Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling has been found in several types of human cancer, including hepatocellular carcinoma (HCC). NVP-BEZ235 is a novel, orally bioavailable dual PI3K/mTOR inhibitor that has exhibited promising activity against HCC in preclinical models. Autophagy is a cellular lysosomal degradation pathway essential for the regulation of cell survival and death to maintain homeostasis. This process is negatively regulated by mTOR signaling and often counteracts the efficacy of certain cancer therapeutic agents. In this study, we explored the role of autophagy in apoptosis induced by NVP-BEZ235 in two HCC cell lines, Hep3B and PLC/PRF/5, and identified the mechanism of combinatorial treatment. NVP-BEZ235 was effective in inhibiting the growth of the two HCC cell lines possibly though induction of apoptosis. NVP-BEZ235 also potently increased the expression of LC3-II and decreased the expression of p62, indicating induction of autophagy. When NVP-BEZ235 was used in combination with Atg5 siRNA or the autophagy inhibitor 3-methyladenine (3-MA), enhancement of the inhibitory effects on the growth of HCC cells was detected. In addition, enhanced induction of apoptosis was observed in cells exposed to the combination of NVP-BEZ235 and Atg5 siRNA or 3-MA. Thus, induction of autophagy by NVP-BEZ235 may be a survival mechanism that counteracts its anticancer effects. Based on these data, we suggest a strategy to enhance the anticancer efficacy of BEZ235 by blockade of autophagy. Thus, our study provides a rationale for the clinical development of combinations of NVP-BEZ235 and autophagy inhibitors for the treatment of HCC and other malignancies.

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ObjectiveTo describe the prostatic arterial supply using Cone-beam computed tomography (CT) and digital subtraction angiography (DSA) before prostatic arterial embolization (PAE) for benign prostatic hyperplasia (BPH).MethodsIn a retrospective study from January 2012 to January 2014, 55 male patients (110 hemipelves) with BPH who underwent PAE were evaluated by Cone-beam CT in addition to pelvic DSA during embolization planning. Each hemipelvis was evaluated regarding the number of prostatic arteries (PA) and their origins, diameters, territorial perfusion, and anastomoses with adjacent arteries.ResultsA total of 114 PAs were identified in 110 hemipelves. There was one PA in 96.4% of the hemipelves (n=106), and two independent PAs in the other 3.6% (n=4). The PA was found to originate from the anterior trunk of the internal iliac artery in 39.5% of cases (n=45) , from the superior vesical artery in 32.6% (n=37), and from the internal pudendal artery in 27.9% of cases (n=32). Extra-prostatic anastomoses between PA and adjacent arteries were found in 39.1% of hemipelves (n=43). Intra-prostatic anastomoses between PAs and contra-lateral prostatic branches were found in 61.8% of hemipelves (n=68). In 67.3% of our study population (n=37), the prostate was dominantly supplied via a unilateral PA.ConclusionThe prostatic vascularization is complex with frequent anatomic variations. Knowledge of the vascular anatomy of the prostate may provide indications for planning PAE and avoiding nontarget embolization.