The natural product mensacarcin induces mitochondrial toxicity and apoptosis in melanoma cells

Abstract

Mensacarcin is a highly oxygenated polyketide that was first isolated from soil-dwelling bacteria. It exhibits potent cytostatic properties (mean of 50% growth inhibition = 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 biochemical features, we demonstrated 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 BRAF mutation associated with drug resistance, showed characteristic chromatin condensation as well as distinct poly(ADP-ribose)polymerase-1 cleavage. Flow cytometry identified a large population of apoptotic melanoma cells, and single-cell electrophoresis indicated 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 was localized to mitochondria within 20 min of treatment. Live-cell bioenergetic flux analysis confirmed 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 provide evidence that mensacarcin targets mitochondria. Mensacarcin's unique mode of action suggests that it may be a useful probe for examining energy metabolism, particularly in BRAF-mutant melanoma, and represent a promising lead for the development of new anticancer drugs.

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“…2d). Some agents that inhibit ATP production by oxidative phosphorylation may produce a compensatory increase in glycolysis, characterized by increased extracellular acidification rate (ECAR) 15 . Thus, we monitored the ECAR of DLD1 and HCT116 cells in the absence and presence of AVNs.…”

Bioenergetics underlying single-cell migration on aligned nanofiber scaffolds

“…C2C12 cells were plated at a confluency of 30 -40% in a MatTek six-well plate. The cells were incubated with 1 M mensacarcin, a compound known to influence mitochondrial function (28,35), for 30 min in Krebs-Henseleit buffer containing (in mM) 118 NaCl, 24 NaHCO3, 4.8 KCl, 2 CaCl2, 1.2 MgSO4, 1.2 KH2PO4, and 10 glucose. Radioactive 2DG (1.5 Ci/mL) and 2DG (10 M) were placed in the media for an additional 30 min.…”

<p>Molecular Mechanisms of Anticancer Activities of Puerarin</p>

“…[45][46][47] Plant-derived NPs induce apoptosis in cancer cells through the mitochondrial-dependent pathway. 48,49 Pue significantly induces apoptosis in HT-29 colon cancer cells, 50 human mental cell lymphoma (MCL) Z138, 51 SMMC7721, 43 MDA-MB-231, 52 MCF-7, 52 NB4, 53 A549 cells 53 and HS578T 52 cell lines through the intrinsic apoptosis pathway. 43,[50][51][52][53][54][55] In this pathway, Pue downregulates Bcl-2, 50,51,[53][54][55] which causes Bax [50][51][52][53]55 upregulation and increases the permeability of the mitochondria to apoptosisinducing factor (AIF), 43 which is then released from the mitochondria to the cytosol.…”