1. The antiproliferative activity of the heat shock protein 90 inhibitor IPI-504 is not dependent on NAD(P)H:quinone oxidoreductase 1 activity in vivo.
- Author
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Douglas M, Lim AR, Porter JR, West K, Pink MM, Ge J, Wylie AA, Tibbits TT, Biggs K, Curtis M, Palombella VJ, Adams J, Fritz CC, and Normant E
- Subjects
- Animals, Benzoquinones metabolism, Cell Line, Tumor, HCT116 Cells, HSP90 Heat-Shock Proteins metabolism, HT29 Cells, Humans, Hydroquinones metabolism, Immunoblotting, K562 Cells, Lactams, Macrocyclic metabolism, Male, Mice, Mice, Nude, Mutation, NAD(P)H Dehydrogenase (Quinone) genetics, Neoplasms drug therapy, Neoplasms metabolism, Neoplasms pathology, Protein Binding, Tumor Burden drug effects, Xenograft Model Antitumor Assays, Benzoquinones pharmacology, Cell Proliferation drug effects, HSP90 Heat-Shock Proteins antagonists & inhibitors, Lactams, Macrocyclic pharmacology, NAD(P)H Dehydrogenase (Quinone) metabolism
- Abstract
IPI-504, a water-soluble ansamycin analogue currently being investigated in clinical trials, is a potent inhibitor of the protein chaperone heat shock protein 90 (Hsp90). Inhibition of Hsp90 by IPI-504 triggers the degradation of important oncogenic client proteins. In cells, the free base of IPI-504 hydroquinone exists in a dynamic redox equilibrium with its corresponding quinone (17-AAG); the hydroquinone form binding 50 times more tightly to Hsp90. It has been proposed recently that the NAD(P)H:quinone oxidoreductase NQO1 can produce the active hydroquinone and could be essential for the activity of IPI-504. Here, we have devised a method to directly measure the intracellular ratio of hydroquinone to quinone (HQ/Q) and have applied this measurement to correlate NQO1 enzyme abundance with HQ/Q ratio and cellular activity of IPI-504 in 30 cancer cell lines. Interestingly, the intracellular HQ/Q ratio was correlated with NQO1 levels only in a subset of cell lines and overall was poorly correlated with the growth inhibitory activity of IPI-504. Although artificial overexpression of NQO1 is able to increase the level of hydroquinone and cell sensitivity to IPI-504, it has little effect on the activity of 17-amino-17-demethoxy-geldanamycin, the major active metabolite of IPI-504. This finding could provide an explanation for the biological activity of IPI-504 in xenograft models of cell lines that are not sensitive to IPI-504 in vitro. Our results suggest that NQO1 activity is not a determinant of IPI-504 activity in vivo and, therefore, unlikely to become an important resistance mechanism to IPI-504 in the clinic.
- Published
- 2009
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