Anα-Acetoxy-Tirucallic Acid Isomer Inhibits Akt/mTOR Signaling and Induces Oxidative Stress in Prostate Cancer Cells

Abstract

Here we provide evidence that aATA(8,24) (3a-acetyloxy-tir-8,24-dien-21-oic acid) inhibits Akt/mammalian target of rapamycin (mTOR) signaling. aATA(8,24) and other tirucallic acids were isolated from the acetylated extract of the oleo gum resin of Boswellia serrata to chemical homogeneity. Compared with related tirucallic acids, aATA(8,24) was the most potent inhibitor of the proliferation of androgen-insensitive prostate cancer cells in vitro and in vivo, in prostate cancer xenografted onto chick chorioallantoic membranes. aATA(8,24) induced loss of cell membrane asymmetry, caspase-3 activation, and DNA fragmentation in vitro and in vivo. These effects were selective for cancer cells, because aATA(8,24) exerted no overt toxic effects on peripheral blood mononuclear cells or the chick embryo. At the molecular level, aATA(8,24) inhibited the Akt1 kinase activity. Prior to all biochemical signs of cellular dysfunction, aATA(8,24) induced inhibition of the Akt downstream target mTOR as indicated by dephosphorylation of S6K1. This event was followed by decreased expression of cell cycle regulators, such as cyclin D1, cyclin E, and cyclin B1, as well as cyclindependent kinases CDK4 and CDK2 and phosphoretinoblastoma protein, which led to inhibition of the cell-cycle progression. In agreement with the mTOR inhibition, aATA(8,24) and rapamycin increased the volume of acidic vesicular organelles. In contrast to rapamycin, aATA(8,24) destabilized lysosomal and mitochondrial membranes and induced reactive oxygen species production in cancer cells. The ability of aATA(8,24) to inhibit Akt/ mTOR signaling and to induce simultaneously oxidative stress could be exploited for the development of novel antitumor therapeutics with a lower profile of toxic side effects.

Cellular and molecular effects of the mTOR inhibitor everolimus

“…However, cancer cell lysosomes are more vulnerable to rupture, causing leakage of lysosomal contents and activation of apoptosis [211,212], posing a new option for therapeutic developments. El Gaafary et al [213] demonstrated that treatment with both αATA(8,24) (3α-acetyloxy-tir-8,24-dien-21-oic acid) and rapamycin resulted in accumulation of acidic vesicular organelles and inhibition of mTOR/Akt signalling. Interestingly, and in contrast with rapamycin, αATA(8,24) alone was able to destabilize lysosomal and mitochondrial membranes, and induce ROS (reactive oxygen species) production.…”

Aqueous and Ethanolic Extracts of Boswellia serrata Protect Against Focal Cerebral Ischemia and Reperfusion Injury in Rats

“…It is important to note that the yield content of ABS and EBS from B. serrata is about 30%. In addition to boswellic acids and their respective O-acetyl derivatives, B. serrata is also characterized by the presence of euphane and tirucallane triterpenes, especially tirucallic acids, as inhibitors of Akt/mTOR signalling pathway with potential immunomodulatory properties (Badria et al, 2003;Estrada et al, 2010;Zhang et al, 2013;El Gaafary et al, 2015). The well-known inhibitors of Akt/mTOR signalling such as tacrolimus or sirolimus (rapamycin) have been shown to exert neuroprotective properties against cerebral I-R injury (Furuichi et al, 2003;Chauhan et al, 2011).…”

Boswelliaextrakte/Boswelliasäuren bei malignen Tumoren: Eine Übersicht

“…B. Temozolomid) und Bestrahlung, wie an Gliomzellen gezeigt wurde [23]. Von den bisher bekannten Inhaltsstoffen eines Boswelliaextraktes verfügen über eine Antitumorwirkung ▪ Acetyl-11-keto-β-boswelliasäure ▪ 11-Keto-β-boswelliasäure ▪ β-Boswelliasäure ▪ Acetyl-β-boswelliasäure ▪ Ursolsäure ▪ Ätherisches Öl aus dem Harz Kürzlich wurde eine Tirucalsäure aus Olibanum mit Antitumorwirkung beschrieben [39]. Diese hemmt die Akt1-Kinaseaktivität, die ein Signal für die Tumorentstehung darstellt.…”

“…Ihre Hemmung führt zur Unterbrechung des Zellzyklus. Eine solche wurde bei Prostatakarzinomzellen durch ein Isomer der Tirucalsäure, einem Inhaltsstoff eines Boswelliaharzes, beschrieben [39]. Über eine Hemmung von mTOR-Targets durch Acetyl-Lupeolsäure berichteten 2017 Schmidt et al [21].…”