Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Asian Pac J Cancer Prev. 2020 Sep 1;21(9):2673-2681. doi: 10.31557/APJCP.2020.21.9.2673.
Cholangiocarcinoma (CCA) is a fatal cancer with high resistance to anticancer drugs. The development of new drugs or compounds to be used alone or in combination with currently available chemotherapeutic agents to improve the treatment of CCA is needed. Compound A (CpdA), which is a small plant-derived glucocorticoid receptor modulator, strongly inhibited the growth and survival of several cancers. However, the effect of CpdA on cholangiocarcinoma has not been elucidated. The aim of this study was to investigate the effect of CpdA on CCA.
Cytotoxicity of CpdA was tested in primary cells including peripheral blood mononuclear cells (PBMCs), fibroblasts, and human umbilical vein endothelial cells (HUVECs), as well as on CCA cell lines (KKU-100, KKU-055, and KKU-213) was examined. Cell cycle distribution and IL-6 expression was assessed by flow cytometry and real-time polymerase chain reaction, respectively. The effect of combination CpdA and cisplatin was evaluated by cell viability assay.
CpdA significantly inhibited cell cycle at G1 phase in CCA cell lines, and reduced IL-6 mRNA expression. However, combination CpdA and cisplatin did not enhance the inhibitory effect. TGFβR-II expression was increased in CCA cells after the combination treatment.
These results indicate the potential of CpdA for CCA treatment. However, combination treatment with CpdA and cisplatin increased CCA cell survival. The molecular mechanism is likely attributable to promotes cell survival via the TGFβR-II signaling pathway. The combination of CpdA with other anticancer drugs for CCA treatment should be further examined.
胆管癌（CCA）是一种致命的癌症，对抗癌药物具有高抗性。需要开发新的药物或化合物，单独使用或与现有的化疗药物联合使用，以改善 CCA 的治疗效果。化合物 A（CpdA）是一种源自植物的糖皮质激素受体调节剂，强烈抑制了几种癌症的生长和存活。然而，CpdA 对胆管癌的影响尚未阐明。本研究旨在探讨 CpdA 对 CCA 的作用。
在包括外周血单核细胞（PBMCs）、成纤维细胞和人脐静脉内皮细胞（HUVECs）在内的原代细胞以及 CCA 细胞系（KKU-100、KKU-055 和 KKU-213）中测试了 CpdA 的细胞毒性。通过流式细胞术和实时聚合酶链反应分别评估细胞周期分布和 IL-6 表达。通过细胞活力测定评估 CpdA 与顺铂联合使用的效果。
CpdA 显著抑制 CCA 细胞系的细胞周期进入 G1 期，并降低 IL-6 mRNA 表达。然而，CpdA 和顺铂联合使用并未增强抑制作用。联合治疗后 CCA 细胞中 TGFβR-II 表达增加。
这些结果表明 CpdA 具有治疗 CCA 的潜力。然而，CpdA 和顺铂联合治疗增加了 CCA 细胞的存活率。其分子机制可能归因于通过 TGFβR-II 信号通路促进细胞存活。应进一步研究 CpdA 与其他抗癌药物联合用于 CCA 治疗的效果。
