The most attractive advantage of targeting Hsp90 is the combined impact on many oncogenic pathways involved in multiple steps of carcinogenesis and cancer progression, as Hsp90 inhibition eventually leads to the ubiquitin-proteasome degradation of a large population of oncogenic client proteins (Workman, 2004
). This review not only provides an up-to-date overview of mechanistic studies and the clinical prospect of currently available Hsp90 inhibitors, but also wishes to enhance the perspective both for designing and discovering novel inhibitors as well as to provide insight into less-understood and under-represented potential of Hsp90 in cancer therapy (illustrated in ).
Schematic illustration for designing and discovering Hsp90 inhibitor, as well as more potential of Hsp90 inhibition.
Most studies have focused on the discovery or synthesis of Hsp90 inhibitors specifically acting against the ATP binding site at the N-terminus of Hsp90. Further evaluation of these Hsp90 inhibitors and development of new inhibitors belonging to this class remains of great interest. However, there are considerable possibilities for inhibition of the super-chaperone system in other ways. Targeting co-chaperone/Hsp90 interactions should receive more attention, as this approach is likely to improve the specificity
of Hsp90 inhibition compared with direct inhibition of ATP binding. Another appealing advance is derived from the interference with post-translational modifications of Hsp90, where a majority of the efforts have been put into the hyperacetylation of Hsp90 by HDAC inhibitors. Disruption of client/Hsp90 interactions was suggested to provide the highest selectivity (Pearl et al., 2008
). While the basis for antagonizing client/Hsp90 associations is the structural and biochemical understanding of the interactions, the reality is that even nowadays little is known about these interactions (Pearl et al., 2008
). Besides, the initially-raised benefit of Hsp90 targeting is the simultaneous impact on multiple
oncogenic pathways, which could be eliminated by only focusing on a specific client/Hsp90 interaction. Therefore, the strategy of targeting these client/Hsp90 associations is not only highly challenging, but also need to be further validated. A few studies have been performed to compare the properties and functions of distinct Hsp90 isoforms, but most details remain to be understood. The different functions of Hsp90 isoforms and the isoform selectivity of Hsp90 inhibitors will require further investigation. The inhibition of cancer metastasis by cell-impermeable Hsp90 inhibitors is an interesting area for research as well as specific targeting of cancer stem cells. Since the importance of CSCs in resistance to chemotherapy has been recognized, the evaluation the effect of Hsp90 inhibitors on CSCs properties would provide useful insight and clinical perspective for the future.
Since dose-limiting toxicity is likely to be an important issue when Hsp90 inhibitors are used as single agents, an alternative approach for the application of Hsp90 inhibition is to combine Hsp90 inhibitors with other therapeutic agents to enhance the efficacy with lowered dose-limiting toxicity. This perspective is substantiated by a large number of preclinical and clinical evaluations of Hsp90 inhibitors that have shown promising results in combination with chemotherapeutic drugs or other agents (Solit and Chiosis, 2008
). 17-AAG and 17-DMAG are being investigated in preclinical, Phase I and II trials for breast cancers in association with trastuzumab, a Her-2 monoclonal antibody (Didelot et al., 2007
). For example, a Phase I dose-escalation study has indicated that co-administration of trastuzumab and 17-AAG is well tolerated and exhibit anti-tumor activity in patients with trastuzumab-refractory Her-2 positive breast cancer (Modi et al., 2007
). A recent Phase I study with 17-AAG plus paclitaxel was conducted in patients with advanced solid malignancies to determine the recommended Phase II dose of these two drugs (Ramalingam et al., 2008
). Another Phase I dose-escalation trial using 17-AAG and irinotecan suggested that 17-AAG potentiated the anti-proliferative activity of irinotecan possibly by depleting checkpoint kinase (Chk1) (Tse et al., 2008
). Co-administration of 17-AAG and proteasome inhibitors such as bortezomib has also been reported to produce synergistic anti-cancer effects, which might result from the concomitant increase in protein misfolding and impairment of proteasome-dependent clearance (Whitesell and Lindquist, 2005
). IPI-504 was demonstrated to be more effective when combined with imatinib than when used alone in prolonging survival of mice with Bcr-Abl positive leukemia cells (Peng et al., 2007
). A recent report indicated cisplatin-mediated abrogation of the heat shock response through inhibition of HSF-1 activity that may, at least in part, contribute to the synergistic effect of GA and cisplatin (McCollum et al., 2008a
). An interesting observation by our group is that an Hsp90 inhibitor and glycolysis inhibitor synergistically inhibited tumor growth in a pancreatic tumor model, possibly by preferentially targeting hypoxic tumor cells (Cao et al., 2008
In summary, the targeting of Hsp90 for anti-cancer therapeutics has a potentially bright future. Further progress in the development of Hsp90 inhibitors and a deeper understanding of the Hsp90 characteristics further strengthen its promise in cancer therapy.