Thymoquinone Induces Caspase-Independent, Autophagic Cell Death in CPT-11-Resistant LoVo Colon Cancer via Mitochondrial Dysfunction and Activation of JNK and p38

• Published in: Journal of agricultural and food chemistry 2015-02, Vol.63 (5), p.1540-1546
• Main Authors: Chen, Ming-Cheng, Lee, Nien-Hung, Hsu, Hsi-Hsien, Ho, Tsung-Jung, Tu, Chuan-Chou, Hsieh, Dennis Jine-Yuan, Lin, Yueh-Min, Chen, Li-Mien, Kuo, Wei-Wen, Huang, Chih-Yang
• Format: Article
• Language: English
• Subjects: adverse effects; apoptosis; Apoptosis - drug effects; autophagy; Autophagy - drug effects; Benzoquinones - pharmacology; Caspases - genetics; Caspases - metabolism; Cell Line, Tumor; Colonic Neoplasms - drug therapy; Colonic Neoplasms - enzymology; Colonic Neoplasms - genetics; Colonic Neoplasms - physiopathology; colorectal neoplasms; Drug Resistance, Neoplasm; drug therapy; Humans; JNK Mitogen-Activated Protein Kinases - genetics; JNK Mitogen-Activated Protein Kinases - metabolism; membrane permeability; Mitochondria - drug effects; Mitochondria - metabolism; mitochondrial membrane; mitogen-activated protein kinase; neoplasm cells; Nigella sativa - chemistry; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; phytopharmaceuticals; Plant Extracts - pharmacology
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/jf5054063

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.