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Research ArticleArticle

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

Samy A. F. Morad, Maximilian Schmid, Berthold Büchele, Hans-Ullrich Siehl, Menna El Gafaary, Oleg Lunov, Tatiana Syrovets and Thomas Simmet
Molecular Pharmacology February 2013, 83 (2) 531-541; DOI: https://doi.org/10.1124/mol.112.081349
Samy A. F. Morad
Institutes of Pharmacology of Natural Products and Clinical Pharmacology (S.A.F.M., M.S., B.B., M.E.G., O.L., T.Sy., T.Si.), and Organic Chemistry I (M.S., H.U.S.), Ulm University, Ulm, Germany; and Department of Pharmacology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt (S.A.F.M.)
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Maximilian Schmid
Institutes of Pharmacology of Natural Products and Clinical Pharmacology (S.A.F.M., M.S., B.B., M.E.G., O.L., T.Sy., T.Si.), and Organic Chemistry I (M.S., H.U.S.), Ulm University, Ulm, Germany; and Department of Pharmacology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt (S.A.F.M.)
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Berthold Büchele
Institutes of Pharmacology of Natural Products and Clinical Pharmacology (S.A.F.M., M.S., B.B., M.E.G., O.L., T.Sy., T.Si.), and Organic Chemistry I (M.S., H.U.S.), Ulm University, Ulm, Germany; and Department of Pharmacology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt (S.A.F.M.)
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Hans-Ullrich Siehl
Institutes of Pharmacology of Natural Products and Clinical Pharmacology (S.A.F.M., M.S., B.B., M.E.G., O.L., T.Sy., T.Si.), and Organic Chemistry I (M.S., H.U.S.), Ulm University, Ulm, Germany; and Department of Pharmacology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt (S.A.F.M.)
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Menna El Gafaary
Institutes of Pharmacology of Natural Products and Clinical Pharmacology (S.A.F.M., M.S., B.B., M.E.G., O.L., T.Sy., T.Si.), and Organic Chemistry I (M.S., H.U.S.), Ulm University, Ulm, Germany; and Department of Pharmacology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt (S.A.F.M.)
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Oleg Lunov
Institutes of Pharmacology of Natural Products and Clinical Pharmacology (S.A.F.M., M.S., B.B., M.E.G., O.L., T.Sy., T.Si.), and Organic Chemistry I (M.S., H.U.S.), Ulm University, Ulm, Germany; and Department of Pharmacology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt (S.A.F.M.)
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Tatiana Syrovets
Institutes of Pharmacology of Natural Products and Clinical Pharmacology (S.A.F.M., M.S., B.B., M.E.G., O.L., T.Sy., T.Si.), and Organic Chemistry I (M.S., H.U.S.), Ulm University, Ulm, Germany; and Department of Pharmacology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt (S.A.F.M.)
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Thomas Simmet
Institutes of Pharmacology of Natural Products and Clinical Pharmacology (S.A.F.M., M.S., B.B., M.E.G., O.L., T.Sy., T.Si.), and Organic Chemistry I (M.S., H.U.S.), Ulm University, Ulm, Germany; and Department of Pharmacology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt (S.A.F.M.)
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Abstract

The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and its uncontrolled activation is a hallmark of cancer. Moreover, mTOR activation has been implicated in the resistance of cancer cells to many anticancer drugs, rendering this pathway a promising pharmacotherapeutic target. Here we explored the capability of a semisynthetic compound to intercept mTOR signaling. We synthesized and chemically characterized a novel, semisynthetic triterpenoid derivative, 3-cinnamoyl-11-keto-β-boswellic acid (C-KβBA). Its pharmacodynamic effects on mTOR and several other signaling pathways were assessed in a number of prostate and breast cancer cell lines as well as in normal prostate epithelial cells. C-KβBA exhibits specific antiproliferative and proapoptotic effects in cancer cell lines in vitro as well as in PC-3 prostate cancer xenografts in vivo. Mechanistically, the compound significantly inhibits the cap-dependent transition machinery, decreases expression of eukaryotic translation initiation factor 4E and cyclin D1, and induces G1 cell-cycle arrest. In contrast to conventional mTOR inhibitors, C-KβBA downregulates the phosphorylation of p70 ribosomal S6 kinase, the major downstream target of mTOR complex 1, without concomitant activation of mTOR complex 2/Akt and extracellular signal–regulated kinase pathways, and independently of protein phosphatase 2A, liver kinase B1/AMP-activated protein kinase/tuberous sclerosis complex, and F12-protein binding. At the molecular level, the compound binds to the FKBP12-rapamycin-binding domain of mTOR with high affinity, thereby competing with the endogenous mTOR activator phosphatidic acid. C-KβBA represents a new type of proapoptotic mTOR inhibitor that, due to its special mechanistic profile, might overcome the therapeutic drawbacks of conventional mTOR inhibitors.

Footnotes

  • This work was partially supported by the Deutsche Krebshilfe [Grant 102383 to T.Sy. and T.Si.].

  • dx.doi.org/10.1124/mol.112.081349.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Received July 18, 2012.
  • Accepted December 3, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (2)
Molecular Pharmacology
Vol. 83, Issue 2
1 Feb 2013
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Research ArticleArticle

A Novel Semisynthetic FRB Domain Inhibitor of mTOR

Samy A. F. Morad, Maximilian Schmid, Berthold Büchele, Hans-Ullrich Siehl, Menna El Gafaary, Oleg Lunov, Tatiana Syrovets and Thomas Simmet
Molecular Pharmacology February 1, 2013, 83 (2) 531-541; DOI: https://doi.org/10.1124/mol.112.081349

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Research ArticleArticle

A Novel Semisynthetic FRB Domain Inhibitor of mTOR

Samy A. F. Morad, Maximilian Schmid, Berthold Büchele, Hans-Ullrich Siehl, Menna El Gafaary, Oleg Lunov, Tatiana Syrovets and Thomas Simmet
Molecular Pharmacology February 1, 2013, 83 (2) 531-541; DOI: https://doi.org/10.1124/mol.112.081349
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