A role for ceramide in driving cancer cell resistance to doxorubicin

Liu, Yong‐Yu; Yu, Jing; Yin, Dongmei; Patwardhan, Gauri A.; Gupta, Vineet; Hirabayashi, Yoshio; Holleran, Walter M.; Giuliano, Armando E.; Jazwinski, S. Michal; Gouazé-Andersson, Valérie; Consoli, David P.; Cabot, Myles C.

doi:10.1096/fj.07-092981

Cited by 139 publications

(164 citation statements)

References 60 publications

(62 reference statements)

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“…Altered composition of GSL and an increase in GL1 levels are characteristic of multidrug-resistant cancer cells such as KBV-1 and NCI/ADR-RES cells (5,33,34). Quantitative analysis of GCS and GM3S (GM3 synthase) mRNA levels by real-time PCR and measurement of GL1 levels by mass spectrometry confirmed KBV-1 cells exhibit increased expression of GCS and GM3S mRNAs and higher GL1 levels when compared to parental KB3-1.…”

Section: Exposure Of Drug-resistant Cancer Cells To Genz-123346 Lowersmentioning

confidence: 94%

The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function

Madden¹

2011

Int J Oncol

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Abstract. Glucosylceramide synthase (GCS) is a key enzyme engaged in the biosynthesis of glycosphingolipids and in regulating ceramide metabolism. Studies exploring alterations in GCS activity suggest that the glycolase may have a role in chemosensitizing tumor cells to various cancer drugs. The chemosensitizing effect of inhibitors of GCS (e.g. PDMP and selected analogues) has been observed with a variety of tumor cells leading to the proposal that the sensitizing activity of GCS inhibitors is primarily through increases in intracellular ceramide leading to induction of apoptosis. The current study examined the chemosensitizing activity of the novel GCS inhibitor, Genz-123346 in cell culture. Exposure of cells to Genz-123346 and to other GCS inhibitors at nontoxic concentrations can enhance the killing of tumor cells by cytotoxic anti-cancer agents. This activity was unrelated to lowering intracellular glycosphingolipid levels. Genz-123346 and a few other GCS inhibitors are substrates for multi-drug reisistance efflux pumps such as P-gp (ABCB1, gP-170). In cell lines selected to over-express P-gp or which endogenously express P-gp, chemosensitization by Genz-123346 was primarily due to the effects on P-gp function. RNA interference studies using siRNA or shRNA confirmed that lowering GCS expression in tumor cells did not affect their responsiveness to commonly used cytotoxic drugs.

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Section: Exposure Of Drug-resistant Cancer Cells To Genz-123346 Lowersmentioning

confidence: 94%

The chemosensitizing activity of inhibitors of glucosylceramide synthase is mediated primarily through modulation of P-gp function

Madden¹

2011

Int J Oncol

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“…In adriamycin-resistant K562/AO2 cells, increased levels of Bcl-2 have been reported rather than that in sensitive K562 cells. Following the inhibition of GCS by PPMP or downregulation by siRNA transfection, decreased Bcl-2 gene expression levels have been reported [63]. Likewise, b-catenin-and cSrc signaling are responsible for the development of drug resistance due to increased levels of GCS in colon, cervical, breast, and ovary cancer cells that resist doxorubicin.…”

Section: Glucosylceramide Synthase In Drug Resistancementioning

confidence: 99%

Therapeutic potential of targeting ceramide/glucosylceramide pathway in cancer

Yandım

Apohan

Baran

2012

Cancer Chemother Pharmacol

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Sphingolipids including ceramides and its derivatives such as ceramide-1-phosphate, glucosylceramide (GlcCer), and sphingosine-1-phosphate are essential structural components of cell membranes. They now recognized as novel bioeffector molecules which control various aspects of cell growth, proliferation, apoptosis, and drug resistance. Ceramide, the central molecule of sphingolipid metabolism, generally mediates anti-proliferative responses such as inhibition of cell growth, induction of apoptosis, and/or modulation of senescence. There are two major classes of sphingolipids. One of them is glycosphingolipids which are synthesized from the hydrophobic molecule, ceramide. GlcCer, generated by glucosylceramide synthase (GCS) that transfers the glucose from UDPglucose to ceramide, is an important glycosphingolipid metabolic intermediate. GCS regulates the balance between apoptotic ceramide and antiapoptotic GlcCer. Downregulation or inhibition of GCS results in increased apoptosis and decreased drug resistance. The mechanism underlying the drug resistance which develops with increased glucosylceramide expression is associated with P-glycoprotein. In various types of cancers, overexpression of GCS has been observed which renders GCS a good target for the treatment of cancer. This review summarizes our current knowledge on the structure and functions of glucosylceramide synthase and glucosylceramide and on the roles of glucosylceramide synthase in cancer therapy and drug resistance.

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“…pro-apoptotic sphingolipid metabolite, ceramide, is endogenously generated by chemo-or radio-therapies, [5][6][7] and exogenous short-chain ceramide has been shown to augment chemotherapy-induced cytotoxicity. [7][8][9] One of the exciting aspects of using ceramide as a chemotherapeutic is the preferential selectivity for inducing apoptosis in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

“…[7][8][9] One of the exciting aspects of using ceramide as a chemotherapeutic is the preferential selectivity for inducing apoptosis in cancer cells. For example, we previously demonstrated that nanoliposomal C 6 -ceramide induces cell growth arrest and apoptosis in breast cancer cells and melanomas, but not non-transformed mammary gland epithelial cells or melanocytes.…”

Section: Introductionmentioning

confidence: 99%