Antioxidant and Cytotoxic Isoprenylated Coumarins from<i>Mammea americana</i>

Yang, Hui; Protiva, Petr; Gil, Roberto R.; Jiang, Bei; Baggett, Scott; Basile, Margaret; Reynertson, Kurt A.; Weinstein, I. Bernard; Kennelly, Edward J.

doi:10.1055/s-2005-871257

Cited by 55 publications

(52 citation statements)

References 21 publications

(51 reference statements)

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“…The NMR spectra were recorded using residual solvent peaks (δ 7.27 for 1 H and δ 77.0 for 13 C) were used as internal references. The spectroscopic and physical characteristics of 1 were in agreement with those previously reported for mammea E/BB 2,13,14Compound 1 was determined to be >98% pure by HPLC.…”

Section: Methodssupporting

confidence: 89%

Mammea E/BB, an Isoprenylated Dihydroxycoumarin Protonophore That Potently Uncouples Mitochondrial Electron Transport, Disrupts Hypoxic Signaling in Tumor Cells

Mahdi

Jekabsons

et al. 2010

J. Nat. Prod.

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The mammea-type coumarin mammea E/BB (1) was found to inhibit both hypoxia-induced and iron chelator-induced hypoxia-inducible factor-1 (HIF-1) activation in human breast tumor T47D cells with IC 50 values of 0.96 and 0.89 µM, respectively. Compound 1 suppressed the hypoxic induction of secreted VEGF protein (T47D cells) and inhibited cell viability/proliferation in four human tumor cell lines. Compound 1 (at 5 and 20 µM) inhibited human breast tumor MDA-MB-231 cell migration. While the mechanisms that underlay their biological activities have remained unknown, prenylated mammea coumarins have been shown to be cytotoxic to human tumor cells, suppress tumor growth in animal models, and display a wide variety of antimicrobial effects. Mechanistic studies revealed that 1 appears to exert an assemblage of cellular effects by functioning as an anionic protonophore that potently uncouples mitochondrial electron transport and disrupts mitochondrial signaling in human tumor cell lines.The mammea-type coumarins are a large family of isoprenylated 5,7-dihydroxycoumarin metabolites from Mammea americana L. (Guttiferae/Clusiaceae) and other species of Mammea, Mesua, and Calophyllum.1 Mammea coumarins have been shown to possess a wide array of biological activities. These prenylated coumarins act as radical scavengers,2 are cytotoxic to human tumor cells,2 -6 suppress tumor growth in animal models,7 and exhibit anti-HIV,8 antifungal,9 and antibacterial4 , 10 activities. Recent studies indicate that the inhibitory effects exerted by mammea-type coumarins on tumor cell viability are mediated through mechanisms that involve mitochondrial dysfunction-mediated apoptosis, 7 , 11 , 12 and to a lesser degree necrotic cell death.7 However, the biochemical mechanisms by which this class of prenylated coumarins exerts such a broad range of effects on both eukaryotic and prokaryotic cells have remained unexplained. In a search for small-molecule HIF-1 inhibitors from natural sources, a lipid extract of the plant M. americana was found to inhibit hypoxia (1% O 2 )-induced HIF-1 activation by 89% at 5 µg/mL in a human prostate tumor PC-3 cell-based reporter assay. Bioassay-guided fractionation of the active extract resulted in the isolation of the previously reported mammea-type coumarin mammea E/BB (1).1 At submicromolar concentrations, 1 inhibited hypoxia-induced HIF-1 activation in human breast tumor T47D cells. Mechanistic studies have now revealed that 1 uncouples oxidative phosphorylation by suppressing the ability of cells to maintain the proton gradient Results and DiscussionThe transcription factor HIF-1 regulates the expression of many genes involved in key aspects of cancer biology and has emerged as an important tumor-selective molecular target for anticancer drug discovery.15 Over 20,000 lipid extracts from plants and marine organisms were evaluated in tumor cell-based reporter assays for HIF-1 inhibitory activities. 16 An active extract of the plant M. americana was subjected to bioassay-guided isolation to yield th...

