Combined cytotoxic action of paclitaxel and ceramide against the human Tu138 head and neck squamous carcinoma cell line

Mehta, Shashi; Blackinton, Dilshad; Omar, Imran; Kouttab, Nicola; Myrick, Dorkina; Klostergaard, Jim; Wanebo, Harold J.

doi:10.1007/s002800000140

Cited by 66 publications

(45 citation statements)

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“…It is known that increased ceramide generation in response to various stress stimuli including radiation and chemotherapeutic agents, or treatment with exogenous ceramides, can result in the inhibition of growth and/or induction of cell death in various cancer cells in situ (5 -8). Indeed, the role for exogenous ceramide against HNSCC growth was shown previously, which showed that the combination of paclitaxel and C 6 -ceramide synergistically decreased the growth of the human Tu138 HNSCC cells (9). Similarly, in an independent study, the inhibition of growth in various HNSCC cell lines, but not in normal keratinocytes, by treatment with a recently developed L-threo-C 6 -pyridinium ceramide with high bioavailability and bioactivity was reported (10).…”

Section: Introductionmentioning

confidence: 62%

Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas

Senkal¹,

Ponnusamy²,

Rossi³

et al. 2007

Molecular Cancer Therapeutics

150

126

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In this study, quantitative isobologram studies showed that treatment with gemcitabine and doxorubicin, known inducers of ceramide generation, in combination, supraadditively inhibited the growth of human UM-SCC-22A cells in situ. Then, possible involvement of the human homologue of yeast longevity assurance gene 1 (LASS1)/ C 18 -ceramide in chemotherapy-induced cell death in these cells was examined. Gemcitabine/doxorubicin combination treatment resulted in the elevation of mRNA and protein levels of LASS1 and not LASS2-6, which was consistent with a 3.5-fold increase in the endogenous (dihydro)ceramide synthase activity of LASS1 for the generation of C 18 -ceramide. Importantly, the overexpression of LASS1 (both human and mouse homologues) enhanced the growth-inhibitory effects of gemcitabine/ doxorubicin with a concomitant induction of caspase-3 activation. In reciprocal experiments, partial inhibition of human LASS1 expression using small interfering RNA

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Section: Introductionmentioning

confidence: 62%

Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas

Senkal¹,

Ponnusamy²,

Rossi³

et al. 2007

Molecular Cancer Therapeutics

150

126

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“…The clinical potential for the delivery of C 6 with additional therapeutic agents in liposomal vesicles is significant. Studies have shown that ceramide may act synergistically with chemotherapeutic agents, such as paclitaxel (54) and fenretinide (55). Thus, delivery of chemotherapeutic agents in C 6 -formulated liposomes may further enhance apoptotic actions.…”

Section: Discussionmentioning

confidence: 99%

Systemic Delivery of Liposomal Short-Chain Ceramide Limits Solid Tumor Growth in Murine Models of Breast Adenocarcinoma

