Synergistic roles of p53 and HIF1α in human renal cell carcinoma-cell apoptosis responding to the inhibition of mTOR and MDM2 signaling pathways.

INTRODUCTION: mTOR and MDM2 signaling pathways are frequently deregulated in cancer development, and inhibition of mTOR or MDM2 independently enhances carcinoma-cell apoptosis. However, responses to mTOR and MDM2 antagonists in renal cell carcinoma (RCC) remain unknown. MATERIALS AND METHODS: A498 cells treated with MDM2 antagonist MI-319 and/or mTOR inhibitor rapamycin were employed in the present study. Cell apoptosis and Western blot analysis were performed. RESULTS AND CONCLUSION: We found that the MDM2 inhibitor MI-319 induced RCC cell apoptosis mainly dependent on p53 overexpression, while the mTOR antagonist rapamycin promoted RCC cell apoptosis primarily through upregulation of HIF1α expression. Importantly, strong synergistic effects of MI-319 and rapamycin combinations at relatively low concentrations on RCC cell apoptosis were observed. Depletion of p53 or HIF1α impaired both antagonist-elicited apoptoses to differential extents, corresponding to their expression changes responding to chemical treatments, and double knockdown of p53 and HIF1α remarkably hindered MI-319- or rapamycin-induced apoptosis, suggesting that both p53 and HIF1α are involved in MDM2 or mTOR antagonist-induced apoptosis. Collectively, we propose that concurrent activation of p53 and HIF1α may effectively result in cancer-cell apoptosis, and that combined MDM2 antagonists and mTOR inhibitors may be useful in RCC therapy.

Rapamycin enhances the susceptibility of both androgen-dependent and -independent prostate carcinoma cells to docetaxel.

BACKGROUND: Docetaxel (DOC) therapy is well tolerated and shows high response rates in patients with hormone refractory prostate cancer (HRPC). There are many reports on the effect of rapamycin (RPM) on the treatment of carcinogenesis. The goal of this study was to test whether RPM could enhance the susceptibility of both androgen-dependent and -independent prostate carcinoma cells to DOC. METHODS: Prostate cancer (PC) cell lines (LNCap, PC3 and AILNCap) were cultured and treated with RPM and DOC alone or in combination. The effects of therapeutic agents on cells were determined by the WST-1 assay. Apoptosis induction was confirmed by flow cytometric analysis. The apopcyto caspase colorimetric assay kit was applied to measure the activities of caspases 3 and 9. The antitumor effects of RPM and DOC against PC cells were also assessed in nude mice using four randomized groups: control, RPM, DOC and combination drug therapy by measuring tumor size. All the animals tolerated both RPM and DOC without significant weight loss. RESULTS: RPM and DOC caused dosage-dependent growth suppression of PC cells. RPM could increase the susceptibility of PC cells to DOC significantly, and combined treatment with RPM and DOC caused synergistic growth suppression in all examined PC cell lines by isobolographic analysis. Both RPM and DOC significantly induced apoptosis in a dosage-dependent manner. RPM (10 nmol/L), DOC (1 nmol/L), and combined treatment induced apoptosis rate were 8%, 17% and 38%, respectively (the control was 2%). RPM could promote the apoptosis induced by DOC in PC cell lines. Both RPM and DOC significantly increased the caspase activity in a dosage-dependent manner. The relative activities of caspase 9 in control, RPM, DOC and RPM + DOC groups were 0.22 +/- 0.02, 0.36 +/- 0.06, 0.47 +/- 0.05 and 0.84 +/- 0.08, respectively. The relative activities of caspase 3 were 0.21 +/- 0.02, 0.24 +/- 0.05, 0.42 +/- 0.06 and 0.81 +/- 0.09, respectively. Either RPM or DOC alone significantly inhibited the growth of PC cells in nude mice compared to the control. The combination of RPM and DOC produced a significant reduction in tumor volume when compared to RPM or DOC alone. After 5-week treatment, the tumor sizes of LNCap in control, RPM, DOC and RPM + DOC groups were (570 +/- 56) mm(3), (412 +/- 41) mm(3), (425 +/- 46) mm(3) and (221 +/- 26) mm(3), respectively. CONCLUSIONS: RPM could significantly increase the susceptibility of both androgen-dependent and -independent PC cells to DOC; the synergy of RPM and DOC was demonstrated. RPM enhanced the DOC-induced upregulation of caspase activity, resulting in an increasing number of cells in sub-G1 phases. The synergy of the combined treatment might be observed in both androgen-dependent and -independent PC cell lines.

[Comparison of holmium and thulium laser in transurethral enucleation of the prostate].

OBJECTIVE: To investigate and compare the effect and safety of Holmium laser and Thulium laser in transurethral enucleation of the prostate in BPH patients. METHODS: Ninety-eight BPH patients were divided into 2 groups and underwent transurethral enucleation of the prostate with holmium laser (Ho group) and thulium laser (Th group) respectively. Comparisons were made between the 2 groups in operation time, bleeding volume, electrolyte, IPSS score, PVR and Qmax. RESULTS: No statistically significant differences were noted between the 2 groups in age and preoperative prostate volume, IPSS, PVR and Qmax (P > 0.05). The mean operation time was shorter in the Th group ([84.6 +/- 10.2] min) than in the Ho group ([70.5 +/- 7.5] min) (P = 0.032); blood loss was less in the former ([126.5 +/- 14.6] ml) than in the latter ([176.5 +/- 14.1] ml) (P = 0.071), with no blood transfusion necessitated; and the mean times of catheter indwelling were 2.4 d and 2.5 d respectively. There were no significant differences in the levels of hemoglobin and electrolyte before and after operation between the two groups, and no TURP syndrome was observed. IPSS, PVR and Qmax before operation were significantly different from those obtained 3 months after it (P < 0.05) in both the groups, but none of the indexes exhibited statistically significant differences when compared in the same period (P > 0.05). CONCLUSION: Both holmium and thulium laser transurethral enucleation of the prostate can alleviate LUTS in BPH patients with similar short-time effectiveness. Thulium is superior to holmium laser in hemostasis, but inferior to it in anatomical distinctness.