Astaxanthin enhances pemetrexed-induced cytotoxicity by downregulation of thymidylate synthase expression in human lung cancer cells |
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| Affiliation: | 1. Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan;2. School of Nursing, Chung Jen Junior College of Nursing, Health Science and Management, Chiayi, Taiwan;3. Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan;4. Department of Food Science, National Chiayi University, Chiayi, Taiwan;1. Columbia Center for Translational Immunology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY;;2. Department of Immunobiology, Yale University School of Medicine, New Haven, CT;;3. Division of Hematology/Oncology, Department of Medicine,;4. Department of Medicine,;5. Naomi Berrie Diabetes Center, and;6. Division of Rheumatology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY; and;7. Department of Pediatrics, Columbia University, New York, NY;1. Department of Clinical Pathology, Faculty of Veterinary Medicine, Beni-Suef University, Egypt;2. Department of Toxicology & Forensic Medicine, Faculty of Veterinary Medicine, Cairo University, Egypt;3. Department of Toxicology & Forensic Medicine, Faculty of Veterinary Medicine, Beni-Suef University, Egypt;4. Department of Biochemistry, Faculty of Veterinary Medicine, Beni-Suef University, Egypt;1. Department of Histology, Faculty of Medicine, Minia University, Egypt;2. Department of Pharmacology, Faculty of Medicine, Minia University, Egypt;1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China;2. Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China;3. Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China;4. Guangzhou Concord Cancer Center, Guangzhou, China;5. Department of Radiation Oncology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China;6. Department of Traditional Chinese Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China;1. Marine-Integrated Bionics Research Center, Pukyong National University, Busan 48513, Republic of Korea;2. Department of Biomedical Engineering, Pukyong National University, Busan 48513, Republic of Korea;3. Department of Biomedical Engineering and Center for Marine-Integrated Biotechnology (BK21 Plus), Pukyong National University, Busan 48513, Republic of Korea |
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| 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. |
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| Keywords: | Astaxanthin Pemetrexed Thymidylate synthase ERK1/2 Non-small cell lung cancer |
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