phenoxodiol and Ovarian-Neoplasms

Epithelial ovarian cancer is the fourth leading cause of cancer-related deaths in women and is the most lethal of the gynecological malignancies. Thle high mortality rate arises from difficulties in the early detection of the disease and the widespread development of chemoresistance. Phenoxodiol, a novel isoflavone derivative, has demonstrated antitumor activity. In addition, it has been shown to induce cell death in chemoresistant epithelial ovarian cancer cells. Moreover, suboptimal exposure of these cells to phenoxodiol lowered the IC50 value of numerous chemotherapeutic agents. In this review, the current understanding of the mechanism of action of phenoxodiol, its potential clinical application for the treatment of ovarian cancer and the concept of chemosensitization are discussed.

Topics: Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Caspases; Cells, Cultured; Clinical Trials as Topic; Death Domain Receptor Signaling Adaptor Proteins; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Female; Humans; Isoflavones; Ovarian Neoplasms; Randomized Controlled Trials as Topic; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins

Platinum-resistant ovarian cancer (PROC) constitutes a therapeutic dilemma with limited efficacy from traditional cytotoxic agents. Based on prior data suggesting that scheduling alterations of platinum would increase activity, the aim of the present study was to assess the potential therapeutic benefit of phenoxodiol (PXD), a novel biomodulator shown to have chemoresistance reversing potential, when combined with weekly AUC2-carboplatin in PROC patients.. A multicenter randomized double-blind placebo controlled phase-III-study was conducted to compare oral PXD plus AUC2-carboplatin (group 1) versus placebo plus AUC2-carboplatin (group 2) weekly in PROC patients. The primary end point was progression-free-survival (PFS). Secondary objectives included overall survival (OS), response rates, duration of response and quality of life.. The study was terminated early 14 April 2009, after recruitment of 142 patients due to feasibility and recruitment challenges. A total of 142 patients were randomized. The groups were well balanced in terms of important baseline characteristics. The median PFS for group 1 was 15.4 weeks [95% confidence interval (CI) 11.1-21.0] versus 20.1 weeks for group 2 (95% CI = 13.1-33.4); P = 0.3. The objective response rate and median survival in group 1 versus group 2 was 0% versus 1% and 38.3 weeks (95% CI 32.0-45.3) versus 45.7 weeks (95% CI 35.6-58.0), respectively. PXD appeared to be well tolerated. The main reason for dose modification in both groups was hematologic toxicity.. Orally delivered PXD showed no evidence of clinical activity, when combined with weekly AUC2-carboplatin in PROC. In addition, single-agent weekly AUC2-carboplatin appeared to be inactive by response criteria in a homogenously defined population of PROC. This has implications for the design of future studies.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carboplatin; Disease-Free Survival; Drug Administration Schedule; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Isoflavones; Middle Aged; Neoplasms, Cystic, Mucinous, and Serous; Ovarian Neoplasms; Proportional Hazards Models; Quality of Life; Treatment Outcome

Chemoresistance is a major limitation in the treatment of ovarian cancer. Phenoxodiol is a novel biomodulator capable of reversing chemoresistance in vitro and in vivo. In this study, we determined the safety and efficacy of intravenous phenoxodiol in combination with cisplatin or paclitaxel in women with platinum/taxane-refractory/resistant ovarian cancers.. Thirty-two patients were randomized to 1 of 2 treatment arms according to their previous responses: (1) platinum refractory/resistant, cisplatin (40 mg/m intravenous) weekly on day 2 + phenoxodiol (3 mg/kg) weekly on days 1 and 2 and (2) taxane refractory/resistant, paclitaxel (80 mg/m IV) weekly on day 2 and phenoxodiol (3 mg/kg) weekly on days 1 and 2. Patients continued on treatment until complete response, disease progression, unacceptable toxicity, or voluntary withdrawal.. There were no treatment-related deaths. There was only one treatment-related hospitalization and 2 grade 4 toxicities. In the cisplatin arm, there were 3 partial responses, 9 patients (56%) achieved stable disease, 4 (25%) progressed, and the overall best response rate was 19%. In the paclitaxel arm, there was one complete response and 2 partial responses, 8 patients (53%) achieved stable disease, 4 patients (27%) progressed, and the overall best response rate was 20%.. The combination of IV phenoxodiol with cisplatin or paclitaxel was well tolerated in this study. Cisplatin-phenoxodiol was particularly active and warrants further study in patients with platinum-resistant ovarian cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Ovarian Epithelial; Cisplatin; Drug Resistance, Neoplasm; Fallopian Tube Neoplasms; Female; Humans; Isoflavones; Middle Aged; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Paclitaxel; Peritoneal Neoplasms; Platinum Compounds; Taxoids; Treatment Failure; Treatment Outcome

To investigate whether XIAP down-regulation and autophagy inhibition sensitize ovarian clear cell cancer cells to cisplatin.. The ovarian clear cancer cell line KK was used for in vitro analysis. Hydroxychloroquine (HCQ) and phenoxodiol (PXD) or embelin were used as autophagy and XIAP inhibitors, respectively. Non-specific and XIAP-specific siRNAs were transfected using Lipofectamine. Cytotoxicity was assessed by MTT assays. Protein expression was confirmed by western blotting.. In KK, down-regulation of XIAP using specific siRNAs together with HCQ treatment enhanced the anti-tumor effect of cisplatin. Although embelin sensitized KK to cisplatin through XIAP down-regulation, it induced autophagy. However, PXD increased cisplatin sensitivity through XIAP down-regulation and autophagy inhibition. Expression of Atg7, Atg12, and Beclin 1 was decreased after PXD treatment.. PXD increased cisplatin sensitivity through XIAP down-regulation and autophagy inhibition and could be a new candidate for ovarian clear cell carcinoma treatment.

