Overcoming resistance to γ-rays in squamous carcinoma cells by poly-drug elevation of ceramide levels

Alphonse, Gersende; Bionda, Clara; Aloy, Marie-Thérèse; Ardail, Dominique; Rousson, Robert; Rodriguez-Lafrasse, Claire

doi:10.1038/sj.onc.1207357

Cited by 62 publications

(45 citation statements)

References 66 publications

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“…Ceramide has been shown to decrease endothelial cell growth and induce apoptosis in vitro (23, 48 -50). In addition, elevating endogenous ceramide through radiotherapy induces endothelial cell apoptosis in vivo (49,51,52). In addition, ceramide signaling is required for fenretinide-induced endothelial cell apoptosis and represents a molecular mechanism for the antiangiogenic effects of fenretinide (53).…”

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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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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“…They are in good agreement with previously published observations on the role of ceramide as radio-sensitizer in human glioma cells 34 and in radio-resistant squamous carcinoma. 35 TNFα induces S-SMase activity in vitro. SFGRT is accompanied with an elevation in circulating TNFα levels, that correlates with the clinical outcome of the treatment.…”

Section: Development Of a New Methods To Measure S-smase Activity In Hmentioning

confidence: 99%

Elevated sphingomyelinase activity and ceramide concentration in serum of patients undergoing high dose spatially fractionated radiation treatment: Implications for endothelial apoptosis

Sathishkumar¹,

Boyanovsky²,

Karakashian³

et al. 2005

Cancer Biology & Therapy

113

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“…However, radioresistance may be elicited by either defects in ceramide generation (29)(30)(31)(32) or rapid turnover of ceramide into S1P (33)(34)(35). Rescue of the apoptotic phenotype by restoring ceramide accumulation or limiting S1P signaling is currently being studied both at the basic science and clinical levels (36)(37)(38).…”

Section: Introductionmentioning

confidence: 99%

Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse

et al. 2013

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Escape of prostate cancer (PCa) cells from ionizing radiation-induced (IR-induced) killing leads to disease progression and cancer relapse. The influence of sphingolipids, such as ceramide and its metabolite sphingosine 1-phosphate, on signal transduction pathways under cell stress is important to survival adaptation responses. In this study, we demonstrate that ceramide-deacylating enzyme acid ceramidase (AC) was preferentially upregulated in irradiated PCa cells. Radiation-induced AC gene transactivation by activator protein 1 (AP-1) binding on the proximal promoter was sensitive to inhibition of de novo ceramide biosynthesis, as demonstrated by promoter reporter and ChIP-qPCR analyses. Our data indicate that a protective feedback mechanism mitigates the apoptotic effect of IR-induced ceramide generation. We found that deregulation of c-Jun induced marked radiosensitization in vivo and in vitro, which was rescued by ectopic AC overexpression. AC overexpression in PCa clonogens that survived a fractionated 80-Gy IR course was associated with increased radioresistance and proliferation, suggesting a role for AC in radiotherapy failure and relapse. Immunohistochemical analysis of human PCa tissues revealed higher levels of AC after radiotherapy failure than those in therapy-naive PCa, prostatic intraepithelial neoplasia, or benign tissues. Addition of an AC inhibitor to an animal model of xenograft irradiation produced radiosensitization and prevention of relapse. These data indicate that AC is a potentially tractable target for adjuvant radiotherapy.

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Overcoming resistance to γ-rays in squamous carcinoma cells by poly-drug elevation of ceramide levels

Cited by 62 publications

References 66 publications

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

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

Elevated sphingomyelinase activity and ceramide concentration in serum of patients undergoing high dose spatially fractionated radiation treatment: Implications for endothelial apoptosis

Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse

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