Padthaisong Sureerat, Dokduang Hasaya, Yothaisong Supak, Techasen Anchalee, Namwat Nisana, Yongvanit Puangrat, Khuntikeo Narong, Titapun Attapol, Sangkhamanon Sakkarn, Loilome Watcharin
Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
Cholangiocarcinoma Research Institute (CARI), Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
Oncol Lett. 2018 Aug;16(2):1627-1633. doi: 10.3892/ol.2018.8848. Epub 2018 May 31.
Abnormal activation of the phosphatidylinositol 3-kinase (PI3K) pathway has been demonstrated in certain types of cancer, including cholangiocarcinoma (CCA). This pathway may therefore be a promising target for CCA treatment. The present study assessed the inhibitory effect of NVP-BKM120, a pan-class I PI3K inhibitor, on CCA cell growth. This inhibitory effect was determined using CCA cell lines and in CCA-inoculated mice. The result from sulforhodamine B (SRB) assay demonstrated that NVP-BKM120 treatment inhibited CCA cell growth in a dose-dependent manner, even at the lowest tested concentration. The study revealed that oral administration of NVP-BKM120 (10 or 30 mg/kg) to CCA-inoculated nude mice led to a reduction in tumor growth when compared with controls, which was indicated by an immunohistochemical assay for Ki67 expression. In addition, the result from TUNEL assay demonstrated that NVP-BKM120 induced cancer cell death without any signs of toxicity, which indicated by the body weight of mice (data not shown). Western blot analysis demonstrated that NVP-BKM120 inhibited CCA cell growth by suppressing RAC serine/threonine protein kinase/mechanistic target of rapamycin activation and inhibiting the phosphorylation of phosphatase and tensin homolog, which is the inactivation form of the negative regulator of this pathway. Therefore, the results of the present study indicated that NVP-BKM120 should be considered as a therapeutic agent against CCA that could be used to improve treatment.
磷脂酰肌醇3激酶（PI3K）通路的异常激活已在包括胆管癌（CCA）在内的某些类型癌症中得到证实。因此，该通路可能是CCA治疗的一个有前景的靶点。本研究评估了泛I类PI3K抑制剂NVP-BKM120对CCA细胞生长的抑制作用。使用CCA细胞系和接种CCA的小鼠确定了这种抑制作用。磺酰罗丹明B（SRB）测定结果表明，即使在最低测试浓度下，NVP-BKM120处理也以剂量依赖性方式抑制CCA细胞生长。研究表明，与对照组相比，给接种CCA的裸鼠口服NVP-BKM120（10或30mg/kg）可导致肿瘤生长减少，这通过Ki67表达的免疫组织化学测定得到证实。此外，TUNEL测定结果表明，NVP-BKM120诱导癌细胞死亡且无任何毒性迹象，这通过小鼠体重得以表明（数据未显示）。蛋白质印迹分析表明，NVP-BKM120通过抑制RAC丝氨酸/苏氨酸蛋白激酶/雷帕霉素作用机制靶点的激活并抑制磷酸酶和张力蛋白同源物的磷酸化来抑制CCA细胞生长，磷酸酶和张力蛋白同源物是该通路负调节因子的失活形式。因此，本研究结果表明，NVP-BKM120应被视为一种可用于改善CCA治疗的治疗剂。
