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ABT-737 and erufosine combination against castration-resistant prostate cancer

a promising but cell-type specific response associated with the modulation of anti-apoptotic signaling

Avsar Abdik, Ezgia,*; Kaleagasioglu, Ferdaa,b,*; Abdik, Hüseyina; Sahin, Fikrettina; Berger, Martin R.c

doi: 10.1097/CAD.0000000000000736
Preclinical report: PDF Only

A deeper understanding of the molecular basis of castration-resistant prostate cancer (CRPC) paved the way for the rational design and development of targeted therapies, which yielded promising preclinical results. However, translation of these potentially promising agents into clinics has usually failed, partly because of tumor heterogeneity. In this study, anticancer activities of the Bcl-2 inhibitor ABT-737 and the Akt-inhibitor erufosine (ErPC3) alone and in combination were compared between CRPC (PC-3 and DU-145) and healthy (PNT-1A) cell lines. The combination of ABT-737 and ErPC3 showed synergistic antiproliferative, antimigratory, and apoptotic effects in PC-3 cells. In DU-145 cells, ErPC3 showed a resistant profile, with half-maximal inhibitory concentration (IC50) values more than two-fold of PC-3, and combining ErPC3 with ABT-737 yielded no added benefit for all the incubation periods compared with ErPC3 alone. In PNT-1A cells, ABT-737 and ErPC3 alone and in combination reduced cell survival slightly and only at the highest concentrations. Apoptosis analysis showed that ABT-737 induced increased Akt expression and ErPC3 induced increased Mcl-1 expression in DU-145 cells. In conclusion, the ABT-737 and ErPC3 combination seems to be promising against CRPC, with a favorable safety profile in healthy cells. However, CRPC cell-type-specific resistance may be induced by enhancement of antiapoptotic signaling.

aDepartment of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul

bDepartment of Medical Pharmacology, Faculty of Medicine, Near East University, Mersin, Turkey

cToxicology and Chemotherapy Unit, German Cancer Research Center, Heidelberg, Germany

*Ezgi Avsar Abdik and Ferda Kaleagasioglu contributed equally to the writing of this article.

Correspondence to Ezgi Avsar Abdik, PhD, Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, 26 August Campus, Kayisdagi Street, 326A, Ataşehir, Istanbul 34755, Turkey Tel: +90 216 578 0000/+90 216 578 3198; fax: +90 216 578 0490; e-mail: ezgi.avsar@yeditepe.edu.tr

Received October 2, 2018

Accepted November 30, 2018

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