title: Curcumin reverses cisplatin resistance in cisplatin-resistant lung caner cells by inhibiting FA/BRCA pathway.
abstract: Cisplatin (DDP) is the most widely used chemotherapy agent for treatment of malignancies including lung cancer. However, the effectiveness of DDP is often weakened by acquired resistance of tumor cells. DDP kills cancer cells primarily by creating intrastrand and interstrand DNA cross-links, which block DNA replication. The Fanconi anemia (FA)/BRCA pathway is a DNA cross-link damage repair pathway, which regulates cellular resistance to DNA cross-link agents, such as DDP. Some study has shown that natural compound curcumin sensitize human ovarian and breast cancer cells to DDP. However, whether curcumin may reverse resistance to DDP in DDP-resistant lung cancer cells has not been understood. In this study, we showed that curcumin enhanced the proliferation inhibitory effect of DDP and promote DDP-induced apoptosis in A549/DDP cells (DDP-resistant lung adenocarcinoma cells). Moreover, we observed that FA/BRCA pathway DNA damage repair processes, such as DDP-induced FANCD2 monoubiquitination and nuclear foci formation were downregulated in the presence of curcumin, suggesting that curcumin enhanced sensitivity to DDP in A549/DDP cells through the inhibition of FA/BRCA pathway. Furthermore, the calculation of q value and apoptosis analyses revealed that curcumin in combination with DDP could exert a synergistic cytotoxic effect in A549/DDP cells, further demonstrating that curcumin can reverse cisplatin resistance of A549/DDP cells. In conclusion, by suppressing the FA/BRCA pathway DNA repair, curcumin potentiates DDP-induced proliferation inhibitory effect and apoptosis in A549/DDP cell, indicating that curcumin may serve as a chemosensitizer to cross-link-inducing anticancer drugs DDP.
authors.affiliation: Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, 438 North Jiefang Street, Zhenjiang, 212001, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: He-Guo
authors.initials: HG
authors.lastname: Jiang
authors.forename: Ting
authors.initials: T
authors.lastname: Lan
authors.forename: Yong-Chang
authors.initials: YC
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D003474:Curcumin / Q000008:administration & dosage*; D004260:DNA Repair / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D054875:Ubiquitination / Q000187:drug effects
chemical_list: C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D003474:Curcumin; D002945:Cisplatin