Novel d-erythro N-octanoyl sphingosine analogs as chemo- and endocrine-resistant breast cancer therapeutics

Antoon, James W.; Liu, Jiawang; Ponnapakkam, Adharsh; Gestaut, M.M.; Foroozesh, Maryam; Beckman, Barbara S.

doi:10.1007/s00280-009-1233-0

Cited by 24 publications

(23 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(2), elevation of the apoptotic sphingolipids was found to be coincident with the chemotherapy, suggesting that these sphingolipids may be playing effector roles in those mechanisms. In agreement with this point of view, there are numerous other reports in which exogenous sphingolipids (short chain ceramides in particular) were provided to the cells and cancer eradication was obtained as well [140][141][142]. In fact, providing synthetic sphingolipids might have better outcomes for therapeutic purposes since availability and rapid metabolism of natural sphingolipids limit their utilization.…”

Section: Sphingolipids In the Perspective Of Chemo-therapeutic Responsesupporting

confidence: 49%

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Ekiz

Baran²

2011

ACAMC

View full text Add to dashboard Cite

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.

show abstract

Section: Sphingolipids In the Perspective Of Chemo-therapeutic Responsesupporting

confidence: 49%

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Ekiz

Baran²

2011

ACAMC

View full text Add to dashboard Cite

show abstract

“…However, endogenous ceramide is metabolized into sphingosine, which is then rapidly phosphorylated into S1P, a prosurvival lipid. Therefore, new compounds are modified at the amide group in order to prevent ceramide from being degraded into sphingosine, and as a result, these analogs display increased efficacy compared with previously published ceramide analogs [78]. Thus, these results show that ceramide analogs may have therapeutic potential in treating chemo-and endocrine-resistant breast cancer.…”

Section: Breast Cancermentioning

confidence: 78%

“…Notably, elevated levels of C 16:0 -Cer were associated with a positive lymph node status, indicating a metastatic potential for this ceramide. In another approach, several studies suggested that ceramide analogs have therapeutic potential in treating chemo-and endocrine-resistant breast cancer [76][77][78]. The results indicated that specific alterations in the backbone of D-erythro N-octanoyl sphingosine analogs, also known as C8-ceramide, increased the potency of C8-ceramide and increased its effectiveness as a breast cancer therapeutic [76,77].…”

Section: Breast Cancermentioning

confidence: 96%

Sphingolipids in cancer

Furuya

Shimizu

Kawamori

2011

Cancer Metastasis Rev

113

View full text Add to dashboard Cite

The bioactive sphingolipids including, ceramide, sphingosine, and sphingosine-1-phosphate (S1P) have important roles in several types of signaling and regulation of many cellular processes including cell proliferation, apoptosis, senescence, angiogenesis, and transformation. Recent accumulating evidence suggests that ceramide- and S1P-mediated pathways have been implicated in cancer development, progression, and chemotherapy. Ceramide mediates numerous cell-stress responses, such as induction of apoptosis and cell senescence, whereas S1P plays pivotal roles in cell survival, migration, and inflammation. These sphingolipids with opposing roles can be interconverted within cells, suggesting that the balance between them is related to cell fate. Importantly, these sphingolipids are metabolically related through actions of enzymes including ceramidases, ceramide synthases, sphingosine kinases, and S1P phosphatases thereby forming a network of metabolically interrelated bioactive lipid mediators whose importance in normal cellular function and diseases is gaining appreciation. In this review, we summarize involvement of sphingolipids and their related enzymes in pathogenesis and therapy of cancer and discuss future directions of sphingolipid field in cancer research.

show abstract

“…ER-negative MCF-7TN-R and MDA-MB-231 cells were cultured as previously described (22,23). Briefly, the MDA-MB-231 cell line was obtained from the American Type Culture Collection (ATCC, Manassas, VA).…”

Section: Methodsmentioning

confidence: 99%

Dual inhibition of sphingosine kinase isoforms ablates TNF-induced drug resistance

et al. 2012

View full text Add to dashboard Cite

Recent research has demonstrated that aberrant sphingolipid signaling is an important mechanism of chemo-resistance in solid tumors. Sphingosine kinase (Sphk), the primary enzyme metabolizing the sphingolipid ceramide into sphingosine-1-phosphate (S1P), is a primary mediator of breast cancer promotion, survival and chemoresistance. However, to date the mechanism of Sphk-mediated drug resistance is poorly understood. Using the dual sphingosine kinase isozyme inhibitor, SKI-II (4-[4-(4-chloro-phenyl)-thiazol-2-ylamino]-phenol), we explored the effects of sphingosine kinase inhibition on multi-drug-resistant breast cancer cells. We demonstrate that SKI-II alters endogenous sphingolipid signaling and decreases cancer proliferation, survival and viability. Furthermore, pharmacological inhibition of Sphk1/2 induced intrinsic apoptosis in these cells through modulation of the NF-κB pathway. SKI-II decreases NF-κB transcriptional activity through altered phosphorylation of the p65 subunit. Taken together, these results suggest that Sphk may be a promising therapeutic target in chemoresistant cancers.

show abstract

Novel d-erythro N-octanoyl sphingosine analogs as chemo- and endocrine-resistant breast cancer therapeutics

Abstract: With resistance to current breast cancer chemotherapies on the rise, the development of novel therapeutic targets is of growing importance. Our results show that lipid analogs have therapeutic potential in treating chemo- and endocrine-resistant breast cancer.

Cited by 24 publications

References 10 publications

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Sphingolipids in cancer

Dual inhibition of sphingosine kinase isoforms ablates TNF-induced drug resistance

Contact Info

Product

Resources

About