Novel Agents Targeting Bioactive Sphingolipids for the Treatment of Cancer

Adan-Gokbulut, A.; Yandım, Melis Kartal; Iskender, G.; Baran, Yusuf

doi:10.2174/09298673130111

Cited by 27 publications

(20 citation statements)

References 198 publications

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“…Moreover, ROS generation after capsaicin treatment may enhance ceramide accumulation resulting from the hydrolysis of membrane sphingomyelin by the enzyme sphingomyelinase [15]. Ceramide, one of the two main sphingolipids, plays a regulatory role in cellular processes, including cell arrest, cell death, and apoptosis mediated by death inducers [22], [73]. Ceramide may facilitate apoptosis by activating pro-apoptotic genes, such as BINP3 , a tumor necrosis factor (TNF-related apoptosis-inducing ligand (TRAIL) , and death-associated protein kinase 2 (DAPK2) .…”

Section: Discussionmentioning

confidence: 99%

The Selective Target of Capsaicin on FASN Expression and De Novo Fatty Acid Synthesis Mediated through ROS Generation Triggers Apoptosis in HepG2 Cells

et al. 2014

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The inhibition of the mammalian de novo synthesis of long-chain saturated fatty acids (LCFAs) by blocking the fatty acid synthase (FASN) enzyme activity in tumor cells that overexpress FASN can promote apoptosis, without apparent cytotoxic to non-tumor cells. The present study aimed to focus on the potent inhibitory effect of capsaicin on the fatty acid synthesis pathway inducing apoptosis of capsaicin in HepG2 cells. The use of capsaicin as a source for a new FASN inhibitor will provide new insight into its possible application as a selective anti-cancer therapy. The present findings showed that capsaicin promoted apoptosis as well as cell cycle arrest in the G0/G1 phase. The onset of apoptosis was correlated with a dissipation of mitochondrial membrane potential (ΔΨm). Apoptotic induction by capsaicin was mediated by inhibition of FASN protein expression which was accompanied by decreasing its activity on the de novo fatty acid synthesis. The expression of FASN was higher in HepG2 cells than in normal hepatocytes that were resistant to undergoing apoptosis following capsaicin administration. Moreover, the inhibitory effect of capsaicin on FASN expression and activity was found to be mediated by an increase of intracellular reactive oxygen species (ROS) generation. Treatment of HepG2 cells with capsaicin failed to alter ACC and ACLY protein expression, suggesting ACC and ACLY might not be the specific targets of capsaicin to induce apoptosis. An accumulation of malonyl-CoA level following FASN inhibition represented a major cause of mitochondrial-dependent apoptotic induction instead of deprivation of fatty acid per se. Here, we also obtained similar results with C75 that exhibited apoptosis induction by reducing the levels of fatty acid without any change in the abundance of FASN expression along with increasing ROS production. Collectively, our results provide novel evidence that capsaicin exhibits a potent anti-cancer property by targeting FASN protein in HepG2 cells.

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Section: Discussionmentioning

confidence: 99%

The Selective Target of Capsaicin on FASN Expression and De Novo Fatty Acid Synthesis Mediated through ROS Generation Triggers Apoptosis in HepG2 Cells

et al. 2014

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“…Conversely, decreased ceramide levels – either through decreased production or accelerated metabolism – have been described as a mechanism of resistance to cancer therapies (16,24). To this end, a number of ceramide mimetics and inhibitors of enzymes that metabolize ceramide are currently under development as antineoplastic agents (23,25,26). …”

