Yapasert Rittibet, Banjerdpongchai Ratana
Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
Center for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai 50200, Thailand.
Evid Based Complement Alternat Med. 2022 May 12;2022:6288742. doi: 10.1155/2022/6288742. eCollection 2022.
Most cholangiocarcinoma (CCA) patients undergo chemotherapy as a therapeutic approach due to the disease's frequently late diagnosis. However, because CCA is resistant to currently available treatments, the prognosis for this cancer is still quite poor. Combination therapy has emerged as a novel and promising strategy in cancer treatment, as monotherapy frequently results in tumor recurrence and drug resistance. Gambogic acid has been shown to have a synergism with other compounds in combating certain cancer cells. Moreover, piperine has been shown to improve the efficacy of numerous chemotherapy drugs and other anticancer natural substances. However, no research has been done on the combination of these two compounds in the treatment of bile duct cancer. In this study, the cytotoxic activity was determined by using the MTT assay, and then, the combined effect was assessed by using the combination index (CI). We found that the combination of gambogic acid and piperine inhibited cell viability more effectively than either treatment alone, and it also demonstrated a synergistically cytotoxic effect against CCA cells. Interestingly, the findings allowed the use of lower concentrations of gambogic acid in cancer treatment when combined with piperine, which could reduce its adverse effect on normal cholangiocytes. Furthermore, the combination of the two compounds increased CCA cell death by inducing apoptosis via both the extrinsic and intrinsic or mitochondria-mediated pathways, as determined by caspase-3, -8, and -9 activity and the reduction of mitochondrial transmembrane potential (ΔΨm). It is possible that the use of these two natural compounds together could be a promising strategy for the treatment of bile duct cancer.
由于胆管癌（CCA）常因诊断延迟，大多数患者选择化疗作为治疗方法。然而，由于CCA对现有治疗具有抗性，这种癌症的预后仍然很差。联合治疗已成为癌症治疗中一种新颖且有前景的策略，因为单一疗法常常导致肿瘤复发和耐药。藤黄酸已被证明在对抗某些癌细胞时与其他化合物具有协同作用。此外，胡椒碱已被证明可提高多种化疗药物和其他抗癌天然物质的疗效。然而，关于这两种化合物联合治疗胆管癌尚未有研究。在本研究中，通过MTT法测定细胞毒性活性，然后使用联合指数（CI）评估联合效应。我们发现藤黄酸和胡椒碱联合使用比单独使用任何一种治疗更有效地抑制细胞活力，并且对CCA细胞表现出协同细胞毒性作用。有趣的是，这些发现表明在与胡椒碱联合使用时，在癌症治疗中可以使用较低浓度的藤黄酸，这可以降低其对正常胆管细胞的不良反应。此外，通过caspase-3、-8和-9活性以及线粒体跨膜电位（ΔΨm）的降低确定，这两种化合物的联合通过外在和内在或线粒体介导的途径诱导细胞凋亡，增加了CCA细胞死亡。这两种天然化合物一起使用可能是治疗胆管癌的一种有前景的策略。
