Sulfasalazine modifies metabolic profiles and enhances cisplatin chemosensitivity on cholangiocarcinoma cells in in vitro and in vivo models

Cancer & Metabolism

Sureerat Padthaisong¹  Manida Suksawat¹  Hasaya Dokduang²  Jutarop Phetcharaburanin³  Nisana Namwat³  Poramate Klanrit³  Arporn Wangwiwatsin³  Watcharin Loilome³  Malinee Thanee⁴  Prakasit Sa-ngiamwibool⁴  Attapol Titapun⁵  Narong Khuntikeo⁵  Hideyuki Saya⁶ 

[1] Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand;Department of Biochemistry, Faculty of Meidicine, Khon Kaen University, 40002, Khon Kaen, Thailand;Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand;Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand;Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand;Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand;Department of Biochemistry, Faculty of Meidicine, Khon Kaen University, 40002, Khon Kaen, Thailand;Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand;Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand;Department of Pathology, Faculty of Meidicine, Khon Kaen University, 40002, Khon Kaen, Thailand;Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand;Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand;Department of Surgery, Faculty of Medicine, Khon Kaen University, 40002, Khon Kaen, Thailand;Division of Gene Regulation, Institute for Advanced Medical Research (IAMR), Keio University School of Medicine, 160-8582, Tokyo, Japan;

关键词: Sulfasalazine;    Cholangiocarcinoma therapy;    CD44v9;    Metabolic signature;    Chemosensitivity;   

DOI  :  10.1186/s40170-021-00249-6

来源: Springer

【 摘 要 】

BackgroundSulfasalazine (SSZ) is widely known as an xCT inhibitor suppressing CD44v9-expressed cancer stem-like cells (CSCs) being related to redox regulation. Cholangiocarcinoma (CCA) has a high recurrence rate and no effective chemotherapy. A recent report revealed high levels of CD44v9-positive cells in CCA patients. Therefore, a combination of drugs could prove a suitable strategy for CCA treatment via individual metabolic profiling.MethodsWe examined the effect of xCT-targeted CD44v9-CSCs using sulfasalazine combined with cisplatin (CIS) or gemcitabine in CCA in vitro and in vivo models and did NMR-based metabolomics analysis of xenograft mice tumor tissues.ResultsOur findings suggest that combined SSZ and CIS leads to a higher inhibition of cell proliferation and induction of cell death than CIS alone in both in vitro and in vivo models. Xenograft mice showed that the CD44v9-CSC marker and CK-19-CCA proliferative marker were reduced in the combination treatment. Interestingly, different metabolic signatures and significant metabolites were observed in the drug-treated group compared with the control group that revealed the cancer suppression mechanisms.ConclusionsSSZ could improve CCA therapy by sensitization to CIS through killing CD44v9-positive cells and modifying the metabolic pathways, in particular tryptophan degradation (i.e., kynurenine pathway, serotonin pathway) and nucleic acid metabolism.

【 授权许可】

CC BY