Cisplatin (DDP)-resistant 2008 human ovarian carcinoma cells (C13*) have an elevated mitochondrial membrane potential that confers hypersensitivity to lipophilic cations. We have addressed whether this change was directly linked to the DDP-resistant phenotype or was a random alteration, unrelated to resistance. The elevated mitochondrial membrane potential and ensuing rhodamine 123 (Rh123) hypersensitivity of C13* cells provided a positive selection rationale. Cells with low mitochondrial membrane potential will have a survival advantage over those with a high mitochondrial membrane potential, when exposed to Rh123. We therefore used Rh123 to isolate revertants (RH4) from the 12-fold DDP-resistant C13* cell line that had a low mitochondrial membrane potential. RH4 cells had parental (2008) mitochondrial membrane potential levels as shown by flow cytometry analysis of Rh123 stained cells and by tetraphenylphosphonium cation uptake. The RH4 cells lost a substantial portion of their DDP resistance such that they were only 2- to 3-fold resistant to DDP. Despite this major loss of resistance, they retained a number of the phenotypic changes related to DDP resistance, observed in C13* cells. RH4 cells displayed the same DDP accumulation defect, 2-fold elevated glutathione levels and 2-fold resistance to CdCl2 as C13* cells. We conclude that although the biochemical mechanism by which an elevated mitochondrial membrane potential elicits DDP resistance is unknown, these mitochondrial changes are central to the expression of DDP resistance in C13* cells.

1

Supported by Grant 100-R107 from Bristol-Myers Co., and in part by the Lombardi Cancer Research Center Flow Cytometry Core Facility, USPHS Grant 1P30-CA-51008.

This content is only available via PDF.
©1992 American Association for Cancer Research.
1992
American Association for Cancer Research, Inc.