A Quinone-Containing Compound Enhances Camptothecin-Induced Apoptosis of Lung Cancer Through Modulating Endogenous ROS and ERK Signaling.
The natural compound camptothecin (CPT) derivatives have widely been used for anti-cancer treatments, including lung cancer. However, many chemoresistant cancer cells often develop a relatively higher threshold for inducing apoptosis, causing a limited efficacy of anti-cancer drugs. Likewise, lung cancer cells acquire chemoresistance against CPT analogs, such as irinotecan and topotecan, finally resulting in an unsatisfied outcome and poor prognosis of lung cancer patients. TFPP is a quinone-containing compound as a candidate for CPT-based combination chemotherapy. In this study, we examined the effect of TFPP and CPT cotreatment on non-small cell lung cancer (NSCLC) cells. Cell proliferation and flow cytometry-based Annexin-V/PI staining assays demonstrated the synergistic effect of TFPP on CPT-induced apoptosis in both NSCLC A549 and H1299 cells. The results of CPT and TFPP cotreatment cause the regulation of the ERK-Bim axis and the activation of mitochondrial-mediated caspase cascade, including caspase-9 and caspase-3. Besides, TFPP significantly enhanced CPT-induced endogenous reactive oxygen species (ROS) in the two NSCLC cells. In contrast, the treatment of N-acetyl-L-cysteine (NAC), an ROS scavenger, rescues the apoptosis of NSCLC cells induced by TFPP and CPT cotreatment, suggesting that the synergistic effect of TFPP on CPT-induced anti-NSCLC cells is through upregulating ROS production. Consequently, our results suggest that TFPP sensitizes NSCLC towards CPT-based chemotherapy may act through decreasing the apoptosis-initiating threshold. Therefore, TFPP may be a promising chemosensitizer for lung cancer treatment, and the underlying mechanism warrants further.
Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.|Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung, 80424, Taiwan.
Han-Lin
HL
Chou
Department of Thoracic Surgery, Chi-Mei Medical Center, Tainan, 710, Taiwan.
Yao
Y
Fong
Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
Chi-Ku
CK
Wei
Research Center for Environment Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
Eing-Mei
EM
Tsai
Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
Jeff Yi-Fu
JY
Chen
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.|Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
Wen-Tsan
WT
Chang
Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.|Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan.
Chang-Yi
CY
Wu
Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung, 80424, Taiwan. sting@mail.nsysu.edu.tw.
Hurng-Wern
HW
Huang
Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan. cchiu@kmu.edu.tw.|Research Center for Environment Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan. cchiu@kmu.edu.tw.|Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan. cchiu@kmu.edu.tw.|The Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan. cchiu@kmu.edu.tw.
Chien-Chih
CC
Chiu
D000072283:A549 Cells; D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D016227:Benzoquinones / Q000737:chemistry; D002166:Camptothecin / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D020935:MAP Kinase Signaling System; D008928:Mitochondria / Q000378:metabolism*; D011700:Putrescine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D016227:Benzoquinones; D017382:Reactive Oxygen Species; C049506:2,2,3,3-tetrafluoroputrescine; C004532:quinone; D020169:Caspases; D011700:Putrescine; D000111:Acetylcysteine; D002166:Camptothecin
Apoptosis threshold; Camptothecin; Chemoresistance; ERK signaling pathway; Non-small cell lung cancer; TFPP