Boueroy Parichart, Hahnvajanawong Chariya, Boonmars Thidarut, Saensa-Ard Sunitta, Anantachoke Natthinee, Vaeteewoottacharn Kulthida, Reutrakul Vichai
Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Center of Excellence for Innovation in Chemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Parasitology, Khon Kaen University, Khon Kaen 40002, Thailand.
Oncol Lett. 2016 Dec;12(6):4685-4698. doi: 10.3892/ol.2016.5284. Epub 2016 Oct 18.
Cholangiocarcinoma (CCA) is a malignancy with no effective therapy and poor prognosis. Forbesione, a caged xanthone isolated from , has been reported to inhibit proliferation and to induce apoptosis in human CCA cell lines. The present study aimed to further explore the potential anticancer properties of forbesione by testing its effects against the hamster CCA cell line Ham-1 and . It was observed that forbesione inhibited the growth of Ham-1 cells and suppressed Ham-1 growth as allograft in hamsters by inducing cell cycle arrest at the S phase. This was mediated by decreasing the protein expression of cyclin E, cyclin A and cyclin-dependent kinase 2. In addition, increased expression of p21 and p27 was detected, which could possibly explain the reduced expression of proliferating cell nuclear antigen and of the bile duct cell marker cytokeratin 19 observed in forbesione-treated Ham-1 cells and in tumor tissues of forbesione-treated hamsters. Furthermore, forbesione induced apoptosis through multiple pathways. The death receptor pathway was activated by increased expression of Fas, Fas-associated death domain and activated caspase-3, along with decreased expression of procaspase-8 and procaspase-3. The mitochondrial pathway was driven by increased expression of B-cell lymphoma (Bcl)-2-like protein 4, activated caspase-9 and inhibitor of κB-α, along with decreased expression of Bcl-2, survivin, procaspase-9 and nuclear factor-κB/p65. The endoplasmic reticulum pathway was stimulated by increased expression of activated caspase-12 and decreased expression of procaspase-12. No side effects or toxicity were observed in forbesione-treated hamsters. Thus, forbesione is a potential drug candidate for cancer therapy that deserves further investigation.
胆管癌（CCA）是一种恶性肿瘤，没有有效的治疗方法，预后较差。从[具体来源]中分离出的笼形呫吨酮Forbesione，据报道可抑制人CCA细胞系的增殖并诱导其凋亡。本研究旨在通过测试其对仓鼠CCA细胞系Ham-1和[此处原文缺失部分内容]的作用，进一步探索Forbesione的潜在抗癌特性。观察到Forbesione抑制Ham-1细胞的生长，并通过诱导细胞周期停滞在S期来抑制Ham-1作为仓鼠同种异体移植瘤的生长。这是通过降低细胞周期蛋白E、细胞周期蛋白A和细胞周期蛋白依赖性激酶2的蛋白表达来介导的。此外，检测到p21和p27的表达增加，这可能解释了在经Forbesione处理的Ham-1细胞以及经Forbesione处理的仓鼠肿瘤组织中观察到的增殖细胞核抗原和胆管细胞标志物细胞角蛋白19表达的降低。此外，Forbesione通过多种途径诱导凋亡。死亡受体途径通过Fas、Fas相关死亡结构域和活化的半胱天冬酶-3表达增加，以及原半胱天冬酶-8和原半胱天冬酶-3表达降低而被激活。线粒体途径由B细胞淋巴瘤（Bcl）-2样蛋白4、活化的半胱天冬酶-9和κB-α抑制剂表达增加，以及Bcl-2、生存素、原半胱天冬酶-9和核因子-κB/p65表达降低所驱动。内质网途径通过活化的半胱天冬酶-12表达增加和原半胱天冬酶-12表达降低而被刺激。在经Forbesione处理的仓鼠中未观察到副作用或毒性。因此，Forbesione是一种潜在的癌症治疗候选药物，值得进一步研究。
