A Phase II Study of Topical Ceramides for Cutaneous Breast Cancer

Jatoi, Aminah; Suman, Vera J.; Schaefer, Paul; Block, Margaret; Loprinzi, Charles L.; Roche, Patrick C.; Garneau, Stuart; Morton, Roscoe F.; Stella, Philip J.; Alberts, Steven R.; Pittelkow, Mark R.; Sloan, Jeff A.; Pagano, Richard E.

doi:10.1023/a:1024409123726

Cited by 24 publications

(19 citation statements)

References 20 publications

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“…Topical application of ceramide to skin cancer or application of ceramide through a transarterial catheter to tumors such as hepatoma might be potential. In this context, topical treatment of refractory cutaneous breast cancer with short chain ceramide was recently reported, although the results were not promising [121].…”

Section: Clinical Application Of Ceramidementioning

confidence: 99%

Current Status and Perspectives in Ceramide-Targeting Molecular Medicine

Sawai

Domae²,

Okazaki

2005

CPD

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Ceramide is not only structurally but also functionally a key molecule in diverse kinds of sphingolipids. In the past decade, ceramide has been shown to be of crucial significance in several cell functions including apoptosis, cell growth, senescence, and cell cycle control. Among them, the role of ceramide in apoptosis induction has extensively been studied, and ceramide-targeting molecular medicine for apoptosis-based diseases such as malignant tumors, atherosclerosis and neurodegenerative disorders appears to come out to the clinical field. We here describe the recent advances in research of ceramide-mediated apoptosis signaling. We also show the relation of ceramide level through regulation of ceramide-related enzymes (sphingomyelinase, ceramidase, sphingomyelin synthase and glucosylceramide synthase) with diseases such as cancer, leukemia, bacterial infections, AIDS, Alzheimer's disease, atherosclerosis, diabetes mellitus and atopic dermatitis. The strategies to construct the ceramide-targeting medicine for intractable diseases such as cancer and leukemia are discussed.

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Section: Clinical Application Of Ceramidementioning

confidence: 99%

Current Status and Perspectives in Ceramide-Targeting Molecular Medicine

Sawai

Domae²,

Okazaki

2005

CPD

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“…Further contribution of PS, C6-PS or ceramide III to induction of UVB-induced apoptosis which per se is partially caused by endogenous ceramide generation (19,28) could not be verified at the level of caspase-3 activity and nucleosomal fragmentation. Also in human skin in vivo, no evidence for increased apoptosis has been found in phase II topical trials for cutaneous breast cancer where a 1% mixture of C2-and C6-ceramides was ineffectual in inducing tumor cell apoptosis morphologically or by the TUNEL assay (29). Also, topical application of N-oleoyl phytosphingosine to human skin which had been barrier compromised by tape stripping and subsequently irradiated with 2MED UVB did not lead to any histological differences with regard to apoptotic cells in comparison with the vehicle-treated skin (30).…”

Section: Resultsmentioning

confidence: 99%

Topical ceramides neither enhance UVB‐induced apoptosis in normal human keratinocytes nor affect viability in UVB‐irradiated reconstructed human epidermis

Felsner

Koehler

Farwick

et al. 2014

Experimental Dermatology

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Ceramides are the major lipid of lamellar sheets present in intercellular spaces of the stratum corneum contributing to epidermal barrier properties. Therefore, ceramides and their analogues have been studied for barrier enhancing and waterholding properties for decades. In vitro studies have indicated cytotoxic potential for cell-permeable ceramides thereby raising the question whether topical ceramide application might contribute to UVB-induced apoptosis. Phytosphingosine, N-hexanoylphytosphingosine and N-stearoylphytosphingosine (ceramide III) in concentrations ≤5 lM have been used for co-stimulation with low (160 J/m 2 ) or high (600 J/m 2 ) UVB doses in subconfluent basal and confluent differentiating keratinocytes. Significantly, increased caspase-3 activity was observed in basal keratinocytes irradiated with 600 J/m 2 UVB and in differentiating keratinocytes with both UVB doses. Co-stimulation with the named ceramides did not further increase (i) caspase-3 activity and (ii) nucleosomal fragmentation in differentiating keratinocytes. Moreover, costimulation with 1-mM ceramides did not further affect viability/ lactate dehydrogenase release in UVB-irradiated reconstructed human epidermis corroborating the safety of these ceramides.

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“…In 2003, topical administration of C 2 and C 6 ceramides were employed in a phase II study against cutaneous breast cancer, with mixed results (Clinical trial #: NCT00008320) (ClinicalTrials.gov). The trial found that while the C 2 and C 6 ceramides had little to no toxicity, patients yielded only a 4% response rate, shelving topical administration of short chain ceramides as a potential chemotherapeutic (Jatoi et al, 2003). However, by encapsulating a C 6 ceramide into stable nontoxic nanoliposomes, researchers found that they could increase chemotoxicity as compared to free ceramide alone in in vivo models (Kester et al, 2015; Sun et al, 2008).…”

Section: Deliverable and Clinically Relevantsphingolipid-based Drugs mentioning

confidence: 99%

Novel Sphingolipid-Based Cancer Therapeutics in the Personalized Medicine Era

Shaw

Costa-Pinheiro

Patterson

et al. 2018

Advances in Cancer Research

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Sphingolipids are bioactive lipids that participate in a wide variety of biological mechanisms, including cell death and proliferation. The myriad of pro-death and pro-survival cellular pathways involving sphingolipids provide a plethora of opportunities for dysregulation in cancers. In recent years, modulation of these sphingolipid metabolic pathways has been in the forefront of drug discovery for cancer therapeutics. About two decades ago, researchers first showed that standard of care treatments, e.g., chemotherapeutics and radiation, modulate sphingolipid metabolism to increase endogenous ceramides, which kill cancer cells. Strikingly, resistance to these treatments has also been linked to altered sphingolipid metabolism, favoring lipid species that ultimately lead to cell survival. To this end, many inhibitors of sphingolipid metabolism have been developed to further define not only our understanding of these pathways but also to potentially serve as therapeutic interventions. Therefore, understanding how to better use these new drugs that target sphingolipid metabolism, either alone or in combination with current cancer treatments, holds great potential for cancer control. While sphingolipids in cancer have been reviewed previously (Hannun & Obeid, 2018; Lee & Kolesnick, 2017; Morad & Cabot, 2013; Newton, Lima, Maceyka, & Spiegel, 2015; Ogretmen, 2018; Ryland, Fox, Liu, Loughran, & Kester, 2011) in this chapter, we present a comprehensive review on how standard of care therapeutics affects sphingolipid metabolism, the current landscape of sphingolipid inhibitors, and the clinical utility of sphingolipid-based cancer therapeutics.

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A Phase II Study of Topical Ceramides for Cutaneous Breast Cancer

Abstract: To our knowledge, this trial is one of the first clinical investigations of short chain ceramides. This trial's results are not promising enough to merit further study of ceramides in the manner prescribed.

Cited by 24 publications

References 20 publications

Current Status and Perspectives in Ceramide-Targeting Molecular Medicine

Current Status and Perspectives in Ceramide-Targeting Molecular Medicine

Topical ceramides neither enhance UVB‐induced apoptosis in normal human keratinocytes nor affect viability in UVB‐irradiated reconstructed human epidermis

Novel Sphingolipid-Based Cancer Therapeutics in the Personalized Medicine Era

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