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Introduction of bortezomib, the first generation of proteasome inhibitor, has significantly improved the median overall survival of patients with multiple myeloma (MM). However, the dose-limiting adverse events and acquired drug resistance limit its long-term usage. Here, we report in vitro and in vivo anti-MM activity of the irreversible proteasome inhibitor BSc2118. BSc2118 inhibited the chymotrypsin-like (CT-L) proteasome activity, accompanied by accumulation of ubiquitinated proteins. BSc2118 suppressed tumor cell growth through induction of G2/M phase arrest and induced apoptosis via activation of the apoptotic signaling cascade, in association with up-regulation of p53 and p21. Importantly, BSc2118 was active in vitro against MM cells' acquired bortezomib resistance. Of note, BSc2118 also displayed a novel anti-angiogenesis activity both in vitro and in vivo . Lastly, BSc2118 exhibited a broader safety dose range and higher anti-tumor efficacy in vivo in a human MM xenograft mouse model, compared to bortezomib. Together, these findings indicate the in vitro and in vivo anti-MM activities of BSc2118 through induction of cell cycle arrest and apoptosis, as well as inhibition of tumor angiogenesis. They also suggest that BSc2118 might, at least in vitro , partially overcome acquired bortezomib resistance, likely associated with inhibition of autophagy. [ABSTRACT FROM AUTHOR]

Abstract: Caveolin-1, a 21–24kDa integral membrane protein, is a principal structural component of caveolae in vivo. To investigate the roles of caveolin-1, we established stable transfectants in Hs578T breast adenocarcinoma cells that had up- and down-regulated caveolin-1 expression. In the paper, we demonstrated that caveolin-1 overexpression in Hs578T cells significantly reduced staurosporine-induced apoptosis and the levels of caveolin-1 expression positively correlated with the number of colonies and colony size in soft agar. Our findings indicate for the first time in Hs578T cells that caveolin-1 might play a pivotal role in regulating apoptosis as a suppressor rather than a facilitator through inhibition of neutral-sphingomyelinase, decrease of ceramide, furthermore, activation of Akt signaling pathway. [Copyright &y& Elsevier]