Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
PLoS One. 2012;7(9):e41592. doi: 10.1371/journal.pone.0041592. Epub 2012 Sep 5.
Breast cancer ranks as a common and severe neoplasia in women with increasing incidence as well as high risk of metastasis and relapse. Translational and laboratory-based clinical investigations of new/novel drugs are in progress. Medicinal plants are rich sources of biologically active natural products for drug development. The 27-kDa trichosanthin (TCS) is a ribosome inactivating protein purified from tubers of the Chinese herbal plant Trichosanthes kirilowii Maximowicz (common name Tian Hua Fen). In this study, we extended the potential medicinal applications of TCS from HIV, ferticide, hydatidiform moles, invasive moles, to breast cancer. We found that TCS manifested anti-proliferative and apoptosis-inducing activities in both estrogen-dependent human MCF-7 cells and estrogen-independent MDA-MB-231 cells. Flow cytometric analysis disclosed that TCS induced cell cycle arrest. Further studies revealed that TCS-induced tumor cell apoptosis was attributed to activation of both caspase-8 and caspase-9 regulated pathways. The subsequent events including caspase-3 activation, and increased PARP cleavage. With regard to cell morphology, stereotypical apoptotic features were observed. Moreover, in comparison with control, TCS- treated nude mice bearing MDA-MB-231 xenograft tumors exhibited significantly reduced tumor volume and tumor weight, due to the potent effect of TCS on tumor cell apoptosis as determined by the increase of caspase-3 activation, PARP cleavage, and DNA fragmentation using immunohistochemistry. Considering the clinical efficacy and relative safety of TCS on other human diseases, this work opens up new therapeutic avenues for patients with estrogen-dependent and/or estrogen-independent breast cancers.
乳腺癌是女性中常见且严重的肿瘤，发病率不断上升，且转移和复发风险高。新/新型药物的转化和实验室临床研究正在进行中。药用植物是开发药物的生物活性天然产物的丰富来源。27kDa 的天花粉蛋白（TCS）是从中药天花粉（Trichosanthes kirilowii Maximowicz，俗称天花粉）的块茎中纯化的核糖体失活蛋白。在这项研究中，我们将 TCS 的潜在药用应用从 HIV、杀真菌剂、葡萄胎、侵袭性葡萄胎扩展到乳腺癌。我们发现 TCS 在依赖雌激素的人 MCF-7 细胞和非依赖雌激素的 MDA-MB-231 细胞中均表现出抗增殖和诱导细胞凋亡的活性。流式细胞术分析显示 TCS 诱导细胞周期停滞。进一步的研究表明，TCS 诱导的肿瘤细胞凋亡归因于 caspase-8 和 caspase-9 调节途径的激活。随后的事件包括 caspase-3 的激活和 PARP 的切割增加。关于细胞形态，观察到典型的凋亡特征。此外，与对照组相比，TCS 处理的荷 MDA-MB-231 异种移植肿瘤的裸鼠表现出明显减小的肿瘤体积和肿瘤重量，这是由于 TCS 对肿瘤细胞凋亡的强烈作用，通过增加 caspase-3 激活、PARP 切割和使用免疫组织化学检测 DNA 片段化来确定。考虑到 TCS 在其他人类疾病中的临床疗效和相对安全性，这项工作为雌激素依赖性和/或雌激素非依赖性乳腺癌患者开辟了新的治疗途径。
