Oncotarget

Research Papers:

Acetyl-lupeolic acid inhibits Akt signaling and induces apoptosis in chemoresistant prostate cancer cells in vitro and in vivo

Claudia Schmidt, Cornelia Loos, Lu Jin, Michael Schmiech, Christoph Q. Schmidt, Menna El Gaafary, Tatiana Syrovets and Thomas Simmet _

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Oncotarget. 2017; 8:55147-55161. https://doi.org/10.18632/oncotarget.19101

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Abstract

Claudia Schmidt1,2, Cornelia Loos1,3, Lu Jin1, Michael Schmiech1, Christoph Q. Schmidt1, Menna El Gaafary1,4, Tatiana Syrovets1,* and Thomas Simmet1,*

1Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany

2Present address: Rommelag CMO, Sulzbach-Laufen, Germany

3Present address: Institute of Protein Biochemistry, Ulm University, Ulm, Germany

4Present address: Department of Pharmacognosy, College of Pharmacy, Cairo University, Giza, Egypt

*These authors contributed equally to this work

Correspondence to:

Thomas Simmet, email: thomas.simmet@uni-ulm.de

Keywords: triterpenoids, apoptosis, prostate cancer, allosteric Akt inhibitor

Received: February 09, 2017     Accepted: June 27, 2017     Published: July 08, 2017

ABSTRACT

The triterpenoid acetyl-lupeolic acid (ac-LA) isolated from the oleogum resin of Boswellia carterii reduced the viability of a panel of cancer cell lines more efficiently than lupeol. There was no detectable intracellular conversion of ac-LA to lupeol and vice versa. In contrast to docetaxel, ac-LA did not induce selection of treatment-resistant cancer cells. By various parameters including DNA fragmentation, ac-LA was shown to induce apoptosis in androgen-independent PC-3 cells, whereas in MDA-MB-231 breast cancer cells, ac-LA led to cell accumulation in the G2/M phase of the cell cycle, but not to apoptosis. In silico docking combined with in vitro kinase assays implied that ac LA potently inhibits Akt mainly by direct binding to the pleckstrin homology domain. Consistently, an Akt1 mutant deficient of the PH domain afforded partial resistance to ac-LA and complete resistance to lupeol and the Akt inhibitor III. Ac-LA inhibited phosphorylation of downstream targets of the Akt signaling pathway, which was followed by inhibition of the mTOR target p70 ribosomal six protein kinase and the nuclear accumulation of p65/NF-κB, β-catenin, and c-myc, as well as loss of the mitochondrial membrane potential. Ac-LA exhibited antiproliferative, proapoptotic, and antitumorigenic effects on PC-3-tumors xenografted either on chick chorioallantoic membranes or in nude mice. Ac-LA exhibited a clearly better safety profile than docetaxel or lupeol during chronic administration in vivo. In contrast to lupeol, ac-LA also inhibited release of vascular endothelial growth factor in vitro and accordingly angiogenesis in vivo. Thus, ac-LA deserves further exploration as a potential new antitumor compound.


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