Enhancement of cisplatin cytotoxicity by terbium in cisplatin-resistant MDA/CH human breast cancer cells.
OBJECTIVE
The development of cisplatin resistance is a major problem in the treatment of cancer patients with cisplatin chemotherapy. The membrane binding of terbium (Tb3+) has been shown to increase the cellular accumulation of cisplatin in breast cancer cells. Therefore, the ability of Tb3- to modulate the cytotoxicity of cisplatin was investigated in cisplatin-sensitive (MDA) and cisplatin-resistant (MDA/CH) MDA-MB-231 human breast cancer cells.


METHODS
The cytotoxic parameters of cisplatin were determined using live cell microfluorometry and median effect analysis.


RESULTS
MDA/CH cells (IC50 = 142 +/- 9 microM) were found to be approximately 3.3-fold more resistant to cisplatin than MDA cells (IC50 = 43.5 +/- 3.0 microM). In both cell lines, the IC50 value for cisplatin was reduced two-fold in the presence of 80 microM Tb3+, thus indicating that the cytotoxicity of cisplatin is increased by Tb3+. The cytotoxic activity of cisplatin alone was observed to be 5.7 and 1.6 times more potent than that of Tb3+ alone in MDA and MDA/CH cells, respectively. Combination index analyses revealed that the interaction between cisplatin and Tb3+ was only synergistic at very low indices of cell death in MDA cells. However, in MDA/CH cells, the two drugs were synergistic up to intermediate levels of cell death.


CONCLUSIONS
Our results suggest that the enhancement of cisplatin cytotoxicity by Tb3- is more effective in cisplatin-resistant MDA/CH cells than in cisplatin-sensitive MDA cells. Therefore, terbium is potentially useful in cisplatin combination therapy for breast cancer patients, especially for those patients who have developed resistance to the drug.
Fuller
T L
TL
Department of Physiology and Biophysics, Howard University College of Medicine, Washington, DC 20059, USA.
Canada
R G
RG
D001943:Breast Neoplasms / Q000473:pathology*; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D013725:Terbium / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D013725:Terbium; D002945:Cisplatin