AT-101 acts as anti-proliferative and hormone suppressive agent in mouse pituitary corticotroph tumor cells.

PURPOSE: Gossypol, a naturally occurring compound in cottonseeds, has anticancer effects against several tumor cell lines. It has been extensively studied in clinical trials and is well tolerated with a favorable safety profile. AT-101, a derivative of R (-)-gossypol, binds to Bcl-2 family proteins and induces apoptosis in vitro. Although transsphenoidal surgical excision of the pituitary corticotroph adenoma is the gold standard of care, it is not successful all the time. Medical therapy for Cushing's disease still remains a challenge for the clinicians. We aimed to investigate the cytotoxic and apoptotic effects of AT-101 in mouse pituitary corticotroph tumor AtT20 cells. METHODS: Cytotoxic effect of AT-101 was assessed by XTT cell viability assay. Apoptosis was shown by measuring DNA fragmentation and Caspase-3/7 activity. Changes in mRNA expressions of apoptosis-related genes were investigated by qPCR array after treatment with AT-101. ACTH was measured by ACTH-EIA Kit. RESULTS: AT-101 induced cytotoxicity and apoptosis in AtT20 cells. mRNA levels of pro-apoptotic genes such as TNFR-SF-10B, Bid, PYCARD, Caspase-8, Caspase-3, and Caspase-7 were induced by 2.0-, 1.5-, 1.7-, 1.5-, 1.6-, and 2-fold, respectively, in AtT20 cells by AT-101 treatment. Moreover, some of the anti-apoptotic genes such as BCL2L10, NAIP1, and PAK-7 were reduced by 2.1-, 2.3-, 4.0-fold, respectively, in AtT20 cells. AT-101 also decreased ACTH secretion significantly. CONCLUSION: AT-101 induces apoptosis in mouse pituitary corticotroph tumor cells.

The Effects of Compliance with Nutritional Counselling on Body Composition Parameters in Head and Neck Cancer Patients under Radiotherapy.

Background. Radiotherapy (RT) has been associated with increased risk of malnutrition in cancer patients, particularly in those with head and neck cancer (HNC). The aim of this prospective study was to evaluate the effects of compliance of patients with individual dietary counselling on body composition parameters in HNC patients under RT. Material and Methods. Sixty-nine consecutive patients (mean age: 61.0 ± 13.8) were prospectively followed. Bioelectrical impedance analysis (BIA) was performed to determine body composition parameters before, in the middle of, and at the end of RT. All patients received nutritional counselling and majority of them (94.6%) received oral nutritional supplement (ONS) during RT or chemoradiotherapy. If a patient consumed ≥75% of the recommended energy and protein intake via ONS and regular food, he/she was considered to be "compliant" (n = 18), while those who failed to meet this criteria were considered to be "noncompliant" (n = 30). Results. Body mass index, weight, fat percentage, fat mass, fat free mass, and muscle mass did not decrease significantly over time in compliant patients, but in noncompliant patients, all of these indices decreased significantly from baseline compared to the end of treatment (p < 0.001). Hand grip strength did not differ significantly between the two groups at baseline and over time in each group. When retrospectively evaluated, heavy mucositis was less commonly observed in compliant than noncompliant patients (11.1% versus 88.9%, resp.) (p < 0.009). Conclusion. We conclude that body composition parameters were better in head and neck cancer patients considered as compliant with nutritional counselling than noncompliant ones during RT period.

Retrospective analysis of patients with relapsed or refractory testicular nonseminous germ cell tumors treated with autologous stem cell transplantation.

