Inhibition of the Molecular Chaperone Heat Shock Protein 90 in Cancer: Consequences for the Regulation of Survival Signaling and Induction of Cell Death

Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors

“…The induction of HSP70 family members observed in this study and elsewhere (Hostein et al 2001, Banerji et al 2005b, Smith et al 2005) was of particular interest since this group of molecular chaperones have a well-documented antiapoptotic function (Mosser & Morimoto 2004, Clarke et al 2006. This generated the hypothesis that induction of these pro-survival genes/proteins may be reducing the apoptotic effect of 17-AAG.…”

“…It has been well documented that inhibition of HSP90 function induces the expression of HSP72 and degradation of client proteins (reviewed in Workman 2005, Clarke et al 2006. We have demonstrated the principle of combinatorial inhibition of multiple signal transduction pathways via targeting HSP90 using a panel of human colon cancer cell lines (Hostein et al Endocrine-Related Cancer (2006) 13 S125-S135…”

Inhibitors of the heat shock response: Biology and pharmacology

“…HSP70 chaperones are also intricately involved at several stages in regulating apoptosis [23]. The anti-apoptotic function of HSP70 chaperones has been reviewed extensively elsewhere [6,23,40]. Briefly, HSP70 can prevent the loss of mitochondrial membrane potential in response to apoptotic stimuli and hence block the release of apoptogenic factors including cytochrome c and AIF.…”

“…HSP70 can also function downstream of the mitochondria by interacting directly with APAF-1 or AIF to inhibit their function. In addition, HSP70 chaperones are potent inhibitors of caspase-independent cell death via their modulation of several stages of the pro-apoptotic JNK pathway [6,23,40]. to its open conformation and release the mature substrate.…”

“…Many human tumor cells express elevated levels of HSP70 and to some extent the co-chaperone HSP40, suggesting that cellular transformation causes induction of these chaperone proteins or conversely that HSP70 may play a role in tumorigenesis [6,23]. In addition, a number of cancer chemotherapeutic agents, including paclitaxel, doxorubicin and gemcitabine, have been shown to induce HSP70 expression, resulting in reduced cellular sensitivity to these agents [40]. For these reasons, HSP70 has emerged in recent years as a potential new target for the development of small-molecule inhibitors which may be used alone or in combination with existing therapeutic strategies in the treatment of cancer.…”