Targeted therapy against EGFR and VEGFR using ZD6474 enhances the therapeutic potential of UV-B phototherapy in breast cancer cells.
Targeted therapy against EGFR and VEGFR using ZD6474 enhances the therapeutic potential of UV-B phototherapy in breast cancer cells.
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DOI：
10.1186/1476-4598-12-122
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发表时间：
2013-10-20
期刊：
影响因子：
37.3
通讯作者：
Mandal M
中科院分区：
文献类型：
--
作者：
Sarkar S;Rajput S;Tripathi AK;Mandal M
肿瘤区域的低氧环境刺激了促进血管生成和肿瘤增殖的生长因子的上调。因此，靶向肿瘤血管的同时应用双酪氨酸激酶抑制剂促进肿瘤的增殖可能是治疗晚期乳腺癌的有效方法，结合放射治疗可进一步增强其疗效。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受到毒副作用和肿瘤耐药性的严重影响。使用ZD6474的合理性是为了评价联合使用VEGFR2和EGFR靶向，并在体外进行靶向和局部UV-B光治疗乳腺癌细胞的可行性和有效性，以期治疗乳腺癌细胞浸润性皮肤病变。用UV-B和ZD6474联合照射乳腺癌细胞，进行细胞存活率、细胞凋亡率、侵袭力和运动能力的研究。使用Graph Pad Prism 5.0进行图表和统计分析。ZD6474和UV-B以组合方式降低乳腺癌的细胞活力，而不影响正常的人乳腺上皮细胞。ZD6474联合UV-B可抑制细胞周期蛋白E的表达，并诱导P53的表达。它通过诱导Bax和细胞色素-c转位激活应激诱导的线粒体途径。ZD6474与UV-B联合使用与单独使用相比，也更有效地下调了抗凋亡的bcl2蛋白，上调了促凋亡信号事件，涉及Bax的表达，激活了caspase-3和caspase-7蛋白，并诱导了聚ADP核糖聚合酶导致细胞凋亡。与单独用药相比，ZD6474联合UV-B可抑制乳腺癌细胞的体外侵袭，提示促血管生成生长因子可能参与调节联合治疗的乳腺癌细胞中细胞骨架蛋白的表达和重组。联合治疗还可减少基质金属蛋白酶的表达。总而言之，我们的研究表明，将抗EGFR加VEGFR策略(ZD6474)与光疗(UV-B)相结合，是正在进行的传统放射治疗皮肤浸润性转移性乳腺癌细胞和局部复发乳腺癌的替代方法，而不是单独使用这两种方法中的任何一种。
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.
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影响因子：
6
作者：
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通讯作者：
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