BACKGROUND AND AIM: About 20-25% of the testicular germ cell tumors (TGCT) are relapsed or refractory after first line therapy and optimal treatment for this group is poorly defined. We aimed to analyze the efficacy and safety of autologous stem cell transplantation (ASCT) in this patient group.Material and. METHODS: 19 patients with 28 ASCT were retrospectively analyzed. All the patients were treated with BEP (Bleomycin, etoposide, cisplatin) as first line therapy and TIP(paclitexalifosfamide, cisplatin) was given as salvage chemotherapy. Stem cell collection was performed with TIP and granulocyte stimulating factor. ASCT was performed with carboplatin(700mg/m2) and etoposite(750mg /m 2). The results were provided as median(min-max). P<0.05 was accepted as statistical significant level. RESULTS: After ASCT, complete(CR) and partial remission (PR) rates were 47.3% and 31 .5% respectively. The median overall survival(OS) and progression free survival (PFS) were 18(0-37.4 months) and 7(0-15months) months respectively. Estimated 2-year OS was 47.4% and PFS was 35.3%. Grade 3/4 toxicities including diarrhea, mucositis, and toxic hepatitis were observed in 5 patients. Only one patient died due to complication of transplantation. CONCLUSION: Although the number of the patients in this study is limited, ASCT seems to be a safe and effective treatment modality in relapsed refractory non-seminomatousTGCT with an acceptable OS, PFS and mortality rates.

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

Background. The 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 Methods. The 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. Results. We 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. Conclusion. Therefore, 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 (AU)

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

BACKGROUND: The 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 METHODS: The 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. RESULTS: We 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. CONCLUSION: Therefore, 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.

Cancer stem cell differentiation: TGFß1 and versican may trigger molecules for the organization of tumor spheroids.

Cancer stem cells (CSCs) have the ability to self-renew similar to normal stem cells. This process is linked with metastasis and resistance to chemotherapy and radiotherapy. In the present study, we constructed an in vitro differentiation model for CSCs. CSCs isolated and proliferated for one passage were maintained as monolayers or spheroid-forming cells with serum included media for differentiation process. Differentiation of adhesion molecules and cellular ultrastructural properties were investigated and compared in both monolayer and spheroid cultures. CD133+/CD44+ cancer-initiating cells were isolated from DU-145 human prostate cancer cell line monolayer cultures and propagated as tumor spheroids and compared with the remaining heterogeneous cancer cell bulk population. Microarray-based gene expression analysis was applied to determine genes with differential expression and protein expression levels of candidates were analyzed by immunohistochemistry. Electron microscopy showed detailed analysis of morphology. TGFß1 was found to be significantly upregulated in monolayer CSCs. High expression levels of VCAN, COL7A1, ITGß3, MMP16, RPL13A, COL4A2 and TIMP1 and low expression levels of THBS1, MMP1 and MMP14 were detected when CSCs were maintained as serum-grown prostate CSC spheroids. Immunohistochemistry supported increased immunoreactivity of TGFß1 in monolayer cultures and VCAN in spheroids. CSCs were found to possess multipotential differentiation capabilities through upregulation and/or downregulation of their markers. TGFß1 is a triggering molecule, it stimulates versican, Col7A1, ITGß3 and, most importantly, the upregulation of versican was only detected in CSCs. Our data support a model where CSCs must be engaged by one or more signaling cascades to differentiate and initiate tumor formation. This mechanism occurs with intracellular and extracellular signals and it is possible that CSCc themselves may be a source for extracellular signaling. These molecules functioning in tumor progression and differentiation may help develop targeted therapy.

Sexual dysfunction in cancer patients: a review.

Cancer is a life-threatening disease despite the advanced therapeutic strategies now available. A common problem is that physicians and patients tend to concentrate on intensive medical treatment options and underestimate the treatment-related adverse effects. In this review, we summarize one of these adverse effects in cancer patients; sexual dysfunction (SD). In addition, current therapeutic choices with optimal doses and patient selection strategies are defined. All patients should be informed about problems associated with therapy-related SD and must be guided toward the most appropriate therapeutic options before starting treatment.

Survival analysis of metastatic colorectal cancer patients who were treated with the five major therapeutic agents over the course of disease.

