nitrophenols and Prostatic-Neoplasms--Castration-Resistant

Cancer cell survival depends on the cross-regulation between apoptosis and autophagy which share common signaling pathways including PI3K/Akt/mTOR and Bcl-2. The aim of this study was to elucidate the modulation patterns between apoptosis and autophagy following dual inhibition by Akt inhibitor erufosine and Bcl-2 inhibitor ABT-737 in castration-resistant prostate cancer (CRPC) cell lines, PC-3 (Bax+) and DU-145 (Bax-).. Cell cycle progression, apoptotic and autophagic signaling were examined by flow cytometry, multi-caspase assay, Hoechst staining, acridine orange staining of acidic vesicular organelles (AVOs), qRT-PCR and Western Blot. Dual inhibition increased G2/M arrest in PC-3 and DU-145, but not in the healthy prostate epithelium cells, PNT-1A. Only in PC-3, dual inhibition induced synergistic apoptotic and additive autophagic effects. In DU-145 and PNT-1A cells, ABT-737 did not display any remarkable effect on multicaspase activity and erufosine and ABT-737, neither alone nor in combination induced AVOs. By dual inhibition, AKT, BCL-2 and NF-κB gene expressions were downregulated in PC-3, both ATG-5 and BECLIN-1 gene expressions were upregulated in DU-145 but Beclin-1 protein expression was substantially reduced in both CRPC cells. Dual inhibition-induced synergistic multicaspase activation in PC-3 degrades and disrupts autophagic activity of Beclin-1, enhancing caspase-dependent apoptosis. However, in DU-145, following dual inhibition, rate of multicaspase induction and apoptosis are lower but autophagy is completely abolished despite markedly increased BECLIN-1 gene expression.. In conclusion, antineoplastic drug combinations may display cell-type specific modulation of apoptotic and autophagic signaling and lack of protective autophagy may not necessarily indicate increased chemotherapeutic sensitivity in heterogenous tumor subpopulations.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Biphenyl Compounds; Cell Line, Tumor; Cell Proliferation; Humans; Male; Nitrophenols; Organophosphates; Phosphatidylinositol 3-Kinases; Piperazines; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Quaternary Ammonium Compounds; Signal Transduction; Sulfonamides

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.

Topics: Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Cell Cycle; Cell Proliferation; Drug Therapy, Combination; Humans; Male; Nitrophenols; Organophosphates; Piperazines; Prostatic Neoplasms, Castration-Resistant; Quaternary Ammonium Compounds; Sulfonamides; Tumor Cells, Cultured