Synergistic induction of apoptosis in multiple myeloma cells by bortezomib and hypoxia-activated prodrug TH-302, in vivo and in vitro
Menée in vitro et in vivo, cette étude suggère l'intérêt de combiner un promédicament activé par l'hypoxie, TH-302, et le bortezomib pour le traitement de patients atteints d'un myélome multiple
Recently, we demonstrated that hypoxia is a critical microenvironmental factor in multiple myeloma (MM), and that the hypoxia-activated prodrug TH-302 selectively targets hypoxic MM cells and improves multiple disease parameters in vivo. To explore approaches for sensitizing MM cells to TH-302, we evaluated in this study the anti-tumor effect of TH-302 in combination with the clinically used proteasome inhibitor bortezomib. First, we show that TH-302 and bortezomib synergistically induce apoptosis in MM cell lines in vitro. Second, we confirm that this synergism is related to the activation of caspase cascades and is mediated by changes of Bcl-2 family proteins. The combination treatment induces enhanced cleavage of caspase-3/8/9 and PARP, and therefore triggers apoptosis and enhances the cleavage of pro-apoptotic BH3-only protein BAD and BID as well as the anti-apoptotic protein Mcl-1. In particular, TH-302 can abrogate the accumulation of anti-apoptotic Mcl-1 induced by bortezomib, and decreases the expression of the pro-survival proteins Bcl-2 and Bcl-xL. Furthermore, we found that the induction of the pro-apoptotic BH3-only proteins PUMA and NOXA is associated with this synergism. In response to the genotoxic and ER stresses by TH-302 and bortezomib, the expression of PUMA and NOXA were up-regulated in p53-dependent and p53-independent manners. Finally, in the murine 5T33MMvv model, we demonstrated that the combination of TH-302 and bortezomib can improve multiple disease parameters and significantly prolong the survival of diseased mice. In conclusion, our studies provide a rationale for clinical evaluation of the combination of TH-302 and bortezomib in MM patients.
http://mct.aacrjournals.org/content/early/2013/07/04/1535-7163.MCT-13-0123.abstract 2013