Novel meriolin derivatives activate the mitochondrial apoptosis pathway in the presence of antiapoptotic Bcl-2

Abstract

Abstract Meriolin derivatives represent a new class of kinase inhibitors with a pronounced cytotoxic potential. Here, we investigated a newly synthesized meriolin derivative (termed meriolin 16) that displayed a strong apoptotic potential in Jurkat leukemia and Ramos lymphoma cells. Meriolin 16 induced apoptosis in rapid kinetics (within 2 - 3 h) and more potently (IC50: 50 nM) than the previously described derivatives meriolin 31 and 36 [1]. Exposure of Ramos cells to meriolin 16, 31, or 36 for 5 min was sufficient to trigger severe and irreversible cytotoxicity. Apoptosis induction by all three meriolin derivatives was independent of death receptor signaling but required caspase-9 and Apaf-1 as central mediators of the mitochondrial death pathway. The mitochondrial toxicity of meriolins was further confirmed by the breakdown of the mitochondrial membrane potential (ΔΨm), mitochondrial release of proapoptotic Smac, processing of the dynamin-like GTPase OPA1 and subsequent fission of mitochondria. Remarkably, all meriolin derivatives could directly activate the mitochondrial apoptosis pathway in Jurkat cells even in the presence of antiapoptotic Bcl-2 protein. In addition, meriolins were capable to induce cell death in imatinib-resistant K562 and KCL22 chronic myeloid leukemia cells as well as in cisplatin-resistant J82 urothelial carcinoma and 2102EP germ cell tumor cells. Since tumor cells frequently inactivate the mitochondrial death pathway (e.g. by overexpression of antiapoptotic Bcl-2 proteins) in order to acquire therapy resistance, meriolin derivatives might represent a promising therapeutic option for overcoming treatment resistance.