Cigdem Erten

Docetaxel/zoledronic acid combination triggers apoptosis synergistically through downregulating antiapoptotic Bcl-2 protein level in hormone-refractory prostate cancer cells.

Docetaxel, a semi‐synthetic taxane analogue, is used effectively in the treatment of metastatic prostate cancer. Zoledronic acid, the most potent member of bisphosphonates, has shown pleiotropic anti‐tumoral effects on prostate cancer cells. We have explored the possible additive/synergistic effects and the apoptotic pathways induced by combination treatment of docetaxel and zoledronic acid in hormone and drug refractory, PC‐3 and DU‐145 prostate cancer cells. Combination of docetaxel and zoledronic acid synergistically inhibits cell growth in PC‐3 and DU‐145 cells. Moreover, this effect was due to downregulation of antiapoptotic protein Bcl‐2 in PC‐3 and DU‐145 cells. In conclusion, docetaxel/zoledronic acid combination is potentially a novel and effective approach for the treatment of prostate cancer.

Overcoming drug resistance in hormone- and drug-refractory prostate cancer cell line, PC-3 by docetaxel and gossypol combination.

Drug resistance is a significant challenge of daily oncology practice. Docetaxel and gossypol both have antitumoral activity in hormone-refractory prostate cancer (HRPC). Our results revealed that docetaxel and gossypol were synergistically cytotoxic and apoptotic in PC-3 cells in a dose- and time-dependent manner. We further investigated the expression profiles of genes involved in drug resistance and metabolism with a Human Cancer Drug Resistance and Metabolism PCR Array® (SuperArray). Six of the 84 genes that are known to regulate drug resistance, metabolism, cell cycle, DNA repair and oncogenesis were downregulated ≥3-fold change by the combination treatment. These results may be important in devising mechanism-based and targeted therapeutic strategies for prostate cancer, especially in devising combination therapy for drug resistant prostate cancers.

Enhancement of docetaxel-induced cytotoxicity and apoptosis by all-trans retinoic acid (ATRA) through downregulation of survivin (BIRC5), MCL-1 and LTbeta-R in hormone- and drug resistant prostate cancer cell line, DU-145

BackgroundThe management of hormone-refractory prostate cancer (HRPC) still remains as an important challenge of daily oncology practice. Docetaxel has proved to be a first line treatment choice. All-trans retinoic acid (ATRA) could potently inhibit the growth of prostate cancer cells in vitro and its combination with various anticancer agents results in increased cytotoxicity. Based on these data, our aim was to examine the synergistic/additive cytotoxic and apoptotic effects of combination of docetaxel and ATRA, in hormone- and drug refractory human DU-145 prostate cancer cells. Furthermore, we have searched for the underlying mechanisms of apoptosis by demonstrating apoptosis-related genes.MethodsXTT cell proliferation assay was used for showing cytotoxicity. For verifying apoptosis, both DNA Fragmentation by ELISA assay and caspase 3/7 activity measurement were used. For detecting the mechanism of apoptosis induced by docetaxel-ATRA combination, OligoGeArray® which consists of 112 apoptosis related genes was used.ResultsOur results revealed that docetaxel and ATRA were synergistically cytotoxic and apoptotic in DU-145 cells, in a dose- and time dependent manner. It was also shown by our studies that apoptosis was induced in DU-145 prostate carcinoma cells with significant cytotoxicity, no matter which agent applied first. We have found out that docetaxel-ATRA combination significantly downregulates survivin (BIRC5), myeloid cell leukemia-1 (MCL-1) and lymphotoxin β-receptor (LTβR) genes, which all three have pivotal roles in regulation of apoptosis and cell cycle progression.ConclusionIn conclusion, we strongly suggest that docetaxel and ATRA combination is a good candidate for this challenging era of daily oncologic practice. Also, the combination of docetaxel and ATRA might allow a reduction in docetaxel doses and by this way may diminish docetaxel adverse effects while maintaining the therapeutic effect in patients with HRPC.

Prognostic and Predictive Value of Hematologic Parameters in Patients with Metastatic Renal Cell Carcinoma: Second Line Sunitinib Treatment Following IFN-alpha

