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  • Title: Inhibitors of intracellular pH regulation induce cisplatin resistance in EMT6 mouse mammary tumor cells.
    Author: Laurencot CM, Andrews PA, Kennedy KA.
    Journal: Oncol Res; 1995; 7(7-8):363-9. PubMed ID: 8747599.
    Abstract:
    Previous results from this laboratory indicated that EMT6 cells treated with inhibitors of the intracellular pH (pHi) regulatory mechanisms were resistant to cisplatin (Laurencot, C.M.; Kennedy, K.A. The effect of low pH on the cytotoxicity of cisplatin in EMT6 mouse mammary tumor cells. Oncol. Res. 7:371-380; 1995.) This inhibitor-induced cisplatin resistance was independent of pH. The purpose of the research presented here was to characterize further cisplatin resistance observed in cells cultured with the Na+/H+ antiport inhibitor 5-(N,N hexamethylene) amiloride (NHMA) and the HCO3-/Cl- exchanger inhibitor 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS). Using [195mPt]-DDP, the accumulation of cisplatin into EMT6 mouse mammary tumor cells treated with NHMA and SITS was not changed. Total DNA cross-link formation and DNA-interstrand cross-link formation, however, decreased in NHMA- and SITS-treated cells. Since cisplatin accumulation was unchanged in NHMA- and SITS-treated cells but the amount of DNA cross-links decreased, the intracellular activation of cisplatin appeared to be altered in the cisplatin-resistant cells. Because SITS interferes with chloride transport and chloride has been proposed to be involved in cisplatin activation, cisplatin toxicity in EMT6 cells was evaluated in chloride-deficient medium. EMT6 cells cultured in chloride-deficient medium were less sensitive to cisplatin than cells cultured in chloride-containing medium, but this sensitivity was not altered by NHMA and SITS. Furthermore, the resistance to cisplatin in cells treated with NHMA and SITS was similar in chloride-containing and chloride-deficient medium. These data suggest that the concentration of other ions, in addition to chloride, may be important for cisplatin toxicity.
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