Chapter 4

Molecular Approaches to Target Heat Shock Proteins for Cancer Treatment

Daniel R. Ciocca, Francesco Cappello, F. Darío Cuello-Carrión and André- Patrick Arrigo

Abstract

HSP90 was the first molecular target to inhibit the interaction of this heat shock protein (HSP) with client proteins in cancer cells and tissues. The HSP90 inhibition was attempted to liberate from this chaperone the oncogenic fusion proteins, mutated and activated serine/threonine protein kinases, tyrosine kinases, as well as transcription factors with oncogenic activity, in this manner, the free proteins could be recognized by the proteasome system to be degraded. We should remember here that many HSP family members are overexpressed in different kinds of cancer tissues, these molecules act as chaperones of tumorigenesis. In cancer patients, the first generation of HSP90 inhibitors showed elevated levels of toxicity, which was partially solved with the second-generation of inhibitors that could be intravenously delivered. With the arrival of the third-generation drugs that could be orally administrated, anticancer activities were achieved in clinical trials, however, the results were not as successful as expected 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 drug administration. The main problem is the redundancy of chaperones that the cancer cells have, in fact during HSP90 or HSP70 inhibition the heat shock factor (HSF1) could be liberated increasing the levels of other HSPs and in addition, HSF1 can by itself act as an inducer of the multidrug resistance MDR response and is also implicated in HER2 and hormonal responses. These difficulties, rather than decreasing the interest of having the HSPs as molecular targets, are increasing the exploration of new ways to interfere 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.

Total Pages: 146-199 (54)

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