MRP- and BCL-2-mediated drug resistance in human SCLC: Effects of apoptotic sphingolipids in vitro

M. Khodadadian, M. E. Leroux, E. Auzenne, S. C. Ghosh, D. Farquhar, R. Evans, W. Spohn, Y. Zou, J. Klostergaard

Research output: Contribution to journalArticle

11 Scopus citations

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 ∼160-fold more sensitive to Dox than their combined BCL-2 and MRP-over-expressing (H69AR) counterparts, were only ∼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.

Original languageEnglish (US)
Pages (from-to)48-57
Number of pages10
JournalLung Cancer
Volume66
Issue number1
DOIs
StatePublished - Oct 1 2009

Keywords

  • Apoptosis
  • Doxorubicin
  • Drug resistance
  • MRP
  • SCLC
  • Sphingolipids
  • Taxol
  • VP-16

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

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    Khodadadian, M., Leroux, M. E., Auzenne, E., Ghosh, S. C., Farquhar, D., Evans, R., Spohn, W., Zou, Y., & Klostergaard, J. (2009). MRP- and BCL-2-mediated drug resistance in human SCLC: Effects of apoptotic sphingolipids in vitro. Lung Cancer, 66(1), 48-57. https://doi.org/10.1016/j.lungcan.2009.01.006