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

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.

• Authors: Kai-Sheng Liao, Chia-Li Wei, Jyh-Cheng Chen, Hao-Yu Zheng, Wen-Ching Chen, Chia-Hung Wu, Tai-Jing Wang, Yi-Shuan Peng, Po-Yuan Chang, Yun-Wei Lin
• Journal: Regulatory toxicology and pharmacology : RTP (Regul Toxicol Pharmacol) Vol. 81 Pg. 353-361 (Nov 2016) ISSN: 1096-0295 [Electronic] Netherlands
• PMID: 27693704 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Xanthophylls
• Pemetrexed
• astaxanthine
• Thymidylate Synthase

Topics

• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Drug Screening Assays, Antitumor
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lung Neoplasms (drug therapy, enzymology, genetics, pathology)
• Pemetrexed (pharmacology)
• Structure-Activity Relationship
• Thymidylate Synthase (biosynthesis, genetics)
• Xanthophylls (pharmacology)