A Novel Semisynthetic Inhibitor of the FRB Domain of Mammalian Target of Rapamycin Blocks Proliferation and Triggers Apoptosis in Chemoresistant Prostate Cancer Cells

Morad, Samy A.F.; Schmid, Maximilian; Büchele, Berthold; Siehl, Hans‐Ullrich; Gafaary, Menna El; Lunov, Oleg; Syrovets, Tatiana; Simmet, Thomas

doi:10.1124/mol.112.081349

Cited by 36 publications

(29 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inhibition of mTORC1 by rapamycin was, however, not sufficient to trigger apoptosis in prostate cancer cells, as we show here, and as it has previously been shown by us and others (Zoncu et al, 2011;Morad et al, 2013). Rapamycin, which promotes autophagy, even protects cells against a range of proapoptotic insults.…”

Section: Discussionsupporting

confidence: 72%

“…Activation of caspase-3 was observed in cells treated with docetaxel, but not in those treated with rapamycin. In fact, the latter is known to be rather cytostatic than cytotoxic (Zoncu et al, 2011;Morad et al, 2013) (Fig. 2A).…”

Section: Methodsmentioning

confidence: 99%

“…The kinase assays were performed as described (Syrovets et al, 2005a,b;Estrada et al, 2010;Morad et al, 2013). Active human recombinant His-Akt1 (100 nM) fusion protein (Biaffin GmbH, Kassel, Germany) was treated either with 3-30 mM tirucallic acid, Akt inhibitor VIII (Akti-1/2, 10 mM; Calbiochem), or the solvent dimethylsulfoxide for 15 minutes at 30°C before addition of the substrate and [g- Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Some reports suggest that bioactive triterpenoids may represent the pharmacologically active principle of frankincense (Syrovets et al, 2000(Syrovets et al, , 2005aPoeckel and Werz, 2006;Cuaz-Perolin et al, 2008;Lu et al, 2008;Wang et al, 2009;Abdel-Tawab et al, 2011). Furthermore, many studies show antineoplastic activities of those triterpenoids, especially boswellic acids and their derivatives, on different types of cancer (Syrovets et al, 2000(Syrovets et al, , 2005aAkihisa et al, 2006;Büchele et al, 2006;Lu et al, 2008;Bhushan et al, 2009;Park et al, 2011;Yadav et al, 2012;Morad et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Gaafary

Büchele

Syrovets

et al. 2014

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 72%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Gaafary

Büchele

Syrovets

et al. 2014

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

show abstract

“…Terpenoids are the largest known class of secondary metabolites in plants and possess a broad range of biological activities [23][24][25][26] and potential therapeutic effects on atherosclerosis, psoriasis, and liver cirrhosis associated with schistosomiasis. 27,28 On the basis of their structural diversity and biological activity, from a phytopharmaceutical point of view, specifically sesquiterpenes have been suggested to be of special interest among the terpenoids.…”

mentioning

confidence: 99%

Anti-Inflammatory and Antiatherogenic Effects of the NLRP3 Inflammasome Inhibitor Arglabin in ApoE ₂ .Ki Mice Fed a High-Fat Diet

et al. 2015

Self Cite

View full text Add to dashboard Cite

Background— This study was designed to evaluate the effect of arglabin on the NLRP3 inflammasome inhibition and atherosclerotic lesion in ApoE 2 Ki mice fed a high-fat Western-type diet. Methods and Results— Arglabin was purified, and its chemical identity was confirmed by mass spectrometry. It inhibited, in a concentration-dependent manner, interleukin (IL)-1β and IL-18, but not IL-6 and IL-12, production in lipopolysaccharide and cholesterol crystal–activated cultured mouse peritoneal macrophages, with a maximum effect at ≈50 nmol/L and EC 50 values for both cytokines of ≈ 10 nmol/L. Lipopolysaccharide and cholesterol crystals did not induce IL-1β and IL-18 production in Nlrp3 −/− macrophages. In addition, arglabin activated autophagy as evidenced by the increase in LC3-II protein. Intraperitoneal injection of arglabin (2.5 ng/g body weight twice daily for 13 weeks) into female ApoE 2 .Ki mice fed a high-fat diet resulted in a decreased IL-1β plasma level compared with vehicle-treated mice (5.2±1.0 versus 11.7±1.1 pg/mL). Surprisingly, arglabin also reduced plasma levels of total cholesterol and triglycerides to 41% and 42%, respectively. Moreover, arglabin oriented the proinflammatory M1 macrophages into the anti-inflammatory M2 phenotype in spleen and arterial lesions. Finally, arglabin treatment markedly reduced the median lesion areas in the sinus and whole aorta to 54% ( P =0.02) and 41% ( P =0.02), respectively. Conclusions— Arglabin reduces inflammation and plasma lipids, increases autophagy, and orients tissue macrophages into an anti-inflammatory phenotype in ApoE 2 .Ki mice fed a high-fat diet. Consequently, a marked reduction in atherosclerotic lesions was observed. Thus, arglabin may represent a promising new drug to treat inflammation and atherosclerosis.

