دانلود رایگان مقاله انگلیسی مبارزه مقاومت دارویی کیناز با فعال کننده کاسپاز - الزویر 2018

Protein kinase inhibitors (PKIs) comprise a highly significant class of anti-cancer treatments. In 2001, imatinib (Gleevec), the first FDA-approved, small-molecule PKI, was approved for the treatment of chronic myelogenous leukemia. Since that hallmark, PKIs have become a standard in the treatment of a number of cancers and development of PKIs has expanded dramatically. Today over 40 PKIs are actively used clinically for indications ranging from cancers of many varieties to rheumatoid arthritis, graphversus-host disease, and pulmonary fibrosis. Development of this class of inhibitors is still strong, with four FDA approvals so far in 2018. While kinase inhibitors have proven to be extremely effective in decreasing cell proliferation and blocking other pathways required for cancer survival, PKIs are extremely prone to development of drug resistance, which was identified as early as 2001 (Gorre et al., 2001). PKI resistance can emerge within as little as days in cellbased models. In many instances, resistance emerges in human patients within a year of the beginning of treatment (Gillis and McLeod, 2016). Once resistance emerges, patients treated with PKIs become susceptible to reemergence or growth of their cancers. Second generation inhibitors targeting drug resistant kinases have also entered the market (e.g., Debrafenib, Trametinib, Cobimetinib, etc.), but given the cost and time required for the development of these specialized kinase inhibitors, this is not always a feasible long-term solution. In addition, these second generation PKIs are also susceptible to promoting the emergence of drug resistance (Figure 1). An optimal approach to extending the life of PKIs is the application of new pharmaceuticals that delay or prevent the onset of PKI drug resistance. Peh et al. have developed an approach, co-administration of a procaspase-3 activator PAC-1 with PKIs, which substantially extended the time to development of resistance in treated cells (Peh et al., 2016). PAC-1 is a procaspase-3 activator that functions by removal of zinc from the active site of caspases (Peterson et al., 2009). Caspase-3 is an apoptotic protease that is constitutively inhibited by the presence of physiological levels of zinc (Eron et al., 2018). The zinc-binding properties of PAC-1 enable activation of procaspase-3 to mature caspase-3, and the generation of proteolytic caspase-3 activity.