S. Byun

NVP-BEZ235, a dual PI3K/mTOR inhibitor synergistically potentiates the antitumor effects of cisplatin in bladder cancer cells

The PI3K/Akt/mTOR pathway is a prototypic survival pathway and constitutively activated in many malignant conditions. Moreover, activation of the PI3K/Akt/mTOR pathway confers resistance to various cancer therapies and is often associated with a poor prognosis. In this study, we explored the antitumor effect of NVP-BEZ235, a dual PI3K/mTOR inhibitor in cisplatin-resistant human bladder cancer cells and its synergistic interaction with cisplatin. A human bladder cancer cell line with cisplatin resistance was exposed to escalating doses of NVP-BEZ235 alone or in combination with cisplatin and antitumor effects was determined by the CCK-8 assay. Based on a dose-response study, synergistic interaction between NVP-BEZ235 and cisplatin was evaluated by combination index (CI), three-dimensional model and clonogenic assay. The combination of NVP-BEZ235 and cisplatin caused significant synergistic antitumor effect in cisplatin-resistant bladder cancer cells over a wide dose range and reduced the IC50 of NVP-BEZ235 and cisplatin by 5.6- and 3.6-fold, respectively. Three-dimensional synergy analysis resulted in a synergy volume of 388.25 μM/ml2% indicating a strong synergistic effect of combination therapy. The combination therapy caused cell cycle arrest and caspase-dependent apoptosis. Although NVP-BEZ235 suppressed PI3K/mTOR signaling without any paradoxical induction of Akt activity, it caused MEK/ERK pathway activation. The present study demonstrated that the PI3K/mTOR dual inhibitor NVP-BEZ235 can synergistically potentiate the antitumor effects of cisplatin in cisplatin-resistant bladder cancer cells though the suppression of cell cycle progression and the survival pathway as well as induction of caspase-dependent apoptosis.

Influence of IGFBP3 gene polymorphisms on IGFBP3 serum levels and the risk of prostate cancer in low-risk Korean men.

OBJECTIVES To understand the relationship between the -202 A/C single-nucleotide polymorphism (SNP) of the insulin-like growth factor-binding protein 3 (IGFBP3) gene, IGFBP3 serum levels, and risk of prostate cancer (PCa) in a Korean population, as a potential reason for the lower incidence of PCa in the Korean population. METHODS The IGFBP3 levels were measured and the -202 A/C SNP of the IGFBP3 gene was typed for 225 PCa cases and the same number of matched controls. Linear regression analysis and unconditional logistic regression analysis were used to test for the associations between the genotypes and the circulating IGFBP3 levels and the risk of PCa, respectively. To adjust for the potential bias introduced by the hospital cohort, the result of the genotyping was compared with that of 683 community-indwelling healthy men. RESULTS Significantly lower plasma levels of IGFBP3 were noted in the PCa cases. Lower IGFBP3 plasma levels were associated with an increased number of C alleles (P<.001). Compared with the PCa cases, a lower frequency of the C allele was found in the hospital and community controls (P<.05). Compared with AA genotype, logistic regression analysis revealed an increased risk of PCa in subjects who were CC genotype (odds ratio: 2.39, 95% confidence interval: 1.05-5.48). Larger odds (odds ratio: 3.37, 95% confidence interval: 1.35-8.43) for PCa were associated with CC genotype when the analysis was confined to those who had high-risk PCa. CONCLUSIONS The results supported the protective role of -202 A/C SNP of the IGFBP3 gene against PCa in Korean men.