BACKGROUND Long-term survival is a problem with locally advanced and metastatic renal cell carcinomas. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor, but data on sunitinib use as a second line treatment in metastatic renal cell carcinoma (mRCC) are limited. Prognostic and predictive value of peripheral blood markers has been shown for many cancers. MATERIALS AND METHODS Efficacy and safety profiles of sunitinib after interferon alpha were evaluated based on retrospective data for 23 patients with mRCC. Hematological parameters (neutrophils, lymphocytes, platelets, mean platelet volume, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio) were recorded at the time of metastasis. It was evaluated whether hematological parameters were prognostic and predictive factors. RESULTS Median progression-free survival (PFS) time was 16.5 months (95%CI: 0-34.5). Median overall survival (OS) time was 25.7 months (95%CI: 10.8-40.0). Most common side effects were neutropenia (52.2%), stomatitis (26.1%) and hand-food syndrome (26.1%). PFS was found 3.13 vs 17.1 months in patients with neutrophil / lymphocyte ratio (NLR)>3 vs NLR≤3 (p:0.012). Median OS was 6.96 vs 27.1 months in patients with NLR>3 vs NLR≤3 (p:0.001).While 75% of patients who responded to sunitinib had NLR≤3, in 72% of patients with no response to sunitinib NLR>3 was detected (p:0.036). The association between the Memorial Sloan-Kettering Cancer Center (MSKCC) criteria and NLR was statistically significant (p:0.022). CONCLUSIONS Data on second line sunitinib treatment following cytokine in mRCC are limited. In our study, we observed second line sunitinib treatment following IFN-alpha to be effective and tolerable. NLR appeared to have prognostic and predictive value.

Regulation of growth factors in hormone- and drug-resistant prostate cancer cells by synergistic combination of docetaxel and octreotide.

To evaluate the effects of combined treatment with docetaxel and octreotide, a somatostatin analogue, on human hormone‐ and drug‐refractory prostate cancer cell lines, PC‐3 and DU‐145, and on some growth factors related to tumour growth and angiogenesis in prostate cancer.

The effects of hematological parameters and tumor-infiltrating lymphocytes on prognosis in patients with gastric cancer

BACKGROUND It is well known that tumor-infiltrating lymphocytes (TIL) and, to a lesser extent, peripheral hematologic parameters from patients with cancer have to effect on prognosis. The aim of this study was to evaluate the effect of hematologic parameters and TIL on prognosis of patients with gastric cancer. METHODS 236 patients who had diagnosed as gastric adenocarcinoma. All hematologic parameters were noted at the time of diagnosis. The number of lymphocyte aggregates as well as the number of lymphocytes within these agregat was counted.The prognostic significance and correlations of high neutrophil-lymphocyte ratio (NLR) together with TIL, was evaluated by multivaried analysis. RESULTS The cut-off values of NLR and derived NLR (dNLR) were 3.8 and 2. The NLR was independently associated with survival (P < 0.001). dNLR was not independently associated with overall survival. No significant advantages for overall survival were found for the high TIL (p: 0.372). It was not determined correlation between TIL - NLR and TIL-lymphoid aggregate density (respectivly, P: 0.104; P: 0.246). CONCLUSIONS The results suggest that the elevated NLR predicts poor overall survival following at the time diagnosis for all stage gastric cancer. dNLR was not independently associated with overall survival. There is insufficient evidence to the assesment of TIL by a nonspesific method. Therefore further studies is required, to confirm our hypothesis in larger patient cohorts.

Cisplatin plus gemcitabine chemotherapy in taxane/anthracycline-resistant metastatic breast cancer.

Background: The most commonly used chemotherapeutic regimens in the treatment of metastatic breast cancer (MBC) include anthracyclines and taxanes. In our study, we investigated the efficacy and tolerability of cisplatin plus gemcitabine combination chemotherapy regimen in patients with MBC, who exhibited disease progression after anthracycline- and taxane-based chemotherapy. Methods: Thirty-three patients with taxane/anthracycline-resistant MBC have been treated with gemcitabine 1,000 mg/m2 intravenously and cisplatin 30 mg/m2 intravenously on days 1 and 8 of a 3-week treatment cycle. Results: Thirty-one patients were assessable for response. One of the 31 patients (3.2%) showed complete response, while 7 patients (22.6%) showed partial response; the objective response rate was 25.8%. Stable and progressive disease was observed in 6 (19.4%) and 17 patients (54.8%), respectively. The median time to progression was 4 months (95% CI 2.15–5.85). The median survival time of all patients was 9.5 months (95% CI 7.86–11.14). Conclusion: Gemcitabine and cisplatin combination therapy is moderately active and safe in patients with MBC previously treated with anthracycline and taxanes.

