Defective apoptosis signaling and multidrug resistance are major barriers for successful
cancer treatment. To identify drugs capable of targeting treatment-resistant
cancer cells, we screened small-molecule
kinase inhibitor libraries for compounds that decrease the viability of apoptosis-resistant human MCF7-Bcl-2
breast cancer cells.
SU11652, a multitargeting
receptor tyrosine kinase inhibitor, emerged as the most potent compound in the screen. In addition to MCF7-Bcl-2 cells, it effectively killed HeLa cervix
carcinoma, U-2-OS
osteosarcoma, Du145 prostate
carcinoma, and WEHI-S
fibrosarcoma cells at low micromolar concentration.
SU11652 accumulated rapidly in lysosomes and disturbed their pH regulation and ultrastructure, eventually leading to the leakage of lysosomal
proteases into the cytosol. Lysosomal destabilization was preceded by an early inhibition of
acid sphingomyelinase, a lysosomal
lipase that promotes lysosomal membrane stability. Accordingly, Hsp70, which supports
cancer cell survival by increasing lysosomal
acid sphingomyelinase activity, conferred partial protection against SU11652-induced cytotoxicity. Remarkably,
SU11652 killed multidrug-resistant Du145
prostate cancer cells as effectively as the
drug-sensitive parental cells, and subtoxic concentrations of
SU11652 effectively inhibited multidrug-resistant phenotype in Du145
prostate cancer cells. Notably,
sunitinib, a structurally almost identical and widely used antiangiogenic
cancer drug, exhibited similar lysosome-dependent cytotoxic activity, albeit with significantly lower efficacy. The significantly stronger lysosome-targeting activity of
SU11652 suggests that it may display better efficacy in
cancer treatment than
sunitinib, encouraging further evaluation of its anticancer activity in vivo. Furthermore, our data provide a rationale for novel approaches to target
drug-resistant
cancers by combining classic
chemotherapy with
sunitinib or
SU11652.