Involvement of cytotoxicity and variation of the mitochondrial membrane potential induced by hybrid agent

The pyrrolo[2,1‐c][1,4]benzodiazepine (PBD) derivative DC‐81 is a potent antitumor antibiotic produced by Streptomyces species. The marked cytotoxic potential of this drug may be the result of its interaction with DNA. Because DC‐81 only recognizes three DNA base pairs this has precluded its clinical utility. Combination of DC‐81 with an indole carboxylate moiety was a hybrid designed to have much higher sequence selectivity in DNA Interactivity. In this paper, the association between cytotoxicity and the changes of mitochondria membrane potential ΔΨ_mt after exposing human melanoma cell line A375 to the hybrid agent was examined using MTS cell proliferation assay and flow cytometry using the fluorochrome rhodamine 123. Our results indicated that the hybrid induced cytotoxity and a significant reduction in ΔΨ_mt of A375 cells. We suggest that the hybrid agent is a potent inducer of cell apoptosis in A375 cells. Drug Dev. Res. 61: 1–5, 2004. © 2004 Wiley‐Liss, Inc.