Investigation of the intrinsic mechanism of drug resistance in multiple myeloma

摘要: The focus of this thesis was to evaluate the mechanisms whereby myeloma cells develop intrinsic resistance with a on in context bortezomib treatment. aims were examine multidrug pumps as mechanism MM, investigate contribution p53 signalling perturbations study AMPK pathway an alternative target overcome MM and finally characterise treatment using 2D-DIGE analysis. Focussing models, we found that overexpression P-gp attenuates activity. Bortezomib is substrate combination inhibitor able resistance. also downregulate expression function P-gp. Our findings therefore suggest positive would be reasonable extend use drug. We have shown apoptotic pathways can accentuated when combined Mdm2 inhibitor. In WT cells, nutlin-3 generates additive toxicity but highly synergistic epithelial models p53-mutated cell lines. This synergy persists presence BMSCs. observation has implications more so cancers mutated where single agent activity mild. We bortezomib-treated patients who had high nutlin-3-suppressed genes significantly shorter progression-free (p=0.001, log-rank test) overall survival (p=0.002, compared those low levels. AMPK activation promising anticancer may chemoprevention target. Metformin AICAR, which activate pathway, both demonstrated useful preclinical properties good therapeutic index patients. explored death showed AICAR pathway. These agents synergise glycolysis inhibitors further increase cytotoxicity cancer cells. Identification proteins whose altered differing states sensitivity provides candidates for better understanding investigated cellular proteomic techniques isolated identified several novel play role phenomenon. are mechanistically consistent since two Hsp70 caspase-3 known literature affected by