The effect of racemic gossypol and AT-101 on angiogenic profile of OVCAR-3 cells: a preliminary molecular framework for gossypol enantiomers

To compare the effect of racemic gossypol with its (–)/(–) enantiomer (AT-101) on expression profiles of angiogenic molecules by mRNA levels in human ovarian cancer cell line OVCAR-3. Methods: Cell viability assay (2,3-bis (2-methoxy-4-nitro-5- sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide) was used to detect cytotoxicity of gossypol enantiomers. DNA fragmentation by an enzyme-linked immunosorbent (ELISA) assay was used to evaluate the rate of apoptosis. The mRNA expression levels of angiogenic molecules were investigated by Human Angiogenesis RT2 ProfilerTM PCR Array (SuperArray, Frederick, MD). Results: Both racemic form and AT-101 resulted in a significant cytotoxicity and induced apoptosis. This effect was observed in a dose- and time dependent manner. However, AT-101 was much more potent. In addition, the treatment of 10 μM of racemic gossypol alone and 3 μM of AT-101 alone resulted in significant down-regulation (≥ 3 fold) in mRNA levels of some pivotal angiogenic molecules in OVCAR-3, but altered gene profiles were different by the treatment of each enantiomer. Conclusion: The efficacy of two gossypol enantiomers in OVCAR-3 cells showed distinction. AT-101 was much more potent than racemic gossypol, not only by means of cell death and apoptosis, but also by modulation of angiogenic molecules released from OVCAR-3 cells. Further studies with endothelial cells should be done to verify the anti-angiogenic effect of gossypol enantiomers in cancer treatment

Docetaxel: A first choice in the management of anthracycline-resistant metastatic breast cancer

Purpose: The role of salvage chemotherapy in patients with anthracycline-resistant metastatic breast cancer (MBC) is still a matter of research. No convincing data exists that combination therapy is superior to single-agent treatment. Docetaxel has been reported as an effective chemotherapeutic agent in patients with previously treated MBC. We designed-agent docetaxel in the management of patients with anthracycline-resistant MBC. Patients and methods: Thirty-five patient with MBC and progressive disease (PD) while receiving anthracycline-containing chemotherapy, and fulfilling the usual criteria, entered this phase II, prospective, nonrandomized study. Docetaxel was administered at a dose of 100 mg/m2 as a short 1-hour infusion every 21 days. All patients received corticosteroid premedication. Response and toxicity were assessed according to standard criteria. Results: Objective responses were seen in 14 patients (one complete response-CR- and 13 partial responses-PRs), resulting in an overall response rate (ORR) of 40%. The median response duration was 5 months (range 4-10 months). The median time to progression (TTP) was 6.5 months (range 4-12 months); the disease-free survival (DFS) and overall survival (OS) at 12 months were 32.4% and 47.8%, respectively. The most common toxicity was neutropenia, which occurred in 74% of the patients. Clinically significant non-hematologic side-effects included fluid retention, neurosensory changes and alopecia. Conclusion: Docetaxel has a high antitumor activity in patients with anthracycline-resistant MBC and appears to be one of the most active agents for the treatment of this patient population

The prevalence and prognostic importance of the androgen receptor in triple-negative breast cancer

Purpose: Triple-negative breast cancer (TNBC) has a significantly more aggressive course, higher recurrence rate, and shorter survival time than the other breast cancer types. The disease has molecular heterogeneity, and in a subset of patients, androgen receptor (AR) expression is present. Our study aimed to demonstrate prevalence of the AR positivity and examine the potential prognostic impact on patient survival. Methods: The study included patients aged >18 years who had a history of triple-negative nonmetastatic breast cancer and were followed-up and treated at Ege University Medical Faculty Hospital between 2005 and 2017. In our study,staining extent was expressed as a percentage, with ?1% positivity in stained preparates evaluated as AR positive. Results: 36% prevalence rate of AR expression was found in the TNBC group, consistent with previous studies.In our study, although no statistically significant relationship was found between overall and disease-free survival and AR expression in the patients with early-stage TNBC, disease-free survival was significantly longer in the AR-positive group. No significant difference in the number of locally advanced patients was found between the AR-positive and AR-negative groups. Conclusion: Although AR expression was found to have no statistically significant relationship with clinicopathological parameters and survival in the patients with TNBC, a larger series of studies is needed to validate the results of the present study. Furthermore, with the inclusion of AR expression level meaurement in routine histopathological examination in the TNBC group, with an expression rate of 36%, future AR-targeted therapies may show promising effectiveness. © 2021 Zerbinis Publications. All rights reserved.This study was funded by scientific research projects no: 20123

Preparation of arsenic trioxide-loaded microemulsion and its enhanced cytotoxicity on MCF-7 breast carcinoma cell line

