A team in the University of\nMacau\u2019s (UM) Faculty of Health Sciences (FHS), led by FHS Dean Chuxia Deng, has\ndiscovered the connection between the ubiquitinated proteasome system and drug resistance.\nThe team has found that the inhibition of proteasome activity can block broad\ndrug resistance in multiple types of cancer. The findings could help address\ndrug resistance in cancer patients, and the study has been published in the\ninternationally renowned journal Advanced Science<\/i>.<\/p>
A major reason for the\npersistently high cancer mortality rate is the body’s automatic development of\ndrug resistance. When cancer cells are treated with several drugs\nsimultaneously or successively, they may become multidrug resistant, making\nthis type of cancer very difficult to treat, such as primary drug resistance of\ntumor cells and acquired drug resistance. Many tumours, even if initially well\ntreated with chemotherapy, gradually become drug resistant and difficult to\ncontrol. In addition, many cancers treated with one drug often develop\ncross-resistance, or broad drug resistance, to many other new drugs with\ndifferent structures and mechanisms of action, leaving many leading medical\ninstitutions scratching their heads.<\/p>
The\nUM research team has found that enhanced proteasome activity and lower mitochondrial\nactivity can contribute to drug resistance in cisplatin through genome-wide\nRNAi screening and evolutionary drug resistance model. Cisplatin is one of the\nmost widely used chemotherapy drugs in the treatment of different types of\ncancers. Further studies have indicated that cisplatin treatment induces\nprotein damage, which activates the mitochondrial protein input monitoring\npathway. The activation leads to a decrease in mitochondrial activity and enhances\nproteasome activity, thereby increasing the clearance rate of damaged proteins\nand saving cell viability. In addition, the team has confirmed that enhanced\nproteolysis and lower mitochondrial activity are common mechanisms for resistance\nto up to 40 cancer drugs, and that proteasome inhibitor therapy reverses resistance\nto 27 of these drugs through screening against a library of 69 drugs and\nscreening of patients’ organs. The results have further shown that cisplatin\nand bortezomib in nanoparticle form can further enhance anti-tumour effects and\nreduce the side effects associated with drug combination therapy.<\/p>
In identifying all human\ngenes potentially associated with drug resistance through whole genome RNAi\nscreening, the team has identified 45 genes associated with cisplatin\nresistance and 104 genes associated with cisplatin sensitivity. Using multiple\nmodels, the researchers have demonstrated that targeting the cellular functions\ninvolved in these candidate genes can overcome a broad spectrum of drug\nresistance. These studies show that despite the different structures, cellular\ntargets, and mechanisms of action of different cancer drugs, cancer cells\nactivate similar defense systems to maintain cell survival. In addition, it has\nbeen shown that enhanced proteolysis is a common mechanism for these drug\nresistances and that by targeting this universal defense system, it is possible\nto reverse multidrug resistance. These findings have important implications for\ntranslational medicine.<\/p>