title: Thymoquinone induces caspase-independent, autophagic cell death in CPT-11-resistant lovo colon cancer via mitochondrial dysfunction and activation of JNK and p38.
abstract: Chemotherapy causes unwanted side effects and chemoresistance, limiting its effectiveness. Therefore, phytochemicals are now used as alternative treatments. Thymoquinone (TQ) is used to treat different cancers, including colon cancer. The irinotecan-resistant (CPT-11-R) LoVo colon cancer cell line was previously constructed by stepwise CPT-11 challenges to untreated parental LoVo cells. TQ dose-dependently increased the total cell death index and activated apoptosis at 2 μM, which then diminished at increasing doses. The possibility of autophagic cell death was then investigated. TQ caused mitochondrial outer membrane permeability (MOMP) and activated autophagic cell death. JNK and p38 inhibitors (SP600125 and SB203580, respectively) reversed TQ autophagic cell death. TQ was also found to activate apoptosis before autophagy, and the direction of cell death was switched toward autophagic cell death at initiation of autophagosome formation. Therefore, TQ resulted in caspase-independent, autophagic cell death via MOMP and activation of JNK and p38 in CPT-11-R LoVo colon cancer cells.
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University , Taichung 404, Taiwan.
authors.forename: Ming-Cheng
authors.initials: MC
authors.lastname: Chen
authors.forename: Nien-Hung
authors.initials: NH
authors.lastname: Lee
authors.forename: Hsi-Hsien
authors.initials: HH
authors.lastname: Hsu
authors.forename: Tsung-Jung
authors.initials: TJ
authors.lastname: Ho
authors.forename: Chuan-Chou
authors.initials: CC
authors.lastname: Tu
authors.forename: Dennis Jine-Yuan
authors.initials: DJ
authors.lastname: Hsieh
authors.forename: Yueh-Min
authors.initials: YM
authors.lastname: Lin
authors.forename: Li-Mien
authors.initials: LM
authors.lastname: Chen
authors.forename: Wei-Wen
authors.initials: WW
authors.lastname: Kuo
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D031881:Nigella sativa / Q000737:chemistry*; D010936:Plant Extracts / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D016227:Benzoquinones; D010936:Plant Extracts; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; C003466:thymoquinone
keywords: CPT-11-R LoVo colon cancer cells; apoptosis; autophagy; caspase-independent; thymoquinone