show abstract

Current stage of preclinical and clinical development of guggulsterone in cancers: Challenges and promises

Ijaz,

Iqbal,

Abbasi

et al. 2023

Cell Biology International

View full text Add to dashboard Cite

Throughout human history, the utilization of medicinal herbs has been recognized as a crucial defense against various ailments, including cancer. Natural products with potential anticancer properties, capable of inducing apoptosis in cancer cells, have garnered substantial attention. One such agent under investigation is guggulsterone (GS), a phytosterol derived from the gum resin of the Commiphora mukul tree. This review aims to provide a comprehensive summary of recent studies elucidating the anticancer molecular mechanisms and molecular targets of GS, guiding future research and potential applications as an adjuvant drug in cancer therapy. Recent in vivo and in vitro studies have explored the biological activities of the active ingredients in Commiphora mukul. Specifically, GS emerges as a potential cancer chemopreventive and therapeutic agent. The investigations delve into the impact of GS on constitutively activated survival pathways, including Janus kinase/signal transducer and activator of transcription (JAK/STAT), nuclear factor‐kappa B (NF‐kB), and PI3‐kinase/AKT signaling pathways. These pathways regulate antiapoptotic and proinflammatory genes, exerting control over growth and inflammatory responses. The findings highlight the potential of GS in disrupting survival pathways crucial for cancer cell viability. The inhibition of JAK/STAT, NF‐kB, and PI3‐kinase/AKT signaling pathways positions GS as a promising candidate for cancer therapy. The review synthesizes evidence from diverse studies, underscoring the multifaceted biological activities of GS in cancer prevention and treatment. To advance our understanding, future clinical and translational studies are imperative to determine effective doses in humans. Additionally, there is a need for the development of new pharmaceutical forms of GS to optimize therapeutic effects. This comprehensive review provides a foundation for ongoing research, offering insights into the potential of GS as a valuable addition to the armamentarium against cancer.

show abstract

A Novel Semisynthetic Inhibitor of the FRB Domain of Mammalian Target of Rapamycin Blocks Proliferation and Triggers Apoptosis in Chemoresistant Prostate Cancer Cells

Abstract: The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and its uncontrolled activation is a hallmark of cancer. Moreover,

Cited by 36 publications

References 42 publications

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

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

Anti-Inflammatory and Antiatherogenic Effects of the NLRP3 Inflammasome Inhibitor Arglabin in ApoE ₂ .Ki Mice Fed a High-Fat Diet

Current stage of preclinical and clinical development of guggulsterone in cancers: Challenges and promises

Contact Info

Product

Resources

About

A Novel Semisynthetic Inhibitor of the FRB Domain of Mammalian Target of Rapamycin Blocks Proliferation and Triggers Apoptosis in Chemoresistant Prostate Cancer Cells

Abstract: The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and its uncontrolled activation is a hallmark of cancer. Moreover,

Cited by 36 publications

References 42 publications

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

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

Anti-Inflammatory and Antiatherogenic Effects of the NLRP3 Inflammasome Inhibitor Arglabin in ApoE 2 .Ki Mice Fed a High-Fat Diet

Current stage of preclinical and clinical development of guggulsterone in cancers: Challenges and promises

Contact Info

Product

Resources

About

Anti-Inflammatory and Antiatherogenic Effects of the NLRP3 Inflammasome Inhibitor Arglabin in ApoE ₂ .Ki Mice Fed a High-Fat Diet