Salinomycin enhances cisplatin-induced cytotoxicity in human lung cancer cells via down-regulation of AKT-dependent thymidylate synthase expression.
Salinomycin, a polyether antibiotic, acts as a highly selective potassium ionophore and has anticancer activity on various cancer cell lines. Cisplatin has been proved as chemotherapy drug for advanced human non-small cell lung cancer (NSCLC). Thymidylate synthase (TS) is a key enzyme in the pyrimidine salvage pathway, and increased expression of TS is thought to be associated with resistance to cisplatin. In this study, we showed that salinomycin (0.5-2μg/mL) treatment down-regulating of TS expression in an AKT inactivation manner in two NSCLC cell lines, human lung adenocarcinoma A549 and squamous cell carcinoma H1703 cells. Knockdown of TS using small interfering RNA (siRNA) or inhibiting AKT activity with PI3K inhibitor LY294002 enhanced the cytotoxicity and cell growth inhibition of salinomycin. A combination of cisplatin and salinomycin resulted in synergistic enhancement of cytotoxicity and cell growth inhibition in NSCLC cells, accompanied with reduced activation of phospho-AKT, and TS expression. Overexpression of a constitutive active AKT (AKT-CA) expression vector reversed the salinomycin and cisplatin-induced synergistic cytotoxicity. In contrast, pretreatment with LY294002 further decreased the cell viability in salinomycin and cisplatin cotreated cells. Our findings suggested that the down-regulation of AKT-mediated TS expression by salinomycin enhanced the cisplatin-induced cytotoxicity in NSCLC cells. These results may provide a rationale to combine salinomycin with cisplatin for lung cancer treatment.
Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Taiwan; Institute of Technology Law, National Chiao Tung University, Hsinchu, Taiwan.
Jen-Chung
JC
Ko
Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
Hao-Yu
HY
Zheng
Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
Wen-Ching
WC
Chen
Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
Yi-Shuan
YS
Peng
Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
Chia-Hung
CH
Wu
Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
Chia-Li
CL
Wei
Department of Food Science, National Chiayi University, Chiayi, Taiwan.
Jyh-Cheng
JC
Chen
Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan. Electronic address: linyw@mail.ncyu.edu.tw.
Yun-Wei
YW
Lin
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation; D004359:Drug Therapy, Combination; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011714:Pyrans / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism*; D000095662:Polyether Polyketides
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D002945:Cisplatin; D051057:Proto-Oncogene Proteins c-akt; D011714:Pyrans; D012333:RNA, Messenger; D013940:Thymidylate Synthase; C010327:salinomycin; D000095662:Polyether Polyketides
AKT; ALLN (PubChem CID: 4332); Actinomycin D (PubChem CID: 2019); Cisplatin; Cisplatin (PubChem CID: 441203); Crystal violet (PubChem CID: 11057); Cycloheximide (PubChem CID: 6197); LY294002 (PubChem CID: 3973); MG132 (PubChem CID: 462382); Non-small cell lung cancer; Penicillin (PubChem CID: 5904); Salinomycin; Salinomycin (PubChem CID: 3085092); Sodium bicarbonate (PubChem CID: 516892); Streptomycin (PubChem CID: 19649); Thymidylate synthase; Trypan blue (PubChem CID: 9562061); Wortmannin (PubChem CID: 101764112); l-Glutamine (PubChem CID: 5961)