Apoptotic effects of proteasome and histone deacetylase inhibitors in prostate cancer cell lines.

Prostate cancer is one of the most common types of urological cancers. Despite the implementation of effective radiotherapy and chemotherapy methods, prostate cancer cells can still show resistance to treatment. In recent years, a combination of proteasome and histone deacetylase inhibitors has been used to treat various malignancies. In this study, we examined the cytotoxic and apoptotic effects of the proteasome inhibitor bortezomib (Velcade/PS-341) and histone deacetylase inhibitor trichostatin A (TSA), used either alone or in combination, on the human prostate LNCaP and PC3 cell lines. We investigated the cytotoxic activity of these inhibitors using a WST-1 assay, IkBα and caspase-3 mRNA levels by real-time polymerase chain reaction, and caspase-3 activity and activation of phosphorylated (p-IkBα) protein by Western blotting. Low-dose bortezomib and TSA synergistically induced apoptosis in both prostate cancer cell lines. Combination treatment with TSA with bortezomib effectively inactivated NFkB signaling, upregulated the predominant endogenous apoptotic factor caspase-3, and disrupted the NFkB pathway in the androgen-independent PC3 cell line. In contrast, androgen-dependent LNCaP cells showed upregulation of caspase-3 through a pathway other than NFkB. This study examined the possible clinical use of bortezomib and TSA, together with reduced doses of chemotherapeutic agents with high cytotoxicity, to determine their apoptotic effects on the NFkB pathway in prostate cancer cell lines. Therefore, combination bortezomib and TSA treatment may represent a novel therapeutic strategy for prostate cancer.

Different surgical techniques and L-carnitine supplementation in an experimental varicocele model.

We aimed to investigate the impact of various varicocelectomy techniques and/or L-carnitine as an adjunct treatment, following the emergence of oxidative stress, on the expression levels of SCF/c-kit signalling pathways in spermatogenesis. Forty-two rats were divided into seven groups: group 1 (G1) control; group 2 (G2) sham; group 3 (G3) varicocele; group 4 (G4) varicocele + varicocelectomy with testicular nonartery sparing; group 5 (G5) same as G4 but with artery sparing; group 6 (G6) same as G4 but with L-carnitine and group 7 (G7) same as G5 with L-carnitine. mRNA expression levels of SCF and c-kit were measured quantitatively using real-time polymerase chain reaction. CASP-3 activity at protein level was determined, and histological evaluation was performed. mRNA expression level of SCF increased in G6 as compared to control group (3.52-folds change; P = 0.035), whereas mRNA expression level of c-kit gene remained the same. We found that in the left testis of G6 group, mRNA expression level of SCF increased 2.2-folds in comparison with the right testis (P < 0.05). There were no statistically significant differences in the CASP-3 protein expression levels between the control and other groups. When Cosentino Score analyses of immunostaining were conducted, we observed no significant differences among groups. Spermatogenic failure could be primarily due to a sertoli cell dysfunction. Although surgical treatment has been the best option for management of varicocele, auxiliary agents like L-carnitine may be considered as supportive treatment regimes in addition to conventional surgical treatments.

Is varicocele a prognostic factor for determining sperm retrieval rate before testicular sperm extraction?

66 nonobstructive azoospermic mean with normal genetic analysis composed of 32 (48%) patients with and 34 (52%) patients without varicocele were evaluated for the rate of sperm extraction five months after the varicocelectomy. Sperm retrieval was successful in 22 of 32 patients (68%) who had been operated because of varicocele and in 13 of 34 patients (38.2%) who had no varicocele (OR = 3.55) (CI: 1.15-11.27) (p = 0.025). Overall, sperm extraction was successful in 35 of 66 patients (53%). Repair of varicocele in non-obstructive azoospermic patients may return spermatogenesis to normal in spermatogenic focuses. So, the present of varicocele and its treatment might be considered as a prognostic factor for sperm retrieval in these patients.

The results of concomitant and sequential chemoradiotherapy with cisplatin and etoposide in patients with locally advanced non-small cell lung cancer.

PURPOSE: To report on the treatment results and demographic characteristics of patients with locally advanced non small cell lung carcinoma (NSCLC) who were treated with concomitant or sequential chemoradiotherapy. PATIENTS AND METHODS: 132 patients with locally advanced NSCLC (stage IIIB) were evaluated. Their median age was 60 years (range 33-80). Histopathological diagnosis was epidermoid carcinoma in 96 (73%) patients, adenocarcinoma in 33 (25%) patients and large cell carcinoma in 3 (2%) patients. Karnofsky performance status (KPS) score was >/= 70 in 112 (85%) patients. Weight loss was greater than 5% in 34 (26%) patients at presentation. One hundred and six (80%) patients were treated with sequential chemoradiotherapy which consisted of 3 monthly cycles of cisplatin (100 mg/m(2), day 1) and etoposide (100 mg/m(2)/day, days 1-3) before radiotherapy. Radiotherapy consisted of a total dose of 60 Gy in 30 fractions (2 Gy / fraction), given to a volume including primary tumor and mediastinum. Two to 4 cycles of chemotherapy were administered after completion of radiotherapy to patients whose disease had not progressed after initial chemotherapy. Twenty-six patients were treated with concomitant chemoradiotherapy. The same radiotherapy regimen was started with the 2nd cycle of chemotherapy which consisted of cisplatin (80 mg/m(2), day 1) and etoposide (100 mg/m(2)/day, days 1-3). Chemotherapy was completed after 4 cycles in all patients. RESULTS: Overall survival (OS) was 14.5 months in 106 patients treated with sequential chemoradiotherapy and 14.6 months in 26 patients treated with concomitant chemoradiotherapy (p=0.99). Median time to progression was 9.77 months in the concomitant group and 11.6 months in the sequential group (p=0.47). However, progression-free survival was better in patients of both groups whose KPS was >70 (12.4 months versus 11.5 months, p= 0.02). While presence of anemia was found as an adverse prognostic factor only in univariate analysis, non-epidermoid histology, KPS less than 70 and presence of N2-N3 disease were found as adverse prognostic factors in both univariate and multivariate analysis. CONCLUSION: The addition of chemotherapy to radiation concomitantly or sequentially prolongs survival in locally advanced NSCLC patients with acceptable adverse event profiles in both arms compared with results of the trials in the literature in which radiotherapy is used as single treatment modality.