School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur-721302, West Bengal, India.
Mol Cancer. 2013 Oct 20;12(1):122. doi: 10.1186/1476-4598-12-122.
The hypoxic environment of tumor region stimulated the up regulation of growth factors responsible for angiogenesis and tumor proliferation. Thus, targeting the tumor vasculature along with the proliferation by dual tyrosine kinase inhibitor may be the efficient way of treating advanced breast cancers, which can be further enhanced by combining with radiotherapy. However, the effectiveness of radiotherapy may be severely compromised by toxicities and tumor resistance due to radiation-induced adaptive response contributing to recurrence and metastases of breast cancer. The rational of using ZD6474 is to evaluate the feasibility and efficacy of combined VEGFR2 and EGFR targeting with concurrent targeted and localized UV-B phototherapy in vitro breast cancer cells with the anticipation to cure skin lesions infiltrated with breast cancer cells.
Breast cancer cells were exposed to UV-B and ZD6474 and the cell viability, apoptosis, invasion and motility studies were conducted for the combinatorial effect. Graphs and statistical analyses were performed using Graph Pad Prism 5.0.
ZD6474 and UV-B decreased cell viability in breast cancers in combinatorial manner without affecting the normal human mammary epithelial cells. ZD6474 inhibited cyclin E expression and induced p53 expression when combined with UV-B. It activated stress induced mitochondrial pathway by inducing translocation of bax and cytochrome-c. The combination of ZD6474 with UV-B vs. either agent alone also more potently down-regulated the anti-apoptotic bcl-2 protein, up-regulated pro-apoptotic signaling events involving expression of bax, activation of caspase-3 and caspase-7 proteins, and induced poly (ADP-ribose) polymerase resulting in apoptosis. ZD6474 combined with UV-B inhibited invasion of breast cancer cells in vitro as compared to either single agent, indicating a potential involvement of pro-angiogenic growth factors in regulating the altered expression and reorganization of cytoskeletal proteins in combinatorial treated breast cancer cells. Involvement of combination therapy in reducing the expression of matrix metalloprotease was also observed.
Collectively, our studies indicate that incorporating an anti-EGFR plus VEGFR strategy (ZD6474) with phototherapy (UV-B), an alternative approach to the ongoing conventional radiotherapy for the treatment of infiltrating metastatic breast cancer cells in the skin and for locally recurrence breast cancer than either approach alone.
肿瘤区域的缺氧环境刺激了负责血管生成和肿瘤增殖的生长因子的上调。因此，通过双重酪氨酸激酶抑制剂靶向肿瘤血管生成和增殖可能是治疗晚期乳腺癌的有效方法，通过与放射治疗相结合可以进一步增强这种方法。然而，由于辐射诱导的适应性反应导致乳腺癌的复发和转移，放射治疗的有效性可能会因毒性和肿瘤耐药性而严重受损。使用 ZD6474 的合理性在于评估在体外乳腺癌细胞中同时靶向和局部 UV-B 光疗联合使用 VEGFR2 和 EGFR 靶向治疗的可行性和疗效，以期治愈浸润乳腺癌细胞的皮肤病变。
将乳腺癌细胞暴露于 UV-B 和 ZD6474 下，并进行细胞活力、凋亡、侵袭和迁移研究，以评估联合作用的效果。使用 Graph Pad Prism 5.0 进行图表和统计分析。
ZD6474 和 UV-B 以组合方式降低了乳腺癌细胞的活力，而对正常的人乳腺上皮细胞没有影响。ZD6474 与 UV-B 联合使用可抑制 cyclin E 的表达并诱导 p53 的表达。它通过诱导 bax 和细胞色素 c 的易位激活应激诱导的线粒体途径。与单独使用任何一种药物相比，ZD6474 与 UV-B 的联合使用也更有效地下调了抗凋亡 bcl-2 蛋白，上调了涉及 bax 表达、caspase-3 和 caspase-7 蛋白激活以及诱导多聚（ADP-核糖）聚合酶导致凋亡的促凋亡信号事件。与单独使用任何一种药物相比，ZD6474 与 UV-B 联合使用抑制了乳腺癌细胞的体外侵袭，表明在联合处理的乳腺癌细胞中，促血管生成生长因子可能参与调节细胞骨架蛋白的改变表达和重组。还观察到组合治疗在降低基质金属蛋白酶表达方面的作用。
总之，我们的研究表明，将抗 EGFR 加 VEGFR 策略（ZD6474）与光疗（UV-B）相结合，是一种替代传统放射治疗的方法，可用于治疗皮肤浸润性转移性乳腺癌细胞和局部复发的乳腺癌，优于单独使用任何一种方法。
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