Stöver

Sharma

Robertson

et al. 2005

Clinical Cancer Research

169

173

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In vitro tumor cell culture models have illuminated the potential therapeutic utility of elevating the intracellular concentration of the antimitogenic and proapoptotic sphingolipid, ceramide. However, although cell-permeable, short-chain ceramide is an effective apoptotic agent in vitro, its use as an in vivo, systemically delivered therapeutic is limited by its inherent lipid hydrophobicity and physicochemical properties. Here, we report that the systemic i.v. delivery of C 6 -ceramide (C 6 ) in a pegylated liposomal formulation significantly limited the growth of solid tumors in a syngeneic BALB/c mouse tumor model of breast adenocarcinoma. Over a 3-week treatment period, a well-tolerated dose of 36 mg/kg liposomal-C 6 elicited a >6-fold reduction in tumor size compared with empty ghost liposomes. Histologic analyses of solid tumors from liposomal-C 6 -treated mice showed a marked increase in the presence of apoptotic cells, with a coincident decrease in cellular proliferation and in the development of a microvessel network. Liposomal-C 6 accumulated within caveolae and mitochondria, suggesting putative mechanisms by which ceramide induces selective cancer cell cytotoxicity. A pharmacokinetic analysis of systemic liposomal-C 6 delivery showed that the pegylated liposomal formulation follows first-order kinetics in the blood and achieves a steady-state concentration in tumor tissue. Confirming the therapeutic utility of i.v. liposomal-C 6 administration, we also shown diminution of solid tumor growth in a human xenograft model of breast cancer. Together, these results indicate that bioactive ceramide analogues can be incorporated into pegylated liposomal vehicles for improved solubility, drug delivery, and antineoplastic efficacy.Sphingolipids not only serve a structural role in membranes but also are substrates for the generation of bioactive second messengers that influence mitogenesis and apoptosis. Metabolism of sphingomyelin, the major sphingolipid in membranes, forms ceramide, a potent lipid-derived second messenger that modulates the induction of cell differentiation, cell cycle arrest, and/or apoptosis (1 -4). In addition, chemotherapeutic agents (5 -7) and ionizing radiation (8, 9) are two of the multiple cellular stressors (10 -16) that lead to the accumulation of ceramide within membranes. We and others have shown that ceramide-mediated signaling cascades induce apoptosis in part via the inhibition of Akt prosurvival pathways, mitochondrial dysfunction, and the stimulation of caspase activity, which ultimately leads to DNA fragmentation and cell death (17 -21).Although short-chain, cell-permeable ceramides, such as C 6 -ceramide (C 6 ), have been shown to be antiproliferative and proapoptotic in numerous cancer cell types in vitro (22, 23), there are obstacles to the delivery of ceramide for systemic applications, such as cancer chemotherapy. Despite being more efficacious than physiologic long-chain ceramides (C 18 -C 24 -ceramide), the effectiveness of cell-permeable ceramide analogues re...

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“…The effects of Paclitaxel are linked to the de novo synthesis of ceramide in MDA-MB-468 and MCF-7 breast cancer cells. Furthermore, Paclitaxel-dependent cytotoxicity is abrogated by blocking ceramide production with L-cycloserine, an inhibitor of ceramide synthesis (Mc Closkey et al, 1996;Mehta et al, 2000). Tamoxifen, a triphenylethylene antiestrogen, blocks the conversion of ceramide to glucosylceramide, thereby promoting an increase in cellular ceramide concentration (Cabot et al, 1996;Lavie et al, 1997).…”

Section: Ceramide and Cancermentioning

confidence: 99%

Recent advances in the immunobiology of ceramide

Pandey

Murphy

Agrawal

2007

Experimental and Molecular Pathology

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Ceramide, a sphingosine-based lipid molecule, has emerged as a key regulator of a wide spectrum of biological processes such as cellular differentiation, proliferation, apoptosis and senescence. Sphingomyelinase-dependent hydrolysis of sphingomyelin, and de novo synthesis involving the coordinated action of serinepalmitoyl transferase and ceramide synthase, are the two major pathways involved in ceramide synthesis. Clustering of plasma membrane rafts into ceramide enriched platforms serves as an important transmembrane signaling mechanism for cell surface receptors. Ceramides have been implicated in apoptosis, stress-signaling cascades as well as ion channels. There is accumulating evidence that targeted manipulation of ceramide metabolism pathway has immense therapeutic potential and may eventually prove to be a boon in the design of novel strategies and development of innovative treatments for diverse conditions including cardiovascular diseases, cancer and Alzheimer's disease. As yet uncharacterized natural ceramide analogs and novel inhibitors of ceramide metabolism might prove to be potent drugs. In this review, we discuss significant advances that continue to provide intriguing insights into the complex cellular and molecular mechanisms underlying ceramide-mediated signaling cascades.

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Combined cytotoxic action of paclitaxel and ceramide against the human Tu138 head and neck squamous carcinoma cell line

Abstract: Our results suggest that paclitaxel/ceramide combination therapy may be an attractive alternative to conventional methods of chemotherapy for head and neck cancer, and should be further explored.

Cited by 66 publications

References 0 publications

Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas

Role of human longevity assurance gene 1 and C18-ceramide in chemotherapy-induced cell death in human head and neck squamous cell carcinomas

Systemic Delivery of Liposomal Short-Chain Ceramide Limits Solid Tumor Growth in Murine Models of Breast Adenocarcinoma

Recent advances in the immunobiology of ceramide

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