NSC 338258 Represents a Novel Anti-Neoplastic Agent for the Treatment of Multiple Myeloma.

Abstract

We have shown that high-risk multiple myeloma (MM) can be linked to amplification and overexpression of the cell cycle regulator CKS1B. With this in mind we correlated high expression of this gene in the NCI60 cell line panel with IC50 of over 10,000 anticancer compounds. NSC 338258 (EPED3) was identified in this search. EPED3 is a highly stable, hydrophilic derivative of ellipticine. In vitro, this synthetic compound exhibits drastic cytotoxic activity on myeloma cells, which is unique among most ellipticine derivatives. This efficacy of EPED3 was examined in myeloma cells co-cultured with bone marrow stromal cells. Despite the protective influence of stromal cells, micromolar concentrations of EPED3 were highly effective at killing myeloma cells; however, this lethal activity was exclusive of stromal cells. In co-culture, EPED3-induced cell cycle arrest and massive apoptotic progression appears to be a consequence of its instant impact on cytoplasmic organelles, particularly mitochondria. Disruption of mitochondrial and endoplasmic distribution of cytochrome c initiated the intracellular proteolytic cascade through the intrinsic apoptotic pathway. Effects of EPED3 treatment were further evaluated in myeloma cell lines with selective tolerances to doxorubicin, dexamethasone, and Velcade; EPED3 overcame these acquired drug resistances. In addition, the potency of EPED3 was tested on mononuclear cells isolated from peripheral blood of healthy donors. Under mitogenic stimulation, EPED3 had no significant growth inhibition effects within a range of concentrations killing myeloma cells. Collectively, our current data suggest that EPED3 is an extraordinary agent that, in vitro, targets mitochondrial function to rapidly deplete chemical energy and to initiate apoptosis in myeloma cells at low concentration, while leaving healthy stromal and mononuclear cells unharmed.