At the moment, new enhanced TPZ analogues with higher hypoxic potency are remaining formulated . HIF Inhibitors. Basic and clinical researches have con rmed the expression level of HIF , as well as absolute minimal pO, correlates having a poor prognosis and incidences of each tumor recurrence and distant tumor metastasis aer radiation therapy . Every single of the multiple methods responsible to the activation of HIF has been exploited like a therapeutic target . 1 with the significant targets may be the mechanism behind the stabilization of HIF protein, for the reason that it will be by far the most inuential step in HIF activity. YC , which was mainly synthesized with the aim of activating soluble guanylate cyclase and inhibiting platelet aggregation, was reported to suppress the expression of HIF target genes via the suppression of HIF accumulation and also to grow the antitumor efficacy of radiation treatment signicantly .
An HSP inhibitor, allylamino demethoxygeldanamycin , facilitates the RACK dependent compound libraries for drug discovery ubiquitination of HIF , leading to its degradation through proteasome. Also, antioxidant reagents this kind of as ascorbate and N acetyl cystein , promote the degradation of HIF protein by reducing Fe to Fe , which functions as a cofactor in the PHDs VHL dependent degradation of HIF protein . Inhibiting the dimerization of HIF with HIF was also targeted mainly because it is expected for HIF DNA binding and transcriptional action. Lee et al. identied acriavine as an inhibitor in the dimerization by directly binding to HIF . ey reported that acriavine remedy inhibited intratumoral expression of angiogenic cytokines, mobilization of angiogenic cells into peripheral blood, and tumor vascularization, resulting in the prevention and arrest of tumor growth .
One more strategy would be to inhibit the function of key signaling pathways which up regulate the expression of HIF , this kind of as the PI K Akt mTOR and Ras signaling pathways . An mTOR inhibitor, RAD , basically diminished the level of HIF protein and its downstream Linifanib gene solutions in a mouse model of prostate cancer with substantial oncogenic Akt activity . Other mTOR inhibitors, this kind of as rapamycin, temsirolimus , everolimus , also showed exactly the same effect . In addition, it was reported that doxorubicin and echinomycin suppress the function of HIF by inhibiting HIF ?s binding to HRE . Given that HIF straight and indirectly functions in tumor recurrence aer radiation treatment as described over, HIF inhibitors, at the same time as tirapazamine, have been conrmed to enhance the therapeutic impact of radiation .
Yet, it’s also been reported the inhibition of HIF with unsuitable timing suppresses instead of enhances the effect of radiation treatment considering that its antiangiogenic effect increases the radioresistant hypoxic fraction in malignant sound tumors .