title: MRP- and BCL-2-mediated drug resistance in human SCLC: effects of apoptotic sphingolipids in vitro.
abstract: Multidrug-resistance-associated protein (MRP) and BCL-2 contribute to drug resistance expressed in SCLC. To establish whether MRP-mediated drug resistance affects sphingolipid (SL)-induced apoptosis in SCLC, we first examined the human SCLC cell line, UMCC-1, and its MRP over-expressing, drug-resistant subline, UMCC-1/VP. Despite significantly decreased sensitivity to doxorubicin (Dox) and to the etoposide, VP-16, the drug-selected line was essentially equally as sensitive to treatment with exogenous ceramide (Cer), sphingosine (Sp) or dimethyl-sphingosine (DMSP) as the parental line. Next, we observed that high BCL-2-expressing human H69 SCLC cells, that were approximately 160-fold more sensitive to Dox than their combined BCL-2 and MRP-over-expressing (H69AR) counterparts, were only approximately 5-fold more resistant to DMSP. Time-lapse fluorescence microscopy of either UMCC cell line treated with DMSP-Coumarin revealed comparable extents and kinetics of SL uptake, further ruling out MRP-mediated effects on drug uptake. DMSP potentiated the cytotoxic activity of VP-16 and Taxol, but not Dox, in drug-resistant UMCC-1/VP cells. However, this sensitization did not appear to involve DMSP-mediated effects on the function of MRP in drug export; nor did DMSP strongly shift the balance of pro-apoptotic Sps and anti-apoptotic Sp-1-Ps in these cells. We conclude that SL-induced apoptosis markedly overcomes or bypasses MRP-mediated drug resistance relevant to SCLC and may suggest a novel therapeutic approach to chemotherapy for these tumors.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: M
authors.initials: M
authors.lastname: Khodadadian
authors.forename: M E
authors.initials: ME
authors.lastname: Leroux
authors.forename: E
authors.initials: E
authors.lastname: Auzenne
authors.forename: S C
authors.initials: SC
authors.lastname: Ghosh
authors.forename: D
authors.initials: D
authors.lastname: Farquhar
authors.forename: R
authors.initials: R
authors.lastname: Evans
authors.forename: W
authors.initials: W
authors.lastname: Spohn
authors.forename: Y
authors.initials: Y
authors.lastname: Zou
authors.forename: J
authors.initials: J
authors.lastname: Klostergaard
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002518:Ceramides / Q000633:toxicity; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000378:metabolism*; D013107:Sphingolipids / Q000633:toxicity*; D013110:Sphingosine / Q000633:toxicity
chemical_list: D002518:Ceramides; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013107:Sphingolipids; D013110:Sphingosine