The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Science, Nanjing University, People's Republic of China.
Anticancer Drugs. 2013 Oct;24(9):945-57. doi: 10.1097/CAD.0b013e3283651862.
Angiogenesis is essential for the survival and growth of most tumors. As such, targeting the tumor neovasculature is an attractive strategy for effective cancer therapy. Angiogenesis inhibitors have strong therapeutic potential as antitumor agents in suppressing tumor growth and metastatic progression. The functional domain within amino acid residues 120-180 of vasostatin (VAS) has been confirmed to be effective in inhibiting the proliferation, migration, and invasiveness of cancer cells by its suppressive capacity against angiogenesis. Triptolide (TPL) is an active component extracted from the traditional Chinese herbal medicine Tripterygium wilfordii Hook F that has shown antitumor activities in various cancer cell types. However, its therapeutic application is limited by its toxicity in normal tissues and complications caused in patients. In this study, we attempted to investigate the synergistic antitumor activity of TPL and VAS in solid tumor cells. Our results showed that the sensitivity of combined therapy using TPL and VAS was higher than that of monotherapy using TPL or VAS. Apoptosis induced by the combined treatment was accompanied by activation of caspase-9, caspase-8, and caspase-3. Upregulation of proapoptotic protein (Bax, Bak, and Bad) expression and suppression of NF-κB transcriptional activity and its targeting antiapoptotic genes (c-FLIP, cIAP, Bcl-2, Bcl-xl, and Mcl-1) may contribute to the synergistic effects of this combination therapy. Further, using a mouse xenograft model, we demonstrated that combined treatment completely suppressed tumor growth as compared with treatment with TPL or VAS alone. These results suggest that the combination of TPL and VAS at lower concentrations may produce a synergistic antitumor effect that warrants further investigation for its potential clinical applications.
血管生成对于大多数肿瘤的存活和生长至关重要。因此，针对肿瘤新生血管是一种有效的癌症治疗策略。血管生成抑制剂作为抗肿瘤药物，具有抑制肿瘤生长和转移进展的强大治疗潜力。血管抑肽（VAS）的 120-180 个氨基酸残基的功能域已被证实通过抑制血管生成来有效抑制癌细胞的增殖、迁移和侵袭。雷公藤红素（TPL）是从传统中药雷公藤中提取的一种活性成分，已在多种癌细胞类型中显示出抗肿瘤活性。然而，由于其在正常组织中的毒性和患者并发症，其治疗应用受到限制。在本研究中，我们试图研究 TPL 和 VAS 联合治疗实体瘤细胞的协同抗肿瘤活性。我们的结果表明，TPL 和 VAS 联合治疗的敏感性高于 TPL 或 VAS 单药治疗。联合治疗诱导的细胞凋亡伴随着 caspase-9、caspase-8 和 caspase-3 的激活。促凋亡蛋白（Bax、Bak 和 Bad）表达上调和 NF-κB 转录活性及其靶向抗凋亡基因（c-FLIP、cIAP、Bcl-2、Bcl-xl 和 Mcl-1）的抑制可能有助于这种联合治疗的协同作用。此外，使用小鼠异种移植模型，我们证明与 TPL 或 VAS 单独治疗相比，联合治疗完全抑制了肿瘤生长。这些结果表明，TPL 和 VAS 的联合使用在较低浓度下可能产生协同的抗肿瘤作用，值得进一步研究其在临床应用中的潜力。