Novel combination of docetaxel and thymoquinone induces synergistic cytotoxicity and apoptosis in DU-145 human prostate cancer cells by modulating PI3K–AKT pathway

BackgroundThe treatment of castrate-resistant prostate cancer (CRPC) still remains as an important challenge of daily oncology practice. Docetaxel significantly prolongs overall survival in men with CRPC. Thymoquinone (TQ), one of the flavonoid compounds isolated from Nigealla sativa, has been shown to possess cytotoxic activity against a variety of cancer cell lines.Materials and MethodsThe aim of the study was to investigate the possible synergistic cytotoxic/apoptotic effects of a novel combination, docetaxel and TQ in DU-145 hormone- and drug-refractory prostate cancer cells and their effects on PI3K and ERK signaling pathways.ResultsWe observed that the combination of docetaxel and TQ resulted in a significant synergistic cytotoxicy and apoptosis as compared to any single agent alone, in a dose-dependent manner. It was found that viability of the combination treated cells was not significantly changed in the presence of LY294002 as compared to inhibitor treated cells. However, in the presence of FR180204, viability of combination treated cells was significantly decreased as compared to inhibitor treated cells. In conclusion, cytotoxic effect of the docetaxel and TQ combination is correlated with the block of the PI3K/Akt signaling pathway in DU-145 cells.ConclusionTherefore, this combination strategy may be an alternative approach for the challenging era of daily oncologic practice. Also, the combination of docetaxel and TQ might allow a reduction in docetaxel doses and diminish adverse effects of docetaxel while maintaining the therapeutic effect in patients with CRPC.

Profiling of angiogenic cytokines produced by hormone- and drug-refractory prostate cancer cell lines, PC-3 and DU-145 before and after treatment with gossypol

In this study, we aimed to investigate the angiogenic cytokine profiles of hormone- and drug-refractory prostate carcinoma cell lines, PC-3 and DU-145. We also studied the effect of gossypol, a natural polyphenolic cotton-seed extract, on the angiogenic cytokine profile of these cell lines. XTT cell proliferation assay was used for the assessment of cytotoxicity. For apoptosis, both histone-DNA fragmentation by ELISA assay and caspase 3/7 activity measurement were used. Angiogenic cytokine profiles of supernatants from both cell lines, before and after treatment with gossypol, were investigated using the human angiogenesis antibody array I. It was shown that the two different hormone- and drug-resistant prostate cancer cell lines, PC-3 and DU-145, constitutively express some important angiogenic cytokines, which are known to regulate tumorigenicity and angiogenesis in hormone-refractory prostate cancer. However, PC-3 and DU-145 cells have distinct angiogenic cytokine profiles. In addition, these two cells lines respond differently to gossypol treatment in terms of cytotoxicity and angiogenic cytokine secretion. After treatment with 10 microM of gossypol, there was a 1.5-fold decrease in angiogenin and IL-8 levels and a 1.7- and 1.8-fold decrease in ENA-78 and GRO-alpha levels respectively, in DU-145 cells. For PC-3 cells, there were 1.6- and 1.8-fold decreases in IL-8 and VEGF levels, respectively. We conclude that PC-3 and DU-145 cells secrete significant amounts of different angiogenic cytokines that may explain their aggressive nature and metastatic potential. Gossypol treatment affects angiogenic cytokine secretion from these two cell lines in a different manner. By expanding our knowledge of the heterogeneous biological behavior of these two cell lines, novel treatment approaches can be developed for the treatment of prostate cancer.

Cisplatin Plus Gemcitabine for Treatment of Breast Cancer Patients with Brain Metastases: a Preferential Option for Triple Negative Patients?

BACKGROUND To assess the efficacy and tolerability of Cisplatin plus Gemcitabine combination in patients with brain metastases (BM) from breast cancer (BC). MATERIALS AND METHODS Eighteen BC patients with BM who were treated with Cisplatin plus Gemcitabine regimen between 2003-2011 were evaluated. RESULTS A median of 6 cycles of this regimen were received, in fifteen patients (83.3%) as first-line chemotherapy, in 2 as second- line and in 1 as third-line after diagnosis of BM. Dose reduction was performed in 11 (61.1%) patients; major reasons were neutropenia and leukopenia. Grade III neutropenia and Grade II trombocytopenia rates were 33.3% and 16.7% respectively. Overall response rate (ORR; complete+partial response rate) was 33.4% (n=6) for the entire study population; triple negative patients achieved an 66.6% ORR while hormone receptor (HR) positive patients had 25% and HER2 positive patients 12.5%. Median progression-free survival was 5.6 months (2.4-8.8 months, 95%CI) and longer in patients with triple negative breast cancer (TNBC) (median 7.4 months, 95%CI, 2.4-12.3 months) than the patients with other subtypes (median 5 months for HER2 positive and 3.6 months for HR positive patients). Median PFS of the patients with TNBC who received this regimen as first-line was 9.2 months (5.2-13.2 months, 95%CI). CONCLUSIONS Cisplatin plus Gemcitabine may be a treatment option for patients with BM from breast cancer. Longer PFS and higher response rates are results that support the usage of this regimen especially for the triple negative subtype. However, further prospective and randomized trials are clearly required to provide more exact information.