Modification of intracellular uptake and killing effect of Adriamycin (ADR) by cepharanthine on ADR resistant Ehrlich ascites tumor cells

Adriamycin (ADR) is a well known anticancer agent which is frequently used alone or combination with other anticancer agents. An ADR-resistant cell line derived from Ehrlich ascites tumor cells (EATC) was established in our laboratory. In this report, differences between wild EATC and ADR resistant EATC were studied. The intracellular ADR uptake increased at a temperature (41.0°C) that had a little effect on the viability of wild EATC. The intracellular ADR uptake of ADR-resistant EATC also increased at elevated temperature (41.0°C). However, ADR resistant EATC had an enhanced acquired capacity that increased the efflux of intracellular ADR. Cepharanthine (CP), 1mcg/ml, inhibited the efflux of intracellular ADR and maintained the retention of ADR at high levels in cells from both cell lines, so the killing effects were enhanced with a combination ADR and CP. From these results, the mechanisms of resistance to ADR may be discussed. The killing effects of ADR depend on intracellular ADR uptake, retention and maintenance. Hyperthermic treatment accelerates the influx of ADR. In addition, CP suppresses the efflux of intracellular ADR, and increased markedly the cytotoxic effect of ADR on ADR resistant EATC. The combination of ADR, CP and hyperthermia may be effective and useful therapy to overcome ADR-resistant cancer cells.