alexa Therapeutic Combination of Nanoliposomal Safingol and Nanoliposomal Ceramide for Acute Myeloid Leukemia | OMICS International | Abstract
ISSN: 2329-6917

Journal of Leukemia
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Research Article

Therapeutic Combination of Nanoliposomal Safingol and Nanoliposomal Ceramide for Acute Myeloid Leukemia

Timothy J Brown1,2, Aileen M. Garcia3,4, Lindsey N Kissinger1,2, Sriram S Shanmugavelandy4, Xujung Wang1,2, Myles C Cabot5, Mark Kester2,4, David F Claxton1,2, and Brian M Barth1,2,,4*

1Department of Medicine, Division of Hematology and Oncology, Penn State College of Medicine, Hershey, PA, USA

2Penn State Hershey Cancer Institute, Hershey, PA, USA

3Department of Biomedical Science, Inter American University of Puerto Rico, Ponce, PR, USA

4Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA

5John Wayne Cancer Institute, Santa Monica, CA, USA

*Corresponding Author:
Brian M Barth, Ph.D
Department of Medicine
Division of Hematology and Oncology
Penn State Hershey Cancer Institute
Penn State College of Medicine
500 University Drive, PO Box 850
CH46 Hershey, PA 17033, USA
Tel: 717-531-0003 (289457)
Fax: (717)-531-5076
E-mail: [email protected], [email protected]

Received February 22, 2013; Accepted April 24, 2013; Published April 26, 2013

Citation: Brown TJ, Garcia AM, Kissinger LN, Shanmugavelandy SS, Wang X, et al. (2013) Therapeutic Combination of Nanoliposomal Safingol and Nanoliposomal Ceramide for Acute Myeloid Leukemia. J Leuk (Los Angel) 1:110. doi: 10.4172/2329-6917.1000110

Copyright: ©2013 Brown TJ, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Novel approaches to enhancing the efficacy of ceramide-based therapeutics are of interest for the treatment of acute myeloid leukemia (AML). Ceramide is a bioactive sphingolipid that has long been established as an inducer of apoptosis. We have pioneered the effort to develop nanoliposomal C6-ceramide (Lip-C6) as an anticancer therapeutic and recently have engaged in efforts to enhance its therapeutic efficacy. Ceramide catabolism by acid ceramidase and subsequently sphingosine kinase 1 yields the metabolite oncogenic sphingosine-1-phosphate (S1P). Therefore, in the present study we hypothesized that targeting of this metabolic pathway with the sphingosine kinase 1 inhibitor safingol would augment the anti-AML efficacy of Lip-C6. We generated and evaluated nanoliposomes encapsulating safingol (Lip-Saf), in combination with Lip-C6 using AML cell lines and primary AML patient samples. This combination exerted synergistic therapeutic efficacy using HL-60 and KG-1 cells, and additive efficacy using HL-60/VCR cells. In contrast, the combination of Lip-C6 and Lip-Saf yielded an antagonistic effect using the murine AML cell line C1498 and this effect was correlated with an increase in autophagy as a potent leukemia survival mechanism. Intriguingly, by using an inhibitor of ceramide glycosylation, nanoliposomal tamoxifen, we observed synergistic anti-AML efficacy using the C1498 cell line demonstrating that unique manipulations of ceramide metabolism may be prevalent in different AMLs. Lastly, we evaluated both favorable prognosis and poor prognosis primary patient AML samples and observed combinatorial efficacy of Lip-C6 and Lip-Saf. This was reflected by a decrease in autophagy and concomitant increase in apoptosis, as well as the ability to block colony forming capacity. Altogether, these results demonstrated that the efficacy of Lip-C6 as an experimental anti-AML therapy can be dramatically enhanced through combination with inhibitors of ceramide metabolism.

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