Cytotoxic effects of sphingolipids as single or multi-modality agents on human melanoma and soft tissue sarcoma in vitro

Auzenne, Edmond J.; LeRoux, Michele; Hu, Mei; Pollock, Raphael E.; Feig, Barry W.; Klostergaard, Jim

doi:10.1097/00008390-199806000-00005

Cited by 23 publications

(10 citation statements)

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“…Some ceramide metabolites, such as sphingosine, which might accumulate upon inhibition of GCS and 1-O-ACS (Figure 1), can be toxic to cells and may also synergistically augment ceramide-mediated cytotoxicity. [67][68][69][70][71] Alternatively, PPMP may have synergistic cytotoxicity in MOLT-4 cells that is unrelated to cytotoxic sphingolipids. However, taken together, these data suggest a correlation of increased ceramide levels with the synergistic cytotoxic effects of PPMP and 4-HPR in the ALL cell lines tested.…”

Section: Discussionmentioning

confidence: 99%

N-(4-hydroxyphenyl)retinamide increases ceramide and is cytotoxic to acute lymphoblastic leukemia cell lines, but not to non-malignant lymphocytes

O'Donnell

Reynolds

et al. 2002

Leukemia

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Section: Discussionmentioning

confidence: 99%

N-(4-hydroxyphenyl)retinamide increases ceramide and is cytotoxic to acute lymphoblastic leukemia cell lines, but not to non-malignant lymphocytes

O'Donnell

Reynolds

et al. 2002

Leukemia

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“…This feature of sphingosine is documented in several cell types including both malignant and healthy cells [100]. Leukemic cells including multidrug resistant subtypes [101][102][103], various forms of carcinoma [104], and soft tissue sarcoma cells [105] were shown to undergo apoptosis upon exposure to sphingosine or in response to increased intracellular levels of sphingosine. Apoptotic induction mechanism of sphingosine was shown to be dependent on cytochrome c release from mitochondria in neurons and astrocytes [106].…”

Section: B) Sphingosine Derivatives: Sphingosine and S1pmentioning

confidence: 99%

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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“…Previous studies have shown very interesting relationship between ceramides and apoptosis in tumor cells and the processes that would enhance intracellular ceramide accumulation would provide favorable proapoptotic outcomes in cancer chemotherapy (Bose et al, 1995;Kolesnick and Kronke, 1998). Cell-permeable ceramides (C 2 or C 6 ceramide N-hexanoyl-D-sphingosine) have shown activity against a variety of cancer cell lines (Auzenne et al, 1998;Mehta et al, 2000) (reviewed in (Kolesnick and Kronke, 1998;Radin, 2003)). Previous studies also indicate the potential effects of cell-permeable ceramides (C6 ceramide) to enhance the pro-cell death of known chemotherapeutic agents such as Taxol (Mehta et al, 2000;Qiu et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Exogenous cell-permeable C6 ceramide sensitizes multiple cancer cell lines to Doxorubicin-induced apoptosis by promoting AMPK activation and mTORC1 inhibition

Yang

et al. 2010

Oncogene

133

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New chemotherapy-enhancing strategies are needed for better cancer therapy. Previous studies suggest that exogenous cell-permeable C6 ceramide may be a useful adjunct to the anti-tumor effects of chemotherapeutic agents (such as Taxol) against multiple cancers. Here we demonstrate that exogenous cell-permeable C6 ceramide largely sensitizes multiple progressive cancer cell lines to Doxorubicin-induced cell death and apoptosis. We found for the first time that Doxorubicin induces AMP-activated protein kinase (AMPK) activation in a reactive oxygen species-dependent manner. Activation of AMPK contributes to Doxorubicin-induced cancer cell death and apoptosis. Inhibition of AMPK by small interfering RNA knockdown or a pharmacological inhibitor reduces Doxorubicin-induced cancer cell apoptosis, whereas AMPK activator AICAR enhances it. Importantly, we found that C6 ceramide largely enhances Doxorubicin-induced activation of AMPK, which leads to mTOR complex 1 inhibition and chemo-sensitization. Our data suggest that the combination of C6 ceramide with traditional chemotherapy drugs such as Doxorubicin may have the potential to be used as a new therapeutic intervention against multiple cancers.

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Cytotoxic effects of sphingolipids as single or multi-modality agents on human melanoma and soft tissue sarcoma in vitro

Cited by 23 publications

References 0 publications

N-(4-hydroxyphenyl)retinamide increases ceramide and is cytotoxic to acute lymphoblastic leukemia cell lines, but not to non-malignant lymphocytes

N-(4-hydroxyphenyl)retinamide increases ceramide and is cytotoxic to acute lymphoblastic leukemia cell lines, but not to non-malignant lymphocytes

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Exogenous cell-permeable C6 ceramide sensitizes multiple cancer cell lines to Doxorubicin-induced apoptosis by promoting AMPK activation and mTORC1 inhibition

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