PubMed ID: 15736829In this study, an injectable microemulsion of arsenic trioxide (As 2O3-M) was prepared for intratumoral injection and the suppressive effect of As2O3-loaded microemulsion on human breast cancer cells MCF-7 was compared with those of a solution of the drug. Microemulsion was made up of soybean oil as oil phase, a mixture of Brij 58 and Span 80 as surfactants, absolute ethanol as cosurfactant, and bidistilled water containing As2O3 solution as the aqueous phase. Microemulsion formulation contains 5 × 10-6 M As 2O3. The pH of As2O3-M was adjusted to 7.35 ± 0.1 and the physicochemical stability of the formulation was observed. The particle size distribution and zeta potential of As 2O3-M were measured by Zetasizer 3000 HSA. The mean droplet diameters of As2O3-M were determined as 8.6 ± 0.4 nm. As2O3-M exhibited 13.1 ± 0.9 mV zeta potential. The formulation was physically stable for 12 months at room temperature when kept in ampule forms, as well as after autoclaving at 110°C for 30 min. The antitumor effects of As2O3-M were examined on human breast cancer cells MCF-7. It was clearly demonstrated that As2O3-M had a significant cytotoxic effect on breast cancer cell lines, and the cytotoxic effect of As2O3-M was significantly more than that of regular As2O3 solutions. Even ~3000 times diluted microemulsion formulation loaded with 5 × 10-6 M As2O3 showed a cytotoxic effect. As a result, this diluted concentration (~1.6 × 10-9 M) was found 1000 times more effective than regular As2O3 solutions (5 × 10-6 M). According to the in vitro cytotoxicity studies, we concluded that when As2O3 was incorporated into the microemulsion (As2O3-M), which is a new drug carrier system, it suppresses tumor cell growth on multiple tumor lines. These results indicate that As2O3-M may exert a low cytotoxic effect on normal cells and may be effective as an antitumor agent that induces apoptosis

Potential involvement of calcineurin in regulating the state of differentiation and apoptosis of HL-60 cells during methylprednisolone-treatment

To evaluate the role of calcineurin (protein phosphatase type 2B, PP2B) in methylprednisolone-induced differentiation and apoptosis of leukaemic cells, we have investigated the induction of apoptosis, calcineurin specific protein phosphatase activity and expression of regulatory and catalytic subunits of calcineurin and calmodulin after induction of HL-60 leukaemic cells with methylprednisolone. The cells underwent differentiation and apoptosis within 72 hours time period after methylprednisolone added to cell culture media. Before apoptosis occurred, the specific calcineurin enzyme activity revealed gradual increase during the differentiation process. However, immunoblots of catalytic and regulatory subunits of calcineurin showed no amplification in the amount of these cellular signaling mediators during methylprednisolone-induced differentiation and apoptosis but calmodulin expression gradually increased during the process. Significant increase in the specific calcineurin enzyme activity during differentiation and apoptosis might be crucial to the posttranslational modifications of calcineurin during methylprednisolone-induced differentiation

Fluorouracil and folinic acid bolus schedule (nordic regimen) combined with irinotecan as a first-line chemotherapy in metastatic colorectal cancer

The recent incorporation of irinotecan (CPT-11) for the management of advanced colorectal cancer has generated further improvement in survival. The goal of this retrospective analysis was to evaluate the efficacy and toxicity of irinotecan plus bolus FU/FA (Nordic regimen) as first-line therapy in patients with advanced colorectal cancer. A total of 43 patients with metastatic colorectal cancer treated with irinotecan plus bolus FU/FA (Nordic regimen) as first-line chemotherapy were reviewed. Patients with metastatic adenocarcinoma of the colon or rectum and who had measurable disease and WHO performance status of 2 or less were treated with irinotecan 210 mg/m2 as a 30-90 min intravenous infusion on day 1, followed by 5-FU 500 mg/m2 and FA 60 mg/m2 bolus on days 1 and 2, every 2 weeks, until disease progression or unacceptable toxicity. Patients were evaluated for response rates, survival and toxicity. Median patient age was 56 (29-76) years. Response rates were 72% as a carcino embryogenic antigen (CEA) level and 45% as a clinic evaluation. Disease control rates were 76% as a CEA level and 80% as a clinic evaluation. Median duration of response was 5,8 (2-9) months as a clinic evaluation and median duration of response was 6,6 (2-11) months as a CEA level. Median progression free interval was 9 (2-13) months and median overall survival was 16 (3-18) months. Grade 3-4 neutropenia occurred in 30% of the patients. Non-haematological toxicities were mild. There was no treatment-related death. Irinotecan - Nordic regimen is considered as a reasonable option for first-line treatment of patients with metastatic colorectal cancer