PURPOSE: Exposure to all active agents may be more important than specific sequence of drug administration in the treatment of patients with metastatic colorectal cancer (mCRC). The purpose of this study was to evaluate the overall survival (OS) of mCRC patients who were treated with all 5 major therapeutic agents used in this malignancy. METHODS: We retrospectively reviewed the medical records of 395 mCRC patients referred to our clinic. The study included patients who received 5-fluorouracil (5-FU)-, irinotecan- or oxaliplatin-based chemotherapy and at least 3 cycles of bevacizumab and 4 weeks of cetuximab sequentially in various combinations. RESULTS: Forty mCRC patients received the 5 major therapeutic agents effectively and sequentially, and their mean OS was 26.43±2.04 months. The 3- and 4- year OS survival rates were 26.7% and 16.7%, respectively. When survival analysis was limited to the metastatic patients with at least 6 cycles of bevacizumab therapy in addition to standard duration of other chemotherapeutic agents (N=33), the mean OS was 26.7±2.38 months. With a further survival analysis limited to metastatic patients who were treated with at least both 6 cycles of bevacizumab and 8 weeks of cetuximab in addition to other therapies (N=17), the mean OS was 44.8±11.03 months. CONCLUSION: This study demonstrated that in mCRC patients there may be a significant survival advantage if an adequate tumor response was achieved with all major therapeutic agents. Therefore, we believe that we should treat our patients with the 5 major therapeutic drugs as effectively as possible.

Evaluation of the efficacy of adjuvant chemotherapy in patients with high-risk stage II colon cancer.

PURPOSE: This study aimed at comparing the disease-free survival (DFS) in high-risk TNM stage II colon cancer patients who had been subjected to adjuvant chemotherapy and TNM low-risk stage II patients who did not receive chemotherapy. METHODS: We retrospectively reviewed the medical records of stage II colon cancer patients between January 2006 and December 2011. High-risk patients were defined those with any colonic obstruction/perforation, mucinous histology, inadequate lymph node sampling, T4 disease, lymphatic/ vascular or perineural invasion, preoperatively elevated carcinoembryonic antigen (CEA) and high-grade tumor. All patients with high-risk features received adjuvant chemotherapy. RESULTS: There were 42 patients in the high-risk treatment group and 21 patients in the non-treatment (observation) group. There were no significant differences in terms of gender, tumor size, tumor localization, or the number of excised lymph nodes between the groups. The median follow- up time was 33.9 months in the treatment group and 29.3 months in the non-treatment group. Recurrence developed in 4 patients (6.3%), 3 of which were in the treatment group. DFS in both groups was statistically similar. CONCLUSION: Adjuvant chemotherapy in the high-risk patients resulted in similar DFS as that in the low-risk patients. Although the role of adjuvant chemotherapy for stage II colon cancer is unclear, it is rational to offer adjuvant chemotherapy to patients with high-risk stage II colon cancer.

Effects of exercise on angiogenesis and apoptosis-related molecules, quality of life, fatigue and depression in breast cancer patients.

The aim of this study was to explore the effects of exercise on angiogenesis and apoptosis-related molecules, quality of life, fatigue and depression in patients who completed breast cancer treatment. Sixty breast cancer patients were randomised into three groups, as supervised exercise group, home exercise group and education group. Angiogenesis and apoptosis-related cytokine levels and quality of life (EORTC QOL-C30: European Organisation for Research and Treatment of Cancer Quality of Life C30), fatigue (Brief Fatigue Inventory) and depression (BDI: Beck Depression Inventory) scores were compared before and after a 12-week exercise programme. After the exercise programme, statistically significant decreases were found in interleukin-8 and neutrophil activating protein-78 levels in the home exercise group (P < 0.05). The education group showed a statistically significant increase in monocyte chemoattractant protein-1 level (P < 0.05). Functional score and global health score of EORTC QOL-C30 in the supervised exercise group and functional score of EORTC QOL-C30 in the home exercise group increased significantly after exercise programme (P < 0.05). BDI score was significantly lower in the supervised exercise group after the exercise programme (P < 0.05). Changes in angiogenesis and apoptosis-related molecules in the study groups suggest a possible effect of exercise on these parameters. Exercise programmes are safe and effective on quality of life and depression in breast cancer patients whose treatments are complete.

Alveolar rhabdomyosarcoma originating from the uterine cervix.

