Basiliolides, a Class of Tetracyclic C19 Dilactones fromThapsia garganica, Release Ca²⁺from the Endoplasmic Reticulum and Regulate the Activity of the Transcription Factors Nuclear Factor of Activated T Cells, Nuclear Factor-κB, and Activator Protein 1 in T Lymphocytes

Abstract

Calcium concentration within the endoplasmic reticulum (ER) plays an essential role in cell physiology. We have investigated the effects of basiliolides, a novel class of C19 dilactones isolated from Thapsia garganica, on Ca 2ϩ mobilization in T cells. Basiliolide A1 induced a rapid mobilization of intracellular Ca 2ϩ in the leukemia T-cell line Jurkat. First, a rapid calcium peak was observed and inhibited by 1,2-bis(2-aminophenoxy)ethane-N,N,NЈ,NЈ-tetraacetic acid-acetoxymethyl ester. This initial calcium mobilization was followed by a sustained elevation, mediated by the entry of extracellular calcium through store-operated calcium release-activated Ca 2ϩ (CRAC) channels and sensitive to inhibition by EGTA, and by the CRAC channel inhibitor N-{4- [3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-4-methyl-1,2,3-thiadiazole-5-carboxamide (BTP-2). Basiliolide A1 mobilized Ca 2ϩ from ER stores, but in contrast to thapsigargin, it did not induce apoptosis. Basiliolide A1 induced nuclear factor of activated T cells 1 dephosphorylation and activation that was inhibited by BTP-2 and cyclosporine A. In addition, we found that basiliolide A1 alone did not mediate IB␣ degradation or RelA phosphorylation (ser536), but it synergized with phorbol 12-myristate 13-acetate to induce a complete degradation of the nuclear factor-B inhibitory protein and to activate the c-Jun NH 2 -terminal kinase. Moreover, basiliolide A1 regulated both interleukin-2 and tumor necrosis factor-␣ gene expression at the transcriptional level. In basiliolide B, oxidation of one of the two geminal methyls to a carboxymethyl group retained most of the activity of basiliolide A1. In contrast, basiliolide C, where the 15-carbon is oxidized to an acetoxymethine, was much less active. These findings qualify these compounds as new probes to investigate intracellular calcium homeostasis.The sesquiterpene lactone thapsigargin (TG) is an irreversible inhibitor of sarco(endo)plasmic reticulum Ca 2ϩ ATPases (SERCAs) and has become an indispensable tool to study calcium homeostasis (Treiman et al., 1998). TG causes a net transfer of Ca 2ϩ from the endoplasmic reticulum (ER) to cytosol, elevating [Ca 2ϩ ] i (Thastrup et al., 1990;Rooney and Meldolesi, 1996) and inducing apoptosis via ER stress. We have recently shown that, apart from TG, T. garganica also contains compounds capable of mobilizing Ca 2ϩ from the ER. These were identified in a series of unique C19 dilactones named basiliolides (Appendino et al., 2005).In biological systems, calcium ions (Ca 2ϩ ) function as ubiquitous messengers that play an essential role in signal transThis work was supported by Ministerio de Educación y Ciencia Grant SAF2004-00926 (to E.M.).Article, publication date, and citation information can be found at

A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas

“…The maximum amplitude was approximately the same in both cases, suggesting that the PCI-34051 induced calcium mobilization primarily from intracellular stores. 39,40 This conclusion was supported by the increase in calcium levels with the addition of ionomycin (as indicated by the second arrow) in both cases. In J.gamma1 cells, this rapid calcium mobilization by PCI-34051 was completely abolished (Figure 6c).…”

The [4 + 2] Cycloaddition of 2‐Pyrone in Total Synthesis

“…Transtaganolides and basiliolides ( 451 — 456 , Scheme ) were a class of natural products isolated from Thapsia plants, and demonstrated great inhibitive activities against calcium ATPase residing within the sarco/endoplasmic reticulum (SERCA‐ATPase) . Owing to their interesting biological activities as well as striking structures featuring trans‐decalin skeleton with a bridged lactone and unprecedented cyclic acyl ketene acetal, transtaganolide and basiliolides have attracted significant attentions from synthetic chemists …”

Total Syntheses of Basiliolide A1, Basiliolide A2, Basiliolide C, and their Structural Analogues

“…Recently, a number of C19 terpene dilactones, the basiliolides (some members are also known as transtaganolides, Figure a), were isolated from the same species of Thapsia . Some members of this family were found to show inhibitory activity against SERCA,, but their mode of action has not been studied. Structurally, basiliolides share the same tetracyclic core, which contains a trans ‐decalin with a lactone bridge (ABD‐ring), and an unprecedented seven‐membered acyl ketene acetal ring (C‐ring).…”

“…Structurally, basiliolides share the same tetracyclic core, which contains a trans ‐decalin with a lactone bridge (ABD‐ring), and an unprecedented seven‐membered acyl ketene acetal ring (C‐ring). Due to the significant structural difference from thapsigargin, a different mechanism of action has been proposed for the basiliolides; thus, these compounds could potentially be used as tools, complementary to thapsigargin, for the study of Ca 2+ signalling . Unfortunately, these natural products are very difficult to isolate from the natural source, and this has hampered their further development.…”