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Perturbation of mitochondrial bioenergetics by polycations counteracts resistance to BRAF^E600 inhibition in melanoma cells

Lookup NU author(s): Professor Moein MoghimiORCiD

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Abstract

© 2019 Elsevier B.V.Acquired resistance to the oncogenic BRAFE600 inhibitor vemurafenib is a major clinical challenge in the treatment of melanoma. Vemurafenib resistance is poorly understood; however, available evidence indicates that reprogrammed mitochondrial metabolism could contribute to the resistance mechanism. Here we show that synthetic polycations, such as polyethylenimines and poly(L-lysine)s, prevent vemurafenib resistance in melanoma cells through induction of mitochondrial bioenergetic crisis. Polycations accumulate to a higher degree in hyperpolarized mitochondria (i.e. mitochondria with greater negative charge) which partly explains greater cellular uptake and mitochondrial accumulation of polycations in melanoma cells compared with epidermal melanocytes. Combined treatment of polycations and vemurafenib diminishes the metabolic flexibility of melanoma cells, making them unable to shift between glycolysis and mitochondrial oxidative phosphorylation according to energy demands. Thus, polycations exert considerable detrimental effects on melanoma cells at concentrations better tolerated by epidermal melanocytes and act synergistically with vemurafenib in effectuating bioenergetic crisis, DNA damage and cell death selectively in melanoma cells. Mechanistic understanding of this synergy could lead to the development of macromolecular and polymer therapeutics with structural attributes that encompass even greater cancer-specific cytotoxicity, and provide strategies for tailor-made combination therapies.

Publication metadata

Author(s): Hall A, Maynard S, Wu L-P, Merchut-Maya JM, Strauss R, Moghimi SM, Bartek J

Publication type: Article

Publication status: Published

Journal: Journal of Controlled Release

Year: 2019

Volume: 309

Pages: 158-172

Print publication date: 10/09/2019

Online publication date: 23/07/2019

Acceptance date: 20/07/2019

ISSN (print): 0168-3659

ISSN (electronic): 1873-4995

Publisher: Elsevier B.V.

URL: https://doi.org/10.1016/j.jconrel.2019.07.032

DOI: 10.1016/j.jconrel.2019.07.032

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