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Regul Toxicol Pharmacol. 2016 Nov;81:353-361. doi: 10.1016/j.yrtph.2016.09.031. Epub 2016 Sep 28.

Astaxanthin enhances pemetrexed-induced cytotoxicity by downregulation of thymidylate synthase expression in human lung cancer cells.

Author information

1
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.
2
Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
3
Department of Food Science, National Chiayi University, Chiayi, Taiwan.
4
Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan. Electronic address: linyw@mail.ncyu.edu.tw.

Abstract

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.

KEYWORDS:

Astaxanthin; ERK1/2; Non-small cell lung cancer; Pemetrexed; Thymidylate synthase

PMID:
27693704
DOI:
10.1016/j.yrtph.2016.09.031
[Indexed for MEDLINE]

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