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Section: Methodssupporting

confidence: 89%

Mammea E/BB, an Isoprenylated Dihydroxycoumarin Protonophore That Potently Uncouples Mitochondrial Electron Transport, Disrupts Hypoxic Signaling in Tumor Cells

Mahdi

Jekabsons

et al. 2010

J. Nat. Prod.

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“…Even though the cytotoxicity of coumarin A/AA and other coumarin compounds has been reported by many investigators in different cell lines [24][25][26][27][28], to our knowledge, there are no previous reports on the exact molecular mechanism by which coumarin A/AA exerts its cytotoxic effect. In contrast to the classic cell death mechanism initiated by the basic coumarin 1,2 benzopyrone in HeLa cells [29], in this study we show that coumarin A/AA induces a caspase independent PCD with the release of AIF from mitochondria as an early event in cell death (Figure 6), and no cell cycle arrests preceding the cell death program (Figures 4 and 5).…”

Section: Discussionmentioning

confidence: 95%

Coumarin A/AA induces apoptosis‐like cell death in HeLa cells mediated by the release of apoptosis‐inducing factor

Álvarez-Delgado

Reyes-Chilpa

Estrada-Muñiz

et al. 2009

J Biochem & Molecular Tox

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It has been demonstrated that naturally occurring coumarins have strong biological activity against many cancer cell lines. In this study, we assessed the cytotoxicity induced by the naturally isolated coumarin A/AA in different cancer cell lines (HeLa, Calo, SW480, and SW620) and in normal peripheral-blood mononuclear cells (PBMCs). Cytotoxicity was evaluated using the MTT assay. The results demonstrate that coumarin A/AA was cytotoxic in the four cancer cell lines tested and importantly was significantly less toxic in PBMCs isolated from healthy donors. The most sensitive cancer cell line to coumarin A/AA treatment was Hela. Thus, the programmed cell death (PCD) mechanism induced by this coumarin was further studied in this cell line. DNA fragmentation, histomorphology, cell cycle phases, and subcellular distribution of PCD proteins were assessed. The results demonstrated that DNA fragmentation, but not significant cell cycle disruptions, was part of the PCD activated by coumarin A/AA. Interestingly, it was found that apoptosis-inducing factor (AIF), a proapoptotic protein of the mitochondrial intermembrane space, was released to the cytoplasm in treated cells as detected by the western blot analysis in subcellular fractions. Nevertheless, the active form of caspase-3 was not detected. The overall results indicate that coumarin A/AA induces a caspase-independent apoptotic-like cell death program in HeLa cells, mediated by the early release of AIF and suggest that this compound may be helpful in clinical oncology.

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“…The general consensus was that antioxidants might play a role in modulating the initiation of the carcinogenesis process by protecting against DNA damage. It is quite clear, however, that antioxidants have more complex mechanisms through which they may prevent or modulate the process of carcinogenesis as manifested by recent data showing several cytotoxic effects of antioxidants (Lee et al, 2005;Nemeikaite-Ceniene et al, 2005;Ryan et al, 2005;Yamasaki et al, 2005;Yang et al, 2005). The complexity of such mechanisms may lead to a serious misjudgment of the potential benefits of an antioxidant as a chemopreventive agent.…”

Section: Article In Pressmentioning

confidence: 89%

The role of phytochemicals in inhibition of cancer and inflammation: New directions and perspectives

Issa

Volate

Wargovich

2006

Journal of Food Composition and Analysis

130

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Antioxidant and Cytotoxic Isoprenylated Coumarins fromMammea americana

Cited by 55 publications

References 21 publications

Mammea E/BB, an Isoprenylated Dihydroxycoumarin Protonophore That Potently Uncouples Mitochondrial Electron Transport, Disrupts Hypoxic Signaling in Tumor Cells

Mammea E/BB, an Isoprenylated Dihydroxycoumarin Protonophore That Potently Uncouples Mitochondrial Electron Transport, Disrupts Hypoxic Signaling in Tumor Cells

Coumarin A/AA induces apoptosis‐like cell death in HeLa cells mediated by the release of apoptosis‐inducing factor

The role of phytochemicals in inhibition of cancer and inflammation: New directions and perspectives

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