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Combinatorial Efficacy of Nanoliposomal Ceramide and the Antioxidant 7,8- Benzoflavone for Acute Myeloid Leukemia

Brian M. Barth, Timothy J. Brown, Matthew T. Adams, Aileen M. Garcia, Lindsey N. Fisher, Jennifer L. Fritz, Adam J. Beck, Colin M. McGill, Mark Kester, Melissa A. Tran and David F. Claxton

Ceramide-based therapeutics have gained recent attention as anti-neoplastic therapeutics. These include standard of care therapeutics that in part exert efficacy through the generation of ceramide, as well as new therapeutics that seek to specifically deliver or augment ceramide levels in malignant cells. Ceramide is a bioactive sphingolipid involved in apoptotic and stress cellular signaling pathways. It has also been shown to regulate oxidative stress, which may negate its otherwise anti-neoplastic effects by promoting the proliferation of leukemia cells. Metabolism of ceramide to neutral or pro-oncogenic metabolites can serve as a further pathway of therapeutic resistance. In this study, the antioxidant 7,8-benzoflavone (BF) was identified through a natural products chemical library screening process as a compound that can augment the efficacy of nanoliposomal C6-ceramide (Lip-C6) in cellular models of Acute Myeloid Leukemia (AML). This study demonstrates that BF exerts an antioxidant effect in AML, which likely refines the bioactivity of ceramide as an anti-leukemic agent. Intriguingly, BF has been shown to block drug efflux pumps, such as P-glycoprotein, allowing BF to also impede P-glycoprotein-mediated ceramide glycosylation. In this study, BF was further formulated into nanoliposomes for in vivo studies using two murine models of AML. Treatment of C3H/HeJ mice engrafted with a FLT3-ITD driven AML with a combinatorial nanoliposomal formulation of BF and Lip-C6 significantly augmented the survival of mice beyond that of nanoliposomal formulations containing either agent alone. This was in contrast to the modest extension of survival of C57BL/6J mice engrafted with C1498 AML cells utilizing either single agent or combinatorial nanoliposomal formulations. Altogether this study demonstrates that the anti-AML efficacy of Lip-C6 as a ceramide-based therapeutic can be augmented for particular types of AML, such as that driven by FLT3-ITD, by combinatorial treatment with the antioxidant BF.