Terbium phosphorescence was used to investigate a thermosensitive calcium binding protein located in the plasma membrane of human MCF-7 breast tumor cells. The cells were pretreated at 25, 37, or 43 degrees C for 1 h, before binding experiments were performed at 25 degrees C. The delta Imax for the Tb(3+)-MCF/7 complex increased significantly after cellular exposure to 43 degrees C. The Kd for the Tb(3+)-MCF/7 complex did not change with the temperature. These results suggested that hyperthermia can unmask preexisting calcium binding sites on the surface of the plasma membrane, without affecting their affinity. After treatment at 43 degrees C, the quenching of the Tb(3+)-MCF/7 intensity by cisplatin was significantly greater than that at 37 degrees C. Hyperthermia was determined to increase the affinity of cisplatin for the calcium binding protein. The effect of hyperthermia on the calcium receptor binding of cisplatin is hypothesized to be the basis for the synergism between their cytotoxicities.
In agreement with earlier studies, the plasma membrane of MDA cell lines contain a specific Tb(3+)-binding protein. Our findings suggest that the Tb(3+)-binding protein may be intimately associated with the accumulation of DDP in breast tumor cells.
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.
In this investigation, we report a relationship between the terbium (Tb3+) binding protein and the accumulation of cisplatin in human ovarian cancer cells. The number of Tb3+ binding sites in cisplatin-resistant C13+ cells is significantly greater by 79% than those in cisplatin-sensitive 2008 cells. Exposure to Tb3+ also increased the cellular accumulation of cisplatin. The accumulation of cisplatin as a function of the Tb3+ concentration in the C13+ cells (0.85%/microM Tb3+) was significantly greater than the accumulation of cisplatin in 2008 cells with respect to Tb3+ (0.46%/microM Tb3+). The number of Tb3+ binding sites in revertant RH4 cells was similar to that in 2008 cells. The RH4 cells were less sensitive to the stimulatory effects of Tb3+ than the C13+ cells. Our results show that the Tb3+ binding protein correlates with cisplatin resistance, and the receptor binding of Tb3+ increases the accumulation of cisplatin in cisplatin-resistant cells.
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