Antiproliferative Activity of Abietane Diterpenoids against Human Tumor Cells

Abstract

In the present study, the cytotoxicity of 30 diterpenoids with an abietane or a halimane skeleton was determined against five human tumor cell lines (HL-60, U937, Molt-3, SK-MEL-1, and MCF-7). Diterpenoids containing an abietane skeleton including taxodone (1) and taxodione (2), as well as the semisynthetic derivatives 12, 14, 15, 17, and 22, were the most cytotoxic compounds for human leukemia cells. Overexpression of the protective mitochondrial proteins Bcl-2 and Bcl-xL did not confer resistance to abietane diterpene-induced cytotoxicity. Studies performed on HL-60 cells indicated that growth inhibition triggered by compounds 1, 12, 14, and 15 was caused by induction of apoptosis. This was prevented by the nonspecific caspase inhibitor Z-VAD-FMK and, in the case of compounds 14 and 15, reduced by the selective caspase-8 inhibitor Z-IETD-FMK. Cell death induced by these abietane diterpenes was found to be associated with the release of mitochondrial proteins, including cytochrome c, Smac/DIABLO, and AIF (apoptosis-inducing factor), accompanied by dissipation of the mitochondrial membrane potential (ΔΨ), and modulated by inhibition of extracellular signal-regulated kinases signaling and the p38 mitogen-activated protein kinase pathway.

Taxodione and arenarone inhibit farnesyl diphosphate synthase by binding to the isopentenyl diphosphate site

“…1), both of which have been reported to have antiinfective or anticancer activity (34)(35)(36)(37)(38)(39). All three terpenoid inhibitors (compounds 11, 12, and 13) thus contain either the hydroxyquinone methide fragment found in the terpenoid celastrol (compound 9) and compound 10 or a quinone moiety (compound 13); all three compounds (11, 12, and 13) are quite active against FPPS (SI Appendix, Table S1) and have been reported to be active against tumor cells (35,40,41). We also tested compounds 9, 11, and 13 against the MCF-7 tumor cell line and found IC 50 values for cell growth inhibition (SI Appendix, Table S1) of 0.2, 2, and 17 μM, respectively.…”

“…Like celastrol (compound 9), taxodione is a quinone methide that reacts with protein cysteine thiol groups, as was noted as early as 1970 with phosphofructokinase (51). In addition, as does celastrol, taxodione is reported to have diverse biological activities (35,38,52). This chemical reactivity, if combined with FPPS inhibition, might lead to potent multitarget inhibitors, perhaps including more tumor-specific (e.g., ras-bearing) targets.…”

Plectranthus madagascariensis phytosomes: formulation optimization

“…The acetonic extract prepared from P. madagascariensis possess as main compounds two diterpenes with interesting antibacterial 11,16 and anticancer 12 activities, 7α,6β-dihydroxyroyleanone and coleon U, respectively. The abietane diterpenes present in this extract possess conjugated quinone systems which contribute to their cytotoxicity by the induction of free radicals 18 . The coleon U has also shown to be a selective inhibitor of the protein kinase C delta 19 11,12,14-tetrahydroxy-abieta-5,8,11,13-tetraene-7-one (coleon U.…”

“…A inclusão do extrato em fitossomas poderá ser extremamente útil para obter uma forma farmacêutica estável com aplicação terapêutica que poderá será ser a nível de actividade antibacteriana ou antitumoral. O extrato acetónico preparado a partir de P. madagascariensis, possuí como componentes maioritários, dois diterpenos com interessante actividade antibacteriana 11,16 e antitumoral 17,18 , a 7α,6β-dihydroxyroyleanone e a coleona U, respectivamente. Os diterpenos abietânicos presentes neste extrato, possuem na sua estrutura uma quinona conjugada que pode contribuir para a sua citotoxicidade devido à indução de radicais livres 18 .…”

“…O extrato acetónico preparado a partir de P. madagascariensis, possuí como componentes maioritários, dois diterpenos com interessante actividade antibacteriana 11,16 e antitumoral 17,18 , a 7α,6β-dihydroxyroyleanone e a coleona U, respectivamente. Os diterpenos abietânicos presentes neste extrato, possuem na sua estrutura uma quinona conjugada que pode contribuir para a sua citotoxicidade devido à indução de radicais livres 18 . A coleona U também está descrita como um inibidor seletivo da proteína quinase C delta 19 11,12,14-tetrahydroxy-abieta-5,8,11,13-tetraene-7--one (coleon U. Este mecanismo de ação poderá ser útil na modelação de vias moleculares que se encontram alteradas em alguns tipos de cancro.…”