Topics: Adenocarcinoma, Clear Cell; Antineoplastic Agents; Autophagy; Benzoquinones; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cisplatin; Down-Regulation; Female; Humans; Isoflavones; Ovarian Neoplasms; RNA, Small Interfering; X-Linked Inhibitor of Apoptosis Protein

We previously showed that Phenoxodiol is able to sensitize epithelial ovarian cancer cells to Paclitaxel, Carboplatin, Gemcitabine, and Docetaxel. The aim of this study was to determine the value of Phenoxodiol-Topotecan coadministration.. Nine epithelial ovarian cancer cell lines isolated from ascites or ovarian tissue were treated with increasing concentrations of Topotecan (5-500 ng/ml) with or without Phenoxodiol pretreatment (10 microg/ml) for 24 h and cell viability was measured using CellTiter 96 AQueous One Solution Cell Proliferation Assay. The effect of Phenoxodiol-Topotecan combination therapy in vivo was determined using the topotecan resistant A2780 mouse xenograft model.. In vitro, pretreatment with Phenoxodiol lowers the topotecan IC50 from >500 ng/ml to 2.5-100 ng/ml in five out of nine cell lines tested. RESULTS from animal experiments confirmed the advantage of Phenoxodiol-Topotecan combination therapy over monotherapy controls. Median tumour kinetics from animals receiving Phenoxodiol-Topotecan in combination was significantly slower compared to those animals receiving the respective monotherapies. In addition, co-administration with Phenoxodiol reversed Topotecan-induced myelosuppression.. Phenoxodiol-Topotecan combination therapy allows the administration of both agents at lower doses while retaining significant anti-tumor activity compared to monotherapy. These findings suggest that the Phenoxodiol-Topotecan combination may represent an alternative treatment modality for the management of ovarian cancer and justifies further investigation in the clinical setting.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Female; Humans; Isoflavones; Male; Mice; Mice, Inbred BALB C; Ovarian Neoplasms; Topotecan; Xenograft Model Antitumor Assays

Previously, it was demonstrated that phenoxodiol induces apoptosis in epithelial ovarian carcinoma (EOC) cells and that it is capable of sensitizing these cells to Fas-mediated apoptosis. The objectives of this study were to determine whether phenoxodiol can also act as chemosensitizer to chemotherapeutic agents and to characterize the molecular mechanism behind its sensitizing effect.. Ten EOC cell lines were used in this study. The effect of phenoxodiol on the inhibitory concentration 50% (IC50) of carboplatin, paclitaxel, and gemcitabine was determined by the CellTiter 96 Assay. The in vivo effect of combination treatments with phenoxodiol and the above-mentioned agents was determined in animal xenograft models. Apoptosis was measured using the Caspase-Glo Assay and the apoptotic cascade was characterized by Western blot analyses.. The results showed that phenoxodiol is able to sensitize EOC cells to carboplatin, paclitaxel, and gemcitabine both in vitro and in vivo. In addition, it was demonstrated that phenoxodiol is capable of inducing apoptosis by: 1) the activation of the mitochondrial pathway through caspase-2 and Bid signaling, and 2) the proteasomal degradation of the anti-apoptotic protein XIAP.. Understanding the components of the apoptotic pathway activated by phenoxodiol, which allows it to sensitize EOC cells to chemotherapeutic agents, will provide valuable information on the characteristic mode of action of a chemosensitizer. This will help in the identification of novel drugs and in the design of better strategies for combination therapy in patients with recurrent ovarian carcinoma.

Topics: Animals; Antimetabolites, Antineoplastic; Apoptosis; Blotting, Western; Carboplatin; Carcinoma; Caspase 2; Caspases; Cell Line, Tumor; Deoxycytidine; Drug Interactions; Enzyme Activation; Female; Gemcitabine; Humans; Isoflavones; Mice; Ovarian Neoplasms; Paclitaxel; Proteasome Endopeptidase Complex; Transplantation, Heterologous

Topics: Clinical Trials as Topic; Drug Resistance, Neoplasm; Female; Humans; Isoflavones; Ovarian Neoplasms; Tumor Cells, Cultured

Although several pathways have been proposed to explain chemoresistance, all lead to some specific defect in the mechanism of apoptosis. The objective of this study was to characterize the molecular mechanisms of drug resistance to docetaxel in epithelial ovarian cancer cells (EOC) and the use of phenoxodiol as a chemosensitizer. Four established and 12 primary cultures of ovarian carcinoma cell lines (EOC) were treated with docetaxel (5-500 ng/ml) for 24 and/or 48 h. In all the studied cell lines, the best response was seen using 500 ng/ml of docetaxel. Sensitive cell lines were identified as those with IC50 < 100 ng/ml for 48 h while resistant cell lines were identified as those with IC50 > 100 ng/ml. The morphological features of apoptosis and the activation of caspases were seen only in the sensitive cell lines determined by Hoechst staining and Caspase Glo assay. Although X-linked inhibitor of apoptosis protein (XIAP) was expressed in all EOC cells, it was only inactivated in chemosensitive cells. We confirmed the role of XIAP in docetaxel resistance by downregulation of XIAP expression using RNA interference (RNAi) as well as by pretreatment with phenoxodiol. Our results indicate that 1) docetaxel induces its cytotoxic effect through the activation of apoptosis; 2) caspase activation relies on the removal of XIAP; and 3) phenoxodiol restores sensitivity in docetaxel-resistant EOC cells. We demonstrate that phenoxodiol, by interfering with XIAP activity, functions as a chemosensitizer to docetaxel and could provide a more effective treatment for refractory ovarian cancer.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma; Docetaxel; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Humans; