Abstract
BackgroundThe 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).MethodsNude/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.ResultsSunitinib 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.ConclusionsThe 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.
Highlights
The studies reported were undertaken to determine if the angiostatic function of p53 could be exploited as an adjunct to Vascular endothelial growth factor (VEGF)-targeted therapy in the treatment of renal cell carcinoma (RCC)
Sunitinib-induced p53 activation in RCC xenografts To assess the effects of sunitinib treatment on tumor cell p53 levels and transcriptional activity, 1 × 107 786-0 or A498 cells were implanted subcutaneously into the flanks of nude/beige mice and the resulting tumors allowed to grow to a diameter of 10 mm, at which point sunitinib treatment (50 mg/kg daily) was begun
In the case of A498 xenografts, sunitinibinduced growth arrest extends to approximately 40 days, after which the tumors become resistant to treatment
Summary
The studies reported 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). The mechanisms by which tumors manage to evade the effects of these agents are numerous and only partly understood [3,4,5] One such mechanism involves the production of chemokines (e.g. SDF-1, CSF-1, IL-8) that either drive angiogenesis directly or recruit macrophages and other myeloid lineage cells, including CD11b+/Gr-1+ myeloidderived suppressor cells (MDSCs), from the bone marrow into tumor tissue [5,6,7,8,9,10,11]. Little is known about how the p53 status of a tumor might affect the extent to which tumors are infiltrated by MDSC or the facility with which they develop resistance to VEGF-targeted therapy
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