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首页> 外文期刊>Molecular Cancer >Effects of HDM2 antagonism on sunitinib resistance, p53 activation, SDF-1 induction, and tumor infiltration by CD11b+/Gr-1+ myeloid derived suppressor cells
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Effects of HDM2 antagonism on sunitinib resistance, p53 activation, SDF-1 induction, and tumor infiltration by CD11b+/Gr-1+ myeloid derived suppressor cells

机译：HDM2拮抗作用对舒尼替尼耐药，p53活化，SDF-1诱导和CD11b + / Gr-1 +髓样来源的抑制细胞浸润的影响

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Background The studies reported herein were undertaken to determine if the angiostatic function of p53 could be exploited as an adjunct to VEGF -targeted therapy in the treatment of renal cell carcinoma (RCC). Methods Nude/beige mice bearing human RCC xenografts were treated with various combinations of sunitinib and the HDM2 antagonist MI-319. Tumors were excised at various time points before and during treatment and analyzed by western blot and IHC for evidence of p53 activation and function. Results Sunitinib treatment increased p53 levels in RCC xenografts and transiently induced the expression of p21waf1, Noxa, and HDM2, the levels of which subsequently declined to baseline (or undetectable) with the emergence of sunitinib resistance. The development of resistance and the suppression of p53-dependent gene expression temporally correlated with the induction of the p53 antagonist HDMX. The concurrent administration of MI-319 markedly increased the antitumor and anti-angiogenic activities of sunitinib and led to sustained p53-dependent gene expression. It also suppressed the expression of the chemokine SDF-1 ( CXCL12 ) and the influx of CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSC) otherwise induced by sunitinib. Although p53 knockdown markedly reduced the production of the angiostatic peptide endostatin, the production of endostatin was not augmented by MI-319 treatment. Conclusions The evasion of p53 function (possibly through the expression of HDMX) is an essential element in the development of resistance to VEGF -targeted therapy in RCC. The maintenance of p53 function through the concurrent administration of an HDM2 antagonist is an effective means of delaying or preventing the development of resistance.
机译：背景技术进行了本文报道的研究，以确定在肾细胞癌（RCC）的治疗中是否可以利用p53的血管抑制功能作为VEGF靶向疗法的辅助。方法用舒尼替尼和HDM2拮抗剂MI-319的多种组合治疗携带人RCC异种移植物的裸/米色小鼠。在治疗之前和期间的各个时间点切除肿瘤，并通过蛋白质印迹和IHC分析p53激活和功能的证据。结果舒尼替尼治疗可增加RCC异种移植物中的p53水平，并短暂诱导p21 waf1 ，Noxa和HDM2的表达，随后其水平降至基线（或无法检测到） ）出现舒尼替尼耐药。抗性的发展和对p53依赖性基因表达的抑制与p53拮抗剂HDMX的诱导在时间上相关。同时使用MI-319可以显着提高舒尼替尼的抗肿瘤和抗血管生成活性，并导致持续的p53依赖性基因表达。它还抑制了趋化因子SDF-1（CXCL12）的表达以及CD11b + / Gr-1 + 舒尼替尼诱导的髓样抑制细胞（MDSC）。尽管p53基因敲低显着降低了血管抑制肽内皮抑素的产生，但MI-319处理并未增加内皮抑素的产生。结论规避p53功能（可能通过表达HDMX）是RCC对VEGF靶向治疗产生耐药性的重要因素。通过同时施用HDM2拮抗剂来维持p53功能是延迟或预防耐药性发展的有效手段。

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