and Biotechnology, School of Medicine and Health Sciences, Fooyin University, Kaohsiung, Taiwan.
Jian-Sheng
JS
Lin
Department of Medical Laboratory Science and Biotechnology, School of Medicine and Health Sciences, Fooyin University, Kaohsiung, Taiwan.
Zi-Feng
ZF
Chen
Department of Pathology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Nan-Haw
NH
Chow
Department of Molecular Biology and Human Genetics, College of Life Science, Tzu-Chi University, Hualien, Taiwan.
Shu-Hui
SH
Su
Department of Medical Laboratory Science and Biotechnology, School of Medicine and Health Sciences, Fooyin University, Kaohsiung, Taiwan.
Huey-Wen
HW
Shyu
Department of Medical Laboratory Science and Biotechnology, School of Medicine and Health Sciences, Fooyin University, Kaohsiung, Taiwan; Department of Education and Research, Fooyin University Hospital, Pingtung, Taiwan; Department of Laboratory Medicine, Fooyin University Hospital, Pingtung, Taiwan.
Ching-Chiang
CC
Lin
Department of Recreation and Health Care Management, Chia Nan University of Pharmacy & Science, Tainan, Taiwan.
Wu-Tein
WT
Huang
Department of Medical Laboratory Science and Biotechnology, School of Medicine and Health Sciences, Fooyin University, Kaohsiung, Taiwan.
Hua
H
Yeh
Department of Medical Laboratory Science and Biotechnology, School of Medicine and Health Sciences, Fooyin University, Kaohsiung, Taiwan.
Yu-Chia
YC
Chih
Department of Medical Laboratory Science and Biotechnology, School of Medicine and Health Sciences, Fooyin University, Kaohsiung, Taiwan.
Yu-Hsuan
YH
Huang
Department of Medical Laboratory Science and Biotechnology, School of Medicine and Health Sciences, Fooyin University, Kaohsiung, Taiwan. Electronic address: sc096@fy.edu.tw.
Shu-Jem
SJ
Su
D000208:Acute Disease; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured
D017879:Isothiocyanates; D017382:Reactive Oxygen Species; C031403:benzyl isothiocyanate; D005978:Glutathione
Apoptosis; Benzyl isothiocyanate; DNA damage; Oral squamous cell carcinoma; Redox stress