Sphingomyelin Potentiates Chemotherapy of Human Cancer Xenografts

Modrak, David E.; Lew, Walter; Goldenberg, David M.; Blumenthal, Rosalyn D.

doi:10.1006/bbrc.2000.2178

Cited by 28 publications

(12 citation statements)

References 24 publications

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“…SM seems to interact in a synergistic manner with agents that induce apoptosis, thereby enhancing their antitumor effects. This result has been observed in several tumor types, including pancreatic, colorectal (18,19), breast (46), and lymphoma (46), and appears to be effective with several chemotherapeutic agents, as well as with radiation (18 -20, 46). Because SM is nontoxic, the use of SM to maximize the apoptotic potential of tumoricidal agents could have broad applicability in the development of more effective treatment procedures.…”

Section: Discussionmentioning

confidence: 77%

“…We have tested this approach with colonic tumor cells and found that four of seven cell lines had greater sensitivity to both 5-FU and Adriamycin in the presence of exogenous SM (19). Three of these cell lines grown as xenografts in athymic nude mice showed greater sensitivity to 5-FU coadministered with SM, as compared with 5-FU given by itself (18).…”

Section: Discussionmentioning

confidence: 99%

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Synergistic Interaction between Sphingomyelin and Gemcitabine Potentiates Ceramide-Mediated Apoptosis in Pancreatic Cancer

et al. 2004

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We have examined the mechanism by which sphingomyelin (SM) enhances chemotherapy in human pancreatic cancer cells, focusing on the correlation between ceramide metabolism and apoptosis. Dose response curves for gemcitabine in the absence or presence of 0.2 mg/mL SM provided IC 50 values of 78.3 ؎ 13.7 and 13.0 ؎ 3.0 nmol/L, respectively. The cytotoxic effect of the combined treatment was synergistic (combination index ‫؍‬ 0.36). Using annexin-V staining, the percentage of apoptotic cells was 3.6 ؎ 2.6% for the untreated cells, 6.5 ؎ 3.8% for the 0.2 mg/mL SM-treated cells, and 19.9 ؎ 12.9% for the 100 nmol/L gemcitabinetreated cells, but increased significantly to 42.1 ؎ 12.7% with the combined treatment (P < 0.001, compared with gemcitabine-treated group). The percentage of cells losing mitochondrial membrane potential followed a similar trend. The ceramide content of untreated and gemcitabinetreated cells was not significantly different (0.46 ؎ 0.29 and 0.59 ؎ 0.34 pmol ceramide/nmole PO 4 ). However, when 0.2 mg/mL SM was added, ceramide levels were 1.09 ؎ 0.42 and 1.58 ؎ 0.55 pmol ceramide/nmol PO 4 , for the SM alone and SM with gemcitabine-treated cells, respectively (P ‫؍‬ 0.038). Acidic SMase was activated by exposure to gemcitabine but not SM, whereas the activities of neutral SMase and glycosylceramide synthase did not change with either gemcitabine or SM. The data are consistent with gemcitabine-induced activation of acidic SMase and indicate that the addition of SM can yield increased production of ceramide, mitochondrial depolarization, apoptosis, and cell death. Because SM by itself is relatively nontoxic, addition of this lipid to agents that induce apoptosis may prove useful to enhance apoptosis and increase cytotoxicity in cancer cells.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Synergistic Interaction between Sphingomyelin and Gemcitabine Potentiates Ceramide-Mediated Apoptosis in Pancreatic Cancer

et al. 2004

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“…To overcome this, we administered small (<100 nm) sphingomyelin micelles to cells in culture and tumorbearing mice. We have shown that colonic, pancreatic, melanoma, and lymphoma cell lines in culture respond to nontoxic levels of exogenous sphingomyelin with increased chemosensitivity, and that this interaction was synergistic (65,66). 1 An examination of the sphingomyelin effect in Panc1 pancreatic cells revealed that gemcitabine alone did not cause a significant increase in cellular ceramide levels, mitochondrial depolarization, or apoptosis but did activate aSMase.…”

Section: Sphingolipid Metabolism As a Target For Cancer Therapymentioning

confidence: 99%

Sphingolipid targets in cancer therapy

Modrak

Gold

Goldenberg

2006

Molecular Cancer Therapeutics

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Considerable progress has been made recently in our understanding of the role of ceramide in the induction of apoptotic cell death. Ceramide is produced by cancer cells in response to exposure to radiation and most chemotherapeutics and is an intracellular second messenger that activates enzymes, leading to apoptosis. Because of its central role in apoptosis, pharmacologic manipulation of intracellular ceramide levels should result in attenuation or enhancement of drug resistance. This may be achieved through direct application of sphingolipids or by the inhibition/activation of the enzymes that either produce or use ceramide. In addition, attention should be given to the subcellular location of ceramide generation, because this has been shown to affect the biological activity of sphingolipids. This review summarizes the sphingolipid biosynthetic pathway, as it relates to the identification of important targets for drug discovery, and the development of novel agents capable of enhancing chemotherapy. [Mol Cancer Ther 2006;5(2):200 -8]

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“…56 Indeed, sphingomyelin co-administration potentiates chemotherapy of human cancer xenografts. 57 In contrast to doxorubicin, which induces apoptosis only in human epidermoid carcinoma KB-3-1 cells and not in a multidrug-resistant subclone that expresses P-glycoprotein; the ceramide breakdown product, sphingosine, induces apoptosis in both cell types.…”

Section: ± 11mentioning

confidence: 99%

Sphingosine generation, cytochrome c release, and activation of caspase-7 in doxorubicin-induced apoptosis of MCF7 breast adenocarcinoma cells

et al. 2001

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Treatment of human breast carcinoma MCF7 cells with doxorubicin, one of the most active antineoplastic agents used in clinical oncology, induces apoptosis and leads to increases in sphingosine levels. The transient generation of this sphingolipid mediator preceded cytochrome c release from the mitochondria and activation of the executioner caspase-7 in MCF7 cells which do not express caspase-3. Bclx L overexpression did not affect sphingosine generation whereas it reduced apoptosis triggered by doxorubicin and completely blocked apoptosis triggered by sphingosine. Exogenous sphingosine-induced apoptosis was also accompanied by cytochrome c release and activation of caspase-7 in a Bcl-x L -sensitive manner. Furthermore, neither doxorubicin nor sphingosine treatment affected expression of Fas ligand or induced activation of the apical caspase-8, indicating a Fas/ Fas ligand-independent mechanism. Our results suggest that a further metabolite of ceramide, sphingosine, may also be involved in mitochondria-mediated apoptotic signaling induced by doxorubicin in human breast cancer cells. Cell Death and Differentiation (2001) 8, 162 ± 171.

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Sphingomyelin Potentiates Chemotherapy of Human Cancer Xenografts

Cited by 28 publications

References 24 publications

Synergistic Interaction between Sphingomyelin and Gemcitabine Potentiates Ceramide-Mediated Apoptosis in Pancreatic Cancer

Synergistic Interaction between Sphingomyelin and Gemcitabine Potentiates Ceramide-Mediated Apoptosis in Pancreatic Cancer

Sphingolipid targets in cancer therapy

Sphingosine generation, cytochrome c release, and activation of caspase-7 in doxorubicin-induced apoptosis of MCF7 breast adenocarcinoma cells

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