Targeting the hypoxia pathway in malignant plasma cells by using of 17-Allylamino-17-demethoxygeldanamycin
Abstract
Multiple myeloma (MM) is characterized as a clonal expansion of malignant plasma cells in the bone marrow, what is often associated with pancytopenia and osteolytic bone disease. Interestingly, myeloma-infiltrated bone marrow is considered to be hypoxic, providing the selection pressure for developing tumour. Since HSP90 was shown to participate in stabilization of the subunit of the key transcription factor HIF-1, which controls the hypoxic response, the aim of this study was to investigate the influence of a HSP90 inhibitor 17-Allylamino-17-demethoxygeldanamycin (17-AAG), on MM cells cultured in low oxygenation conditions. We confirmed that 17-AAG inhibits hypoxic induction of HIF-1 target genes in malignant plasma cells and demonstrate the concentration range of severe hypoxia-specific cytotoxicity. Next, we selected the malignant plasma cells in severe hypoxia/re-oxygenation culture conditions in the presence or absence of 17-AAG and next, cells which survived were further expanded and analyzed. Interestingly, we have noticed significant changes in the survival and the response to anti-MM drugs between the parental cell lines and those selected in cyclic severe hypoxia in the presence and absence of 17-AAG. Importantly, we also observed that the lack of oxygen itself, irrespectively of HIF-1 inhibition, is the main/pivotal factor driving the selection process in the presented experiments.
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