Based mostly on this, we postulated that sunitinib would radiosensitize these two cell lines but probably not radiosensitize the LNCaP cell line, identified to express none on the offered targets. This without a doubt turned out for being the case when sunitinib radio sensitization was assessed by clonogenic assay. DU145 and PC3 cells had been modestly radiosensitized and LnCaP cells weren’t. Nonetheless, despite the modest radiosensitization observed making use of sunitinib on DU145 and PC3 cells, the reduction in SF2 values observed might be predicted to have clinical impact in a fractioned treat ment protocol in prostate cancer sufferers. Despite rising curiosity in combining novel tyro sine kinase inhibitors with typical techni ques this kind of as radiotherapy, the molecular mechanisms by which TKIs elicit their sensitizing effects remain to be elucidated.
However, normally, it seems that quite a few if not most TKIs inhibit signaling downstream of growth factor receptors mediated by the PI3K AKT and Ras Raf MEK ERK pathways. Activation of each the ERK and AKT pathways are a frequent event in prostate cancers plus a solid association in between the expression of those kinases and bad prognosis is often observed. As a result, we examined whether or not suniti selelck kinase inhibitor nib suppressed p AKT and or p ERK, two appropriate downstream aspects within the signaling pathways below investigation. The outcomes showed that sunitinib sup pressed p ERK in un irradiated and irradiated DU145 and PC3 cells suggesting that radioresistance in these cells lines is mediated through the Ras Raf MEK ERK pathway. This is constant with several reviews within the literature illustrating the significance of this path way in governing radiation response in tumor cells. Possibly one of the most significant mechanism for dictating the cytotoxicity of ionizing radiation involves the repair of radiation induced DNA double strand breaks.
Fix of these lesions critically determines the de gree of cell killing by radiation. Induction and restore of radiation induced DSBs is commonly followed using the detection of H2AX foci. This assay is quite delicate and we’ve applied it previously to show the radiosensitizing action of other molecularly targeted agents consists of an inhibition Vanoxerine of DSB repair detected about the basis of a prolongation of H2AX foci inside the agent plus radiation samples in contrast to radiation alone con trols. During the present research, having said that, we were unable to detect any prolongation of H2AX foci by sunitinib suggesting that sunitinib doesn’t interfere using the restore of radiation induced DSBs. This might not be also surprising since the degree of radiosensitization generated by sunitinib right here is tiny compared to what was observed in our past studies making use of other mo lecularly targeted agents. Consequently, it can be conceivable that sunitinib suppresses DSB repair to a modest degree that is undetectable by this assay or that sunitinib radiosensi tizes by some other mechanism.