Phorboid 20-homovanillates induce apoptosis through a VR1-independent mechanism

Antonio MacHo, Concepción Lucena, Marco A. Calzado, Magdalena Blanco, Ignacio Donnay, Giovanni Appendino, Eduardo Munñoz

Risultato della ricerca: Contributo su rivistaArticolo in rivistapeer review

Abstract

Background: Vanilloids, such as capsaicin and resiniferatoxin (RTX), are recognized at the cell surface by vanilloid receptor type 1 (VR1), which has recently been cloned. VR1 mediates the effects of capsaicin and RTX in VR1-expressing cells, but vanilloids can induce apoptosis through a pathway not mediated by VR1. Phorboid 20-homovanillates can be used to investigate cell death induced by vanilloids. Results: 12, 13-Diacylphorbol-20 homovanillates were prepared by the sequential esterification of the natural polyol. Phorbol 12-phenylacetate 13-acetate 20-homovanillate (PPAHV) induced apoptosis in Jurkat cells to the same extent as RTX. Apoptosis was preceded by an increase in intracellular reactive oxygen species and by the loss of mitochondrial transmembrane potential. PPAHV-induced apoptosis was mediated by a pathway involving caspase-3 activation and was initiated at the S phase of the cell cycle. The cell-death pathway triggered by VR1 activation was studied in 293T cells transfected with the cloned rat vanilloid receptor. In this system, capsaicin and PPAHV induced cell death by an apparent necrotic mechanism, which was selectively inhibited by the competitive vanilloid receptor antagonist capsazepine. Interestingly, phorbol-12, 13-bisnonanoate-20-homovanillate, an analogue of PPAHV, induced cell death in VR1-transfected cells but could not trigger apoptosis in the Jurkat cell line. Conclusions: Vanilloids can induce cell death through different signalling pathways. The cell death induced in a VR1-independent manner has the hallmark of apoptosis, whereas the cell death mediated by vanilloids binding to VR1 is seemingly necrotic. Phorboid homovanillates that have antitumour and anti-inflammatory activities but lack the undesirable side effects of the natural vanilloids could be developed as potential drugs.

Lingua originaleInglese
pagine (da-a)483-492
Numero di pagine10
RivistaChemistry and Biology
Volume7
Numero di pubblicazione7
DOI
Stato di pubblicazionePubblicato - 1 lug 2000
Pubblicato esternamente

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