Sinha Sonam, Khan Sajid, Shukla Samriddhi, Lakra Amar Deep, Kumar Sudhir, Das Gunjan, Maurya Rakesh, Meeran Syed Musthapa
Laboratory of Cancer Epigenetics, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India.
Int J Biochem Cell Biol. 2016 Aug;77(Pt A):41-56. doi: 10.1016/j.biocel.2016.05.014. Epub 2016 May 19.
Available breast cancer therapeutic strategies largely target the primary tumor but are ineffective against tumor metastasis and angiogenesis. In our current study, we determined the effect of Cucurbitacin B (CuB), a plant triterpenoid, on the metastatic and angiogenic potential of breast cancer cells. CuB was found to inhibit cellular proliferation and induce apoptosis in breast cancer cells in a time- and dose-dependent manner. Further, CuB-treatment significantly inhibited the migratory and invasive potential of highly metastatic breast cancer MDA-MB-231 and 4T1 cells at sub-IC50 concentrations, where no significant apoptosis was observed. CuB was also found to inhibit migratory, invasive and tube-forming capacities of HUVECs in vitro. In addition, inhibition of pre-existing vasculature in chick embryo chorioallantoic membrane ex vivo further supports the anti-angiogenic effect of CuB. CuB-mediated anti-metastatic and anti-angiogenic effects were associated with the downregulation of VEGF/FAK/MMP-9 signaling, which has been validated by using FAK-inhibitor (FI-14). CuB-treatment resulted in a significant inhibition of VEGF-induced phosphorylation of FAK and MMP-9 expressions similar to the action of FI-14. CuB was also found to decrease the micro-vessel density as evidenced by the decreased expression of CD31, a marker for neovasculature. Further, CuB-treatment inhibited tumor growth, lung metastasis and angiogenesis in a highly metastatic 4T1-syngeneic mouse mammary cancer. Collectively, our findings suggest that CuB inhibited breast cancer metastasis and angiogenesis, at least in part, through the downregulation of VEGF/FAK/MMP-9 signaling.
现有的乳腺癌治疗策略主要针对原发性肿瘤，但对肿瘤转移和血管生成无效。在我们目前的研究中，我们确定了植物三萜类化合物葫芦素B（CuB）对乳腺癌细胞转移和血管生成潜能的影响。发现CuB以时间和剂量依赖性方式抑制乳腺癌细胞的增殖并诱导其凋亡。此外，在亚IC50浓度下，CuB处理显著抑制高转移性乳腺癌MDA-MB-231和4T1细胞的迁移和侵袭潜能，在此浓度下未观察到明显的细胞凋亡。还发现CuB在体外抑制人脐静脉内皮细胞（HUVECs）的迁移、侵袭和管形成能力。此外，在鸡胚绒毛尿囊膜上对已存在的血管系统进行离体抑制，进一步支持了CuB的抗血管生成作用。CuB介导的抗转移和抗血管生成作用与VEGF/FAK/MMP-9信号通路的下调有关，这已通过使用FAK抑制剂（FI-14）得到验证。CuB处理导致VEGF诱导的FAK磷酸化和MMP-9表达显著抑制，类似于FI-14的作用。还发现CuB可降低微血管密度，这可通过新生血管标记物CD31表达的降低来证明。此外，在高度转移性的4T1同基因小鼠乳腺癌模型中，CuB处理抑制了肿瘤生长、肺转移和血管生成。总的来说，我们的研究结果表明，CuB至少部分通过下调VEGF/FAK/MMP-9信号通路来抑制乳腺癌转移和血管生成。