Cervical alveolar rhabdomyosarcoma is a rare condition associated with poor prognosis. An 18-year-old patient presented with vaginal bleeding and a protruding mass from the vagina. Biopsy of the mass revealed alveoler rhabdomyosarcoma (ARMS), and radiological evaluation demonstrated that it originated from the uterine cervix. First, Wertheim's operation was carried out followed by four cycles of vincristine, actinomycine-D, ifosfamide (VAI) chemotherapy. However, the disease relapsed within three months, and the patient died of disease progression. Despite combination treatment, we could not achieve a desirable survival advantage in ARMS. Future studies may unveil the genomic profile of this rare condition, leading to invention of targeted therapies, which is the emerging trend in the treatment of sarcomas.

Does the tumor localization in advanced pancreatic cancer have an influence on the management of symptoms and pain?

PURPOSE: The symptoms and survival of patients with advanced pancreatic cancer show great variability according to tumor localization. The main purpose of this study was to see for any differences between the intensity of symptoms, mainly pain, and the need for analgesic treatment in advanced pancreatic cancer patients with different (head vs. body-tail) tumor localizations. METHODS: Ninety-six patients with histologically confirmed pancreatic cancer were enrolled in the study. The patients were divided into 2 subgroups according to tumor localization: group 1 (n=50) with head tumors and group 2 (n=46) with body and tail tumors. The demographic features of the patients as well as disease stages, onset of symptoms and necessity and consumption of analgesics were recorded. Patients were followed-up until death, and survival data was also analysed. RESULTS: At the time of diagnosis, patients with body and tail tumors had more advanced disease stages compared to head tumors (p=0.006). While jaundice was the most common initial symptom in head tumors (p<0.0001), it was pain in body and tail tumors (p<0.001). Patients with body and tail tumors had more analgesics consumption as compared to those with head tumors (p=0.009). No statistically significant difference in survival was detected between the 2 groups (p>0.05). CONCLUSION: We believe that pancreatic cancer should be accepted as two diverse disease types according to tumor localization, and pain and symptom management should be organized based on this fact.

Screening for metastasis in primary breast cancer patients having four or more axillary lymph node involvement: is it really necessary?

PURPOSE: To evaluate the necessity and direct cost effectiveness of screening and staging procedures in breast cancer patients having ≥4 positive axillary lymph nodes and to identify further possible biopathological risk factors associated with increased risk of metastasis. METHODS: We reviewed the demographic and clinicopathological data from the medical records of 1897 newly diagnosed breast cancer patients. Patients having ≥4 positive axillary lymph nodes after primary surgery for breast cancer and who had staging examinations for metastasis were eligible. The impact of staging procedures (thoracoabdominal CT, bone scan etc.) for detecting metastasis, decision of adjuvant treatment and direct costs were analyzed in 329 patients with operable breast cancer. RESULTS: Thirty-five (10.6%) patients were found with metastasis at diagnosis. Seven (20.0%) among them had multiple metastases. Eighteen (51.4%) had lung, 17 (48.6%) bone, and 7 (20.0%) liver metastasis. Twenty-one (60.0%) patients needed further radiological investigation for metastasis confirmation. Treatment decision was changed in 27 (77.1%) patients. No statistically significant risk factor was identified among the metastatic patients by means of conventional demographic and biopathological parameters. The cost of screening was lower when compared to the cost of treatment without any screening procedure. CONCLUSION: Since the conventional clinicopathological data seems not sufficient to define the risk of developing metastasis in breast cancer patients with ≥4 axillary lymph node involvement, all of them should undergo full staging examinations until new parameters based on genomic level are defined. Staging procedures need modification for high risk breast cancer patients.

Effects of pilates exercises on functional capacity, flexibility, fatigue, depression and quality of life in female breast cancer patients: a randomized controlled study.

