Molecular Approaches to Target Heat Shock Proteins for Cancer Treatment

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Abstract

HSP90 was the first molecular target to inhibit the interaction of this heatshock protein (HSP) with client proteins in cancer cells and tissues. The HSP90inhibition was attempted to liberate from this chaperone the oncogenic fusion proteins,mutated and activated serine/threonine protein kinases, tyrosine kinases, as well astranscription factors with oncogenic activity, in this manner, the free proteins could berecognized by the proteasome system to be degraded. We should remember here thatmany HSP family members are overexpressed in different kinds of cancer tissues, thesemolecules act as chaperones of tumorigenesis. In cancer patients, the first generation ofHSP90 inhibitors showed elevated levels of toxicity, which was partially solved withthe second-generation of inhibitors that could be intravenously delivered. With thearrival of the third-generation drugs that could be orally administrated, anticanceractivities were achieved in clinical trials, however, the results were not as successful asexpected due to: 1) limited anti-tumor efficacy, 2) acquisition of drug resistance, 3)difficulty to identify the client protein(s) specifically degraded in response to drugadministration. The main problem is the redundancy of chaperones that the cancer cellshave, in fact during HSP90 or HSP70 inhibition the heat shock factor (HSF1) could beliberated increasing the levels of other HSPs and in addition, HSF1 can by itself act asan inducer of the multidrug resistance MDR response and is also implicated in HER2and hormonal responses. These difficulties, rather than decreasing the interest ofhaving the HSPs as molecular targets, are increasing the exploration of new ways tointerfere with several HSPs simultaneously and using HSP inhibitors with more“conventional” anticancer drugs. In this article we review, in addition to HSP90,HSP27, HSP70, and HSP60 as targets for anticancer therapy.
Original languageEnglish
Title of host publicationFrontiers in Clinical Drug Research - Anti-Cancer Agents
Pages3-47
Number of pages45
Publication statusPublished - 2015

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