Inhibition of NADPH oxidase by glucosylceramide confers chemoresistance

Barth, Brian M.; Gustafson, Sally J.; Young, Michelle; Fox, Todd E.; Shanmugavelandy, Sriram S.; Kaiser, James; Cabot, Myles C.; Kester, Mark; Kühn, Thomas

doi:10.4161/cbt.10.11.13438

Cited by 30 publications

(35 citation statements)

References 38 publications

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“…Multidrug transporter, P-glycoprotein (P-gp), was shown to potentiate ceramide glycosylation, and addition of GCS inhibitors sensitized cells to chemotherapy [78]. Chemoresistance conferred by GluCer is mediated by the inhibition of NADPH oxidase; hence augmenting NADPH oxidase activity provides sensitivity to chemotherapy [75]. GluCer was also shown to directly upregulate MDR1 expression via cSrc and -catenin pathways producing chemoresistant cancer subtypes [79].…”

Section: Dihydrosphingosinementioning

confidence: 99%

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Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Ekiz

Baran²

2011

ACAMC

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Sphingolipids are major constituents of the cells with emerging roles in the regulation of cellular processes. Deregulation of sphingolipid metabolism is reflected as various pathophysiological conditions including metabolic disorders and several forms of cancer. Ceramides, ceramide-1-phosphate (C1P), glucosyl ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P) are among the bioactive sphingolipid species that have important roles in the regulation of cell death, survival and chemotherapeutic resistance. Some of those species are known to accumulate in the cells upon chemotherapy while some others are known to exhibit an opposite pattern. Even though the length of fatty acid chain has a deterministic effect, in general, upregulation of ceramides and sphingosine is known to induce apoptosis. However, S1P, C1P and GluCer are proliferative for cells and they are involved in the development of chemoresistance. Therefore, sphingolipid metabolism appears as a good target for the development of novel therapeutics or supportive interventions to increase the effectiveness of the chemotherapeutic drugs currently in hand. Some approaches involve manipulation of the synthesis pathways yielding the increased production of apoptotic sphingolipids while the proliferative ones are suppressed. Some others are trying to take advantage of cytotoxic sphingolipids like short chain ceramide analogs by directly delivering them to the malignant cells as a distinct chemotherapeutic intervention. Numerous studies in the literature show the feasibility of those approaches especially in acute and chronic leukemias. This review compiles the current knowledge about sphingolipids and their roles in chemotherapeutic response with the particular attention to leukemias.

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Section: Dihydrosphingosinementioning

confidence: 99%

“…GluCer is another type of proliferative sphingolipids and it has roles in the development of chemotherapeutic resistance [75][76][77]. Multidrug transporter, P-glycoprotein (P-gp), was shown to potentiate ceramide glycosylation, and addition of GCS inhibitors sensitized cells to chemotherapy [78].…”

Section: Dihydrosphingosinementioning

confidence: 99%

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Ekiz

Baran²

2011

ACAMC

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“…We also recently reported the in vitro efficacy of a nanoliposome incorporating both C 6 -ceramide and the glucosylceramide synthase inhibitor PDMP in the treatment of neuroblastoma. 31 In our current study, we employed this same combination-nanoliposome, Lip-C 6 /PDMP, in the treatment of drug-resistant pancreatic cancer. With PDMP preventing the neutralization of ceramide to glucosylceramide (cerebroside), Lip-C 6 was able to exert a robust toxicity in vitro toward PANC-1 cells.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

“…We previously had showed that the Lip-C 6 /PDMP formulation elicited a more robust therapeutic response in neuroblastoma cells. 31 Of note, the combination of gemcitabine with Lip-C 6 /PDMP induced a dramatic increase in apoptosis of PANC-1 cells beyond that seen with Lip-C 6 / PDMP alone or the combination of Lip-C 6 and gemcitabine (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

Combinatorial therapies improve the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer

Jiang

DiVittore

Kaiser

et al. 2011

Cancer Biology & Therapy

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“…Accordingly, nanocarriers containing ceramide in its composition have been extensively exploited (Hawkins et al 2008 ). Several different ceramide delivery systems have been developed, including polymer-based (van Vlerken et al 2007 ;Devalapally et al 2007Devalapally et al , 2008Barth et al 2010b ) and lipid-based nanocarriers (Barth et al 2010a ;van Lummel et al 2011 ). Focus has been given to the development of combinatorial strategies based on the use of ceramide nanosystems as a platform to deliver either chemotherapeutic agents (Tran et al 2008 ;Jiang et al 2011 ) or modulators of the SL metabolism (Barth et al 2010b ;Jiang et al 2011 ;Dickson et al 2011 ).…”

Section: Nanomedicinal Oncological Products Intended For Clinical Pramentioning

confidence: 99%