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.
Keywords: Cancer, Drug resistance, Heat shock proteins, HSP27, HSP60, HSP70,
HSP90, Molecular targets, New anticancer drugs, Therapy.