BACKGROUND: There are very few randomized controlled studies on exercise in cancer patients. Consequently, there are no guidelines available with regard to the exercises that can be recommended and difficulties are encountered in the clinical practice as to which exercise is more suitable to the patients. AIM: The purpose of this study was to investigate the impact of pilates exercises on physical performance, flexibility, fatigue, depression and quality of life in women who had been treated for breast cancer. DESIGN: Randomized controlled trial. SETTING: Out patient group, Department of Physical Medicine and Rehabilitation and Medical Oncology Department, University Hospital. POPULATION: Fifty-two patients with breast cancer were divided into either pilates exercise (group 1) and control group (group 2). METHODS: Patients in Group 1 performed pilates and home exercises and patients in group 2 performed only home exercises. Pilates exercise sessions were performed three times a week for a period of eight weeks in the rehabilitation unit. MAIN OUTCOME MEASURES: Subjects were assessed before and after rehabilitation program, with respect to, 6-min walk test (6MWT), modified sit and reach test, Brief Fatigue Inventory (BFI), Beck Depression Index (BDI) and the European Organisation for Research and Treatment of Cancer Quality of Life C30 (EORTC QLQ-C30) and EORTC QLQ BR23. RESULTS: After the exercise program, improvements were observed in Group 1 in 6-minute walk test, BDI, EORTC QLQ-C30 functional, and EORTC QLQ-C30 BR23 functional scores (P<0.05). In contrast, no significant improvement was observed in Group 2 after the exercise program in any of parameters in comparison to the pre-exercise period (P>0.05). When the two exercise groups were compared, there were significant differences in 6MWT in pilates-exercise group (P<0.05). CONCLUSION: Pilates exercises are effective and safe in female breast cancer patients. There is a need for further studies so that its effect can be confirmed. CLINICAL REHABILITATION IMPACT: This study addressed the effects of pilates exercise, as a new approach, on functional capacity, fatigue, depression and quality of life in breast cancer patients in whom there are doubts regarding the efficacy and usefulness of the exercise.

Efficacy and safety of bevacizumab plus capecitabine and irinotecan regimen for metastatic colorectal cancer.

Recent phase III trials have proven the fact that adding bevacizumab to irinotecan plus infusional 5-fluorouracil (5-FU)/leucovorin (LV) should be preferred as a first-line treatment for metastatic colorectal cancer (mCRC). But, since the data regarding bevacizumab administered together with capecitabin, an oral fluoropyrimidine, and irinotecan in patients with mCRC is limited, we aimed to analyse the efficacy and safety of bevacizumab with capecitabine plus irinotecan (BEV-CAPIRI) regimen in mCRC patients. Records of patients treated with BEV-CAPIRI regimen between January 2005 and March 2008 were reviewed. Efficacy data regarding response rates (RR) as well as safety data were collected. Progression free survival (PFS) and overall survival (OS) analyses were done by using the Kaplan-Meier method. A total number of 53 metastatic colorectal cancer patients were treated with BEV-CAPIRI regimen. The median age of this population was 57.3 +/- 11.5 (range 29-78). The treatment was well tolerated. The RR was 43.3%, while 30.1% of the patients achieved stable disease (SD). Median PFS and OS were 12.6 +/- 1.4 and 20.6 +/- 1.7 months, respectively. However, median OS was 21.3 months for male and 14.6 months for female patients. In addition, median OS and PFS was 25.3 months and 16.2 months for the patients who received BEV-CAPIRI as first-line treatment, respectively, and for the other patients it was 15.2 months and 10.2 months, respectively. In conclusion, BEV-CAPIRI is an effective and well-tolerated alternative regimen for mCRC, leading to disease control in a vast majority of patients with mCRC.

Radiosensitization of hormone-refractory prostate cancer cells by gossypol treatment.

PURPOSE: many drugs have been tested to increase the sensitivity of prostate cancer cells to radiotherapy. Gossypol, a natural polyphenolic compound extracted from the cotton plant, is one of the agents the efficacy of which has been investigated in the treatment of prostate cancer for this purpose. The main aim of this study was to investigate the best gossypol application with irradiation, when gossypol was applied either sequentially (24 h before and after irradiation) or concurrently in PC-3 hormone-refractory and radioresistant prostate cancer cells. METHODS: The XTT viability assay was used to evaluate the cytotoxicity of different concentrations of gossypol in PC- 3 cells. Irradiation was applied to PC-3 cells via 6 MV photon linear accelerator and delivered 24 h before, 24 h after radiation or at the same time with gossypol administration. RESULTS: gossypol caused radiosensitization of PC-3 cells that are known to be radioresistant, with high Bcl-2 levels. Among different applications of gossypol and irradiation (before, after and concurrent) in prostate cancer cells, the best results were observed by the application of gossypol 24 h before irradiation. CONCLUSION: our study suggests that gossypol represents a promising novel anticancer treatment for radiosensitization of human hormone-refractory prostate cancer cells.

