Abstract 2689: Nanoformulated mellitin from bee venom exhibits excellent anti-prostate cancer efficacy

Abstract

Abstract Melittin, a major peptide component of bee venom, has shown chemopreventive as well as chemotherapeutic effects against many cancers both in cell culture and preclinical animal model systems. However, several issues including nonspecificity, degradation, inefficient systemic delivery, bioavailability, and more importantly its enhanced hemolytic activity have hampered its translation to humans. We recently reviewed the literature on bee venom (Cancer Letters, 2017;402:16-31) and suggested that the use of nanotechnology mediated delivery of melittin can enhance significantly its systemic delivery to target cancer cells and with minimal hemolytic effect. We employed nanotechnology to improve the therapeutic outcome of bee venom by using perfluorocarbon nanoemulsion vesicles to deliver melittin, hereafter referred to as ‘NanoBees'. The nano carriers were synthesized as an oil-in-water emulsion composed of a liquid perfluorooctyl bromide core having a monolayer of phospholipid forming a stabilizing interface with the aqueous media. We concentrated our studies on prostate cancer (PCa) because it is an attractive candidate and suitable target because of its long latency which offers a relatively long period of time for pharmacological interventions. We assessed the effectiveness of delivery of melittin, encapsulated in nanoformulation in vitro against PCa cells and in vivo in animal models. Treatment of PCa cells DU-145, C42 and PC3 PCa cells with formulated NanoBees (0-40 μg/ml) inhibited cell viability and proliferation and induced apoptosis. We observed an increase in the levels of proapototic Bax and concomitant decrease in the levels of antiapoptotic Bcl-2 resulting in a shift in the ratio of these molecules that favored apoptosis. We also observed an increase in poly(ADP-ribose) polymerase (PARP) cleavage and significant increase in the activation of cleaved caspases 3,7,8,9 in all tested PCa cell lines. These proteins were more than two fold up-regulated in the cells treated with NanoBees when compared to native melittin. Treatment of PCa cells with NanoBees inhibited cell proliferation in vitro through inhibition of the PI3K/Akt pathway and simultaneous downregulation in the expression of CyclinD1 and CDK4. We next tested the effect of NanoBees in a xenograft mouse model implanted with PCa PC3 cells. Intraperitoneal administration of NanoBees (5, 10 and 15 mg/Kg) significantly decreased tumor volume and growth rate compared to saline and void nanoparticle treatment. Incorporation of melittin in nanoemulsion prevented side effects associated with native melittin such hemolysis. These data support our hypothesis that nanotechnology could enhance the outcome of cancer therapy of melittin derived from bee venom through boosting bioavailability and limiting toxicity thus leading to a significant potential for possible clinical outcome. Citation Format: Islam R. Abdelaal, Imtiaz A. Siddiqui, Vaqar M. Adhami, Hazem F. Abdelaal, Hadir Mohamed, Mohamad Rady, Hasan Mukhtar. Nanoformulated mellitin from bee venom exhibits excellent anti-prostate cancer efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2689.