For metastatic bladder cancer patients, systemic cisplatin (CDDP)-based 
combination chemotherapy is the first-line choice of treatment. Although up to 
70% of advanced bladder cancer patients initially show good tumor response to 
this form of combination chemotherapy, over 90% of good responders relapse and 
eventually die of the disease. According to the cancer stem cell theory, this 
phenomenon is attributable to the re-growth of bladder cancer-initiating cells 
(BCICs) that have survived chemotherapy. In this study, the authors have 
isolated BCICs from cultured human bladder cancer cells to analyze their 
sensitivity to CDDP and to investigate whether heat-shock protein 90 (Hsp90) 
inhibitors potentiate the cytotoxicity of CDDP on BCICs. First, the authors have 
confirmed that a CD44+ subpopulation of 5637 cells met the requirements to be 
considered tumor-initiating cells. These BCICs were more resistant to CDDP and 
exhibited more activity in the Akt and ERK oncogenic signaling pathways when 
compared with their CD44- counterparts. The Hsp90 inhibitor 
17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), which 
simultaneously inactivated both Akt and ERK signaling at noncytocidal 
concentrations, synergistically potentiated the cytotoxicity of CDDP against 
BCICs by enhancing CDDP-induced apoptosis in vitro. The potentiating effect of 
17-DMAG was more effective than a combination of the two inhibitors specific for 
the Akt and ERK pathways. Finally, the authors have confirmed that, though human 
BCIC xenografts exhibited resistance to a single administration of CDDP and the 
Hsp90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), 17-AAG 
sensitized them to CDDP in a mouse model. These data encourage clinical trials 
of Hsp90 inhibitors as they may improve therapeutic outcomes of CDDP-based 
combination chemotherapy against advanced bladder cancer.