Disorders of sexual development: an overview of 18 years experience in the pediatric Endocrinology Department of Ankara University.

INTRODUCTION: Disorders of sexual development (DSD) occur when the appearance of the internal and/or external genitalia is at variance with normal development for either sex. We reviewed the characteristics of patients with DSD. PATIENTS: Two hundred and eight children aged from newborn to 19 years with DSD from 1990 to 2008. RESULTS: 46,XY DSD (52.4%) was more common than 46,XX DSD (34.6%) and gonadal differentiation disorders (12.99%). Thirty-six (33.02%) patients were diagnosed with androgen resistance syndrome, 41 (37.61%) had 5alpha-reductase deficiency, 23 (21.10%) had testosterone synthesis disorders. Congenital adrenal hyperplasia was the most frequent underlying cause of 46,XX DSD. CONCLUSION: There are many difficult aspects in the diagnosis and management of DSD. Gender assessment teams of endocrine centers need a multidisciplinary approach for the diagnosis, medical and surgical treatment, genetic counseling, and psychosocial support of these patients.

Apoptosis-mediated cytotoxic effects of ibandronic acid on hormone- and drug-refractory prostate cancer cells and human breast cancer cells.

Over 80% of patients with advanced breast and prostate cancer ultimately develop bone metastases. Ibandronic acid has proven efficacy for treatment of bone metastasis secondary to breast cancer. This study was designed to investigate the cytotoxic and apoptotic effects of ibandronic acid on hormone- and drug-refractory prostate carcinoma DU-145 and human breast cancer MCF-7 cell lines. Cytotoxicity was evaluated using an XTT cell proliferation kit, and apoptosis was assessed by enzyme-linked immunosorbent assay (histone-DNA fragmentation) and measurement of caspase 3/7 activity. With increasing concentrations of ibandronic acid there was a dose- and time-dependent decrease in cell numbers. MCF-7 cells were more resistant than DU-145 cells (half maximal inhibitory concentrations of 122 and 90 microM, respectively). Ibandronic acid induced apoptosis in both cell lines. The study showed an apoptosis-mediated cytotoxic effect for ibandronic acid (in addition to the already known osteoclast inhibiting effect) in breast cancer patients with bone metastases; which was also observed in prostate cancer cells. Further clinical studies involving breast and prostate cancer patients with bone metastases are warranted to confirm these findings.

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

AIM: 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 microM of racemic gossypol alone and 3 microM of AT-101 alone resulted in significant down-regulation (>or= 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.

Enhancement of taxane-induced cytotoxicity and apoptosis by gossypol in human breast cancer cell line MCF-7.

PURPOSE: Gossypol is a natural polyphenolic compound extracted from cotton plant (Gossypium species) which has shown potent inhibitory effect on cell growth of many types of cancers. In this study, we aimed to evaluate the interaction of gossypol with some conventional drugs known to be effective in the treatment of breast cancer, like taxanes, doxorubicin, gemcitabine, cisplatin and vinorelbine, in MCF-7 breast cancer cells. MATERIALS AND METHODS: The XTT viability assay was used to evaluate the cytotoxicity of various cytotoxic agents alone and in combination with gossypol in MCF-7 breast cancer cells. The combination effect analysis of Chou and Talalay was used to identify the most synergistic drug combinations. The possible synergistic effects of the combination of drugs on apoptosis were also evaluated by using two different apoptosis assays. RESULTS: We identified strong synergistic cytotoxic and apoptotic activity of gossypol with taxanes among all other studied cytotoxic drugs. CONCLUSION: This study provides proof that gossypol combined with taxanes may have potential as a novel future treatment for breast cancer.