Astaxanthin enhances pemetrexed-induced cytotoxicity by downregulation of thymidylate synthase expression in human lung cancer cells.
Pemetrexed, a multitargeted antifolate agent, has demonstrated clinical activity in non-small cell lung cancer (NSCLC) cells. Increased expression of thymidylate synthase (TS) is thought to be associated with resistance to pemetrexed. Astaxanthin exhibits a wide range of beneficial effects including anti-cancer and anti-inflammatory properties. In this study, we showed that down-regulating of TS expression in two NSCLC cell lines, human lung adenocarcinoma H1650 and squamous cell carcinoma H1703 cells, with astaxanthin were associated with decreased MKK1/2-ERK1/2 activity. Enforced expression of constitutively active MKK1 (MKK1-CA) vector significantly rescued the decreased TS mRNA and protein levels in astaxanthin-treated NSCLC cells. Combined treatment with a MKK1/2 inhibitor (U0126 or PD98059) further decreased the TS expression in astaxanthin-exposed NSCLC cells. Knockdown of TS using small interfering RNA (siRNA) or inhibiting ERK1/2 activity enhanced the cytotoxicity and cell growth inhibition of astaxanthin. Combination of pemetrexed and astaxanthin resulted in synergistic enhancing cytotoxicity and cell growth inhibition in NSCLC cells, accompanied with reduced activation of phospho-MKK1/2, phopho-ERK1/2, and TS expression. Overexpression of MKK1/2-CA reversed the astaxanthin and pemetrexed-induced synergistic cytotoxicity. Our findings suggested that the down-regulation of MKK1/2-ERK1/2-mediated TS expression by astaxanthin is an important regulator of enhancing the pemetrexed-induced cytotoxicity in NSCLC cells.
Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan; School of Nursing, Chung Jen Junior College of Nursing, Health Science and Management, Chiayi, Taiwan.
Kai-Sheng
KS
Liao
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.
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.
Chia-Hung
CH
Wu
Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
Tai-Jing
TJ
Wang
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.
Po-Yuan
PY
Chang
Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan. Electronic address: linyw@mail.ncyu.edu.tw.
Yun-Wei
YW
Lin
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000068437:Pemetrexed / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000096:biosynthesis* / Q000235:genetics; D024341:Xanthophylls / Q000494:pharmacology
D000970:Antineoplastic Agents; D024341:Xanthophylls; D000068437:Pemetrexed; C005948:astaxanthine; D013940:Thymidylate Synthase
Astaxanthin; ERK1/2; Non-small cell lung cancer; Pemetrexed; Thymidylate synthase