Metabolism of short-chain ceramide by human cancer cells--implications for therapeutic approaches.

Academic Article

Abstract

  • Due to recent use of short-chain ceramides in preclinical studies, we characterized C6-ceramide metabolism in cancer cell lines and assessed metabolic junctures for enhancing efficacy. MDA-MB-231 breast cancer cells decreased the amount of C6-ceramide metabolized to C6-sphingomyelin (C6-SM) and increased the amount metabolized to C6-glucosylceramide (C6-GC) in response to increasing concentrations. A similar trend was seen in DU-145 (prostate cancer), PANC-1 (pancreatic cancer), and LoVo (colorectal cancer) cells. KG-1 leukemia cells favored C6-SM synthesis at low (0.6muM) and high-dose (12muM) C6-ceramide. Partnering C6-ceramide with tamoxifen, a P-glycoprotein antagonist that impedes ceramide glycosylation, was an effective regimen for enhancing cytotoxicity in cells. Experiments to assess the mechanism of cell death using KG-1 cells showed that tamoxifen inhibited synthesis of C6-GC and C6-SM from C6-ceramide by 80% and 50%, respectively, which was accompanied by enhanced apoptosis. Radiolabeling of KG-1 cells with [(3)H]palmitic acid produced a 2-fold increase in (3)H-long-chain ceramides when unlabeled C6-ceramide was added and a 9-fold increase when C6-ceramide and tamoxifen were added. The increase in (3)H-palmitate radiolabeling of long-chain ceramides was blocked by inclusion of a ceramide synthase inhibitor; however, inhibiting synthesis of long-chain ceramide did not rescue cells. These studies show that tamoxifen enhances the apoptotic effects of C6-ceramide. The proposed mechanism involves blocking short-chain ceramide anabolism to favor hydrolysis and generation of sphingosine. We propose that use of tamoxifen and other P-glycoprotein antagonists can be an effective means for enhancing cytotoxic potential of short-chain ceramides in the treatment of cancer.
  • Authors

  • Chapman, Jacqueline V
  • Gouazé-Andersson, Valérie
  • Messner, Maria C
  • Flowers, Margaret
  • Karimi, Ramin
  • Kester, Mark
  • Barth, Brian
  • Liu, Xin
  • Liu, Yong-Yu
  • Giuliano, Armando E
  • Cabot, Myles C
  • Status

    Publication Date

  • August 1, 2010
  • Published In

    Keywords

  • Cell Line, Tumor
  • Cell Survival
  • Ceramides
  • Humans
  • Neoplasms
  • Tamoxifen
  • Digital Object Identifier (doi)

    Start Page

  • 308
  • End Page

  • 315
  • Volume

  • 80
  • Issue

  • 3