[show abstract][hide abstract] ABSTRACT: Heat shock protein 90 (Hsp90) is a promising target for anti-tumor therapy. We previously reported the anti-tumor activity of a novel Hsp90 inhibitor, KW-2478, in multiple myeloma (MM) as a single agent. In this study, we examined the combinational effect of KW-2478 and bortezomib, a proteasome inhibitor, in vitro and in vivo. In vitro, KW-2478 enhanced bortezomib-induced cell growth inhibition, both in MM cell lines and primary patient MM cells. The combination of KW-2478 and bortezomib also induced caspase activation in MM cell lines. Interestingly, the combination synergistically enhanced the expression of Hsp70B, a homolog of Hsp70, in human MM cells and peripheral blood mononuclear cells, indicating Hsp70B could be a surrogate biomarker for the combination of Hsp90 and proteasome inhibitors. In vivo, the combination of KW-2478 with bortezomib showed synergistic anti-tumor activity without significant body weight loss in a subcutaneously inoculated human myeloma model. Furthermore, the combination also showed synergistic reduction of tumor burden in bone marrow in an orthotopic myeloma model. Our results strongly suggest that combination of KW-2478 with bortezomib could exhibit enhanced anti-tumor activity against human myeloma.
Blood Cancer Journal 04/2012; 2(4):e68. · 1.40 Impact Factor
[show abstract][hide abstract] ABSTRACT: Selenium is a trace element that is fundamental to human health. Research has mainly focussed on its role in cancer prevention, but recent evidence supports its role in established cancer, with high concentrations inducing tumour cell death and non-toxic concentrations sensitising cells to chemotherapy. However, the precise mechanism of selenium action is not clear. The effect of methylseleninic acid (MSA), an organic selenium compound, on histone deacetylase (HDAC) activity in diffuse large B-cell lymphoma cell lines is reported here.
Lymphoma cell lines were exposed to MSA under normoxic and hypoxic conditions. Protein expression was determined by western blotting, HDAC activity and VEGF concentration by fluorimetric and electrochemiluminescence assays, respectively, and intracellular selenium metabolites quantified by mass spectrometry.
MSA inhibited HDAC activity, which resulted in the acetylation of histone H3 and α-tubulin. However, cellular metabolism of MSA to methylselenol was required for this effect. Dimethylselenide, the methylation product of methylselenol, was found to be the major intracellular metabolite. MSA also inhibited HIF-1α expression and VEGF secretion, a possible consequence of HDAC inhibition.
The ability of methylselenol to inhibit HDAC activity has not been previously reported, thus providing a novel mechanism of selenium action.
Cancer Chemotherapy and Pharmacology 04/2011; 68(3):815-21. · 2.80 Impact Factor