Pleiotropic Role of Puupehenones in Biomedical Research

Martínez‐Poveda, Beatriz; Quesada, Ana R.; Medina, Miguel Ángel

doi:10.3390/md15100325

Cited by 15 publications

(21 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In living sponges, these compounds are mainly secondary metabolites, whose natural functions include defense against predators and competition with other sessile species. The increasing interest for sponge-isolated compounds in biomedical and pharmaceutical research derives from the potential clinical applications exhibited by them, according to their antitumoral, anti-inflammatory, antiangiogenic, and/or antimicrobial properties reported [1,2,3,4,5,6,7].…”

Section: Introductionmentioning

confidence: 99%

Exploring the Antiangiogenic Potential of Solomonamide A Bioactive Precursors: In Vitro and In Vivo Evidences of the Inhibitory Activity of Solo F-OH During Angiogenesis

et al. 2019

View full text Add to dashboard Cite

Marine sponges are a prolific source of bioactive compounds. In this work, the putative antiangiogenic potential of a series of synthetic precursors of Solomonamide A, a cyclic peptide isolated from a marine sponge, was evaluated. By means of an in vitro screening, based on the inhibitory activity of endothelial tube formation, the compound Solo F–OH was selected for a deeper characterization of its antiangiogenic potential. Our results indicate that Solo F–OH is able to inhibit some key steps of the angiogenic process, including the proliferation, migration, and invasion of endothelial cells, as well as diminish their capability to degrade the extracellular matrix proteins. The antiangiogenic potential of Solo F–OH was confirmed by means of two different in vivo models: the chorioallantoic membrane (CAM) and the zebrafish yolk membrane (ZFYM) assays. The reduction in ERK1/2 and Akt phosphorylation in endothelial cells treated with Solo F–OH denotes that this compound could target the upstream components that are common to both pathways. Taken together, our results show a new and interesting biological activity of Solo F–OH as an inhibitor of the persistent and deregulated angiogenesis that characterizes cancer and other pathologies.

show abstract

Section: Introductionmentioning

confidence: 99%

Exploring the Antiangiogenic Potential of Solomonamide A Bioactive Precursors: In Vitro and In Vivo Evidences of the Inhibitory Activity of Solo F-OH During Angiogenesis

et al. 2019

View full text Add to dashboard Cite

show abstract

“…We have previously reported that PUUP exhibits antifungal activity against the major fungal pathogens C. albicans, Cryptococcus neoformans, and Aspergillus fumigatus (8). In addition to antifungal activity, PUUP also possesses antibacterial, antimalarial, antioxidant, and antitumor activities (9). The exact mechanism by which PUUP exerts these biological activities is not well understood.…”

mentioning

confidence: 99%

“…The exact mechanism by which PUUP exerts these biological activities is not well understood. While one report has shown that the antioxidant activity of PUUP is due to lipoxygenase inhibition, another report indicated that it is due to the inhibition of membrane-bound NADPH oxidases (9). Studies on the antitumor activities of PUUP have suggested that it may target (i) glycogen-synthase kinase-3␤, (ii) matrix metallopeptidase 2, and (iii) hypoxia-inducible factor-2 transcription (9).…”

mentioning

confidence: 99%

“…While one report has shown that the antioxidant activity of PUUP is due to lipoxygenase inhibition, another report indicated that it is due to the inhibition of membrane-bound NADPH oxidases (9). Studies on the antitumor activities of PUUP have suggested that it may target (i) glycogen-synthase kinase-3␤, (ii) matrix metallopeptidase 2, and (iii) hypoxia-inducible factor-2 transcription (9). Thus, further mechanistic characterization of PUUP will facilitate the identification of its precise molecular targets as well as the mechanisms involved in its CAS potentiation effects.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Puupehenone, a Marine-Sponge-Derived Sesquiterpene Quinone, Potentiates the Antifungal Drug Caspofungin by Disrupting Hsp90 Activity and the Cell Wall Integrity Pathway

Tripathi

Feng

Liu

et al. 2020

mSphere

View full text Add to dashboard Cite

The cell wall-targeting echinocandin antifungals, although potent and well tolerated, are inadequate in treating fungal infections due to their narrow spectrum of activity and their propensity to induce pathogen resistance. A promising strategy to overcome these drawbacks is to combine echinocandins with a molecule that improves their activity and also disrupts drug adaptation pathways. In this study, we show that puupehenone (PUUP), a marine-sponge-derived sesquiterpene quinone, potentiates the echinocandin drug caspofungin (CAS) in CAS-resistant fungal pathogens. We have conducted RNA sequencing (RNA-seq) analysis, followed by genetic and molecular studies, to elucidate PUUP’s CAS-potentiating mechanism. We found that the combination of CAS and PUUP blocked the induction of CAS-responding genes required for the adaptation to cell wall stress through the cell wall integrity (CWI) pathway. Further analysis showed that PUUP inhibited the activation of Slt2 (Mpk1), the terminal mitogen-activated protein (MAP) kinase in this pathway. We also found that PUUP induced heat shock response genes and inhibited the activity of heat shock protein 90 (Hsp90). Molecular docking studies predicted that PUUP occupies a binding site on Hsp90 required for the interaction between Hsp90 and its cochaperone Cdc37. Thus, we show that PUUP potentiates CAS activity by a previously undescribed mechanism which involves a disruption of Hsp90 activity and the CWI pathway. Given the requirement of the Hsp90-Cdc37 complex in Slt2 activation, we suggest that inhibitors of this complex would disrupt the CWI pathway and synergize with echinocandins. Therefore, the identification of PUUP’s CAS-potentiating mechanism has important implications in the development of new antifungal combination therapies. IMPORTANCE Fungal infections cause more fatalities worldwide each year than malaria or tuberculosis. Currently available antifungal drugs have various limitations, including host toxicity, narrow spectrum of activity, and pathogen resistance. Combining these drugs with small molecules that can overcome these limitations is a useful strategy for extending their clinical use. We have investigated the molecular mechanism by which a marine-derived compound potentiates the activity of the antifungal echinocandin caspofungin. Our findings revealed a mechanism, different from previously reported caspofungin potentiators, in which potentiation is achieved by the disruption of Hsp90 activity and signaling through the cell wall integrity pathway, processes that play important roles in the adaptation to caspofungin in fungal pathogens. Given the importance of stress adaptation in the development of echinocandin resistance, this work will serve as a starting point in the development of new combination therapies that will likely be more effective and less prone to pathogen resistance.

show abstract

“…Another review article by Martínez-Poveda and colleagues from Spain describes various biological activities of puupehenones (named after the famous rock Puu Pehe in Hawaii)—a large family of chemical compounds initially isolated from sponges of the orders Verongida and Dictyoceratida. This review gives an update on the current knowledge and understanding of the bioactivity and biogenesis of puupehenones, and their possible therapeutic applications in human diseases, with special emphasis on cancer [ 5 ].…”

mentioning

confidence: 99%