Accumulation of lactosylceramide and overexpression of a PSC833-resistant P-glycoprotein in multidrug-resistant human sarcoma cells

Abstract

Abstract. The selection pressure for resistance to chemotherapy is accompanied by the enhanced expression of ABC proteins and increased cellular glycosphingolipid content. Thus, a possible connection between glycosphingolipid metabolism and ABC proteins in drug resistance has been suggested. In the present study, we established two human multidrug-resistant (MDR) cell lines derived from MESSA sarcoma cells by culturing with increasing concentrations of doxorubicin (DX5 cells) or doxorubicin together with cyclosporin A (GARF cells). Both resistant cell lines overexpressed the MDR1 gene and the wild-type P-glycoprotein at the same level. The cyclosporin derivative PSC833, a potent inhibitor of P-glycoprotein, sensitized DX5 but not GARF cells to the cytotoxic effects of daunorubicin. Moreover, PSC833 increased the nuclear accumulation of daunorubicin and the cellular accumulation of [ 3 H]vinblastine in the DX5 but not in the GARF cells. The cellular incorporation of [ 3 H]-cyclosporin A was lower in DX5 cells compared to MESSA and GARF cells, which incorporated the same level of [ 3 H]-cyclosporin A. Sphingolipid analysis showed that the lactosylceramide level was 2.5-and 5-fold higher in DX5 and GARF cells, respectively, than in MESSA cells. Whereas the pharmacological inhibition of lactosylceramide synthesis was able to reverse only partially the resistance of GARF cells to daunorubicin without significant increase in nuclear accumulation of the drug, the same treatment before the cotreatment with PSC833 and daunorubicin increased the cytotoxic effect of daunorubicin and its nuclear accumulation. These data suggest a possible relationship between lactosylceramide levels and the resistance of P-glycoprotein to modulation by MDR modulators.

The reversal of antineoplastic drug resistance in cancer cells by β-elemene

“…PSC833 alone did not produce significant adverse effects, but it increased the likelihood of toxic effects when used with antitumor drugs. For example, a significant pharmacokinetic interaction was observed when PSC833 was administered in combination with DOX and TAX [ 40 , 41 ], thus requiring a reduction in the doses of the anticancer drugs. It was subsequently shown that second-generation P-gp inhibitors significantly decreased the excretion of various drugs, thereby increasing the incidence of significant adverse effects [ 41 ].…”

Selenylation, Characterization and Cytotoxic Activity of Seleno-Astragalus Polysaccharide

“…Studies have demonstrated that selenium as essential trace element plays a key role in the field of immunity intervention and tumor prevention [5][6]. However, natural seleno-polysaccharide is scarce in plants, animals and micro-organisms.…”