The Natural Product Mensacarcin Induces Mitochondrial Toxicity and Apoptosis in Melanoma Cells.

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The Natural Product Mensacarcin Induces Mitochondrial Toxicity and Apoptosis in Melanoma Cells.

J Biol Chem. 2017 Oct 26;:

Authors: Plitzko B, Kaweesa EN, Loesgen S

Abstract
Mensacarcin is a highly oxygenated polyketide that was first isolated from soil-dwelling Streptomyces bacteria. It exhibits potent cytostatic properties (GI50: 0.2 μM) in almost all cell lines of the National Cancer Institute (NCI)-60 cell line screen and relatively selective cytotoxicity against melanoma cells. Moreover, its low COMPARE correlations with known standard antitumor agents indicate a unique mechanism of action. Effective therapies for managing melanoma are limited, so we sought to investigate mensacarcin's unique cytostatic and cytotoxic effects and its mode of action. By assessing morphological and bio-chemical features we demonstrate that mensacarcin activates caspase 3,7-dependent apoptotic pathways and induces cell death in melanoma cells. Upon mensacarcin exposure, SK-Mel-28 and SK-Mel-5 melanoma cells, which have the BRAFV600E mutation associated with drug resistance, show characteristic chromatin condensation as well as distinct PARP-1 cleavage. Flow cytometry identifies a large population of apoptotic melanoma cells and single cell electrophoresis indicates that mensacarcin causes genetic instability, a hallmark of early apoptosis. To visualize mensacarcin's subcellular localization, we synthesized a fluorescent mensacarcin-probe that retained activity. The natural product probe is localized to mitochondria within 20 minutes of treatment. Live-cell bioenergetic flux analysis confirms that mensacarcin disturbs energy production and mitochondrial function rapidly. The subcellular localization of the fluorescently-labeled mensacarcin together with its unusual metabolic effects in melanoma cells provides evidence that mensacarcin targets mitochondria. Mensacarcin's unique mode of action suggests it may be a useful probe for examining energy metabolism, particularly in BRAF-mutant melanoma, and represents a promising lead for the development of new anticancer drugs.

PMID: 29074620 [PubMed - as supplied by publisher]

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