Section: Introductionmentioning

confidence: 99%

Ceramide Kinase Promotes Tumor Cell Survival and Mammary Tumor Recurrence

et al. 2014

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Recurrent breast cancer is typically an incurable disease and, as such, is disproportionately responsible for deaths from this disease. Recurrent breast cancers arise from the pool of disseminated tumor cells (DTCs) that survive adjuvant or neoadjuvant therapy, and patients with detectable DTCs following therapy are at substantially increased risk for recurrence. Consequently, the identification of pathways that contribute to the survival of breast cancer cells following therapy could aid in the development of more effective therapies that decrease the burden of residual disease and thereby reduce the risk of breast cancer recurrence. We now report that Ceramide Kinase (Cerk) is required for mammary tumor recurrence following HER2/neu pathway inhibition and is spontaneously up-regulated during tumor recurrence in multiple genetically engineered mouse models for breast cancer. We find that Cerk is rapidly up-regulated in tumor cells following HER2/neu down-regulation or treatment with Adriamycin and that Cerk is required for tumor cell survival following HER2/neu down-regulation. Consistent with our observations in mouse models, analysis of gene expression profiles from over 2,200 patients revealed that elevated CERK expression is associated with an increased risk of recurrence in women with breast cancer. Additionally, although CERK expression is associated with aggressive subtypes of breast cancer, including those that are ER–, HER2+, basal-like, or high grade, its association with poor clinical outcome is independent of these clinicopathological variables. Together, our findings identify a functional role for Cerk in breast cancer recurrence and suggest the clinical utility of agents targeted against this pro-survival pathway.

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“…Conversely, exogenous application of unnatural short chain ceramide analogues to cultured cells results in apoptosis [6,34]. The formation of ceramide in response to pro-apoptotic stimuli is often mediated through rapid hydrolysis of sphingomyelin (SM), resulting in the formation of ceramide-enriched membrane domains (ceramide “rafts”), which act as signaling platforms for pro-apoptotic mediators of the TNF superfamily [29,32,35].…”

Section: Signalling Roles Of Ceramide Sphingosine and S1pmentioning

confidence: 99%

“…Given the broad subject area, it is not possible to comprehensively review current pharmacology related to inhibition of specific sphingolipid metabolic enzymes in the context of cancer therapy. For comprehensive reviews on pharmacology related to inhibition of sphingosine kinases, ceramidases, sphingomyelinases, and glucosylceramide synthase, the reader is referred to recent reviews [3,4,5,6]. …”

Section: Introductionmentioning

confidence: 99%

Re-Configuration of Sphingolipid Metabolism by Oncogenic Transformation

2014

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The sphingolipids are one of the major lipid families in eukaryotes, incorporating a diverse array of structural variants that exert a powerful influence over cell fate and physiology. Increased expression of sphingosine kinase 1 (SPHK1), which catalyses the synthesis of the pro-survival, pro-angiogenic metabolite sphingosine 1-phosphate (S1P), is well established as a hallmark of multiple cancers. Metabolic alterations that reduce levels of the pro-apoptotic lipid ceramide, particularly its glucosylation by glucosylceramide synthase (GCS), have frequently been associated with cancer drug resistance. However, the simple notion that the balance between ceramide and S1P, often referred to as the sphingolipid rheostat, dictates cell survival contrasts with recent studies showing that highly potent and selective SPHK1 inhibitors do not affect cancer cell proliferation or survival, and studies demonstrating higher ceramide levels in some metastatic cancers. Recent reports have implicated other sphingolipid metabolic enzymes such as acid sphingomyelinase (ASM) more strongly in cancer pathogenesis, and highlight lysosomal sphingolipid metabolism as a possible weak point for therapeutic targeting in cancer. This review describes the evidence implicating different sphingolipid metabolic enzymes and their products in cancer pathogenesis, and suggests how newer systems-level approaches may improve our overall understanding of how oncogenic transformation reconfigures sphingolipid metabolism.

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Novel Agents Targeting Bioactive Sphingolipids for the Treatment of Cancer

Cited by 27 publications

References 198 publications

The Selective Target of Capsaicin on FASN Expression and De Novo Fatty Acid Synthesis Mediated through ROS Generation Triggers Apoptosis in HepG2 Cells

The Selective Target of Capsaicin on FASN Expression and De Novo Fatty Acid Synthesis Mediated through ROS Generation Triggers Apoptosis in HepG2 Cells

Ceramide Kinase Promotes Tumor Cell Survival and Mammary Tumor Recurrence

Re-Configuration of Sphingolipid Metabolism by Oncogenic Transformation

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