Anti-tumor activity against multiple myeloma by combination of KW-2478, an Hsp90 inhibitor, with bortezomib.

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.

Promoter variants of the human mannose-binding lectin gene show different binding.

Mannose-binding lectin (MBL) levels in the plasma of humans are highly variable. The level is influenced by gene mutations in exon1 and the promoter. Here we describe the distribution of three point mutations linked with a deletion in the MBL gene promoter in populations of Central Africa, Thailand, and Papua New Guinea. Among African children we find 20% with the wild-type allele, 53% are heterozygous, and 27% are homozygous for the mutation. In Thailand we find 65% with the wild-type allele, 33% are heterozygous, and 2% are homozygous for the variant. In Papua New Guinea the polymorphism is not found. The occurrence of the mutation was associated with MBL levels in the plasma (P = 0.043). Oligonucleotides derived from the variant promoter regions bind proteins differently according to their DNA sequence. The binding of proteins can be influenced by induction with interleukin-6.