Malinee Thanee1,2,3, Sureerat Padthaisong2,4, Manida Suksawat2,4, Hasaya Dokduang1,2, Jutarop Phetcharaburanin1,2,4, Poramate Klanrit1,2,4, Attapol Titapun1,2,5, Nisana Namwat1,2,4, Arporn Wangwiwatsin1,2,4, Prakasit Sa-Ngiamwibool1,2,3, Narong Khuntikeo1,2,5, Hideyuki Saya6, Watcharin Loilome7,8,9. 1. Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand. 2. Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand. 3. Department of Pathology, Faculty of Meidicine, Khon Kaen University, Khon Kaen, 40002, Thailand. 4. Department of Biochemistry, Faculty of Meidicine, Khon Kaen University, Khon Kaen, 40002, Thailand. 5. Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand. 6. Division of Gene Regulation, Institute for Advanced Medical Research (IAMR), Keio University School of Medicine, Tokyo, 160-8582, Japan. 7. Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand. watclo@kku.ac.th. 8. Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand. watclo@kku.ac.th. 9. Department of Biochemistry, Faculty of Meidicine, Khon Kaen University, Khon Kaen, 40002, Thailand. watclo@kku.ac.th.
Abstract
BACKGROUND: Sulfasalazine (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. METHODS: We 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. RESULTS: Our 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. CONCLUSIONS: SSZ 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.
BACKGROUND:Sulfasalazine (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. METHODS: We 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 micetumor tissues. RESULTS: Our 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. CONCLUSIONS:SSZ 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.
Authors: Anthony C Dona; Michael Kyriakides; Flora Scott; Elizabeth A Shephard; Dorsa Varshavi; Kirill Veselkov; Jeremy R Everett Journal: Comput Struct Biotechnol J Date: 2016-03-09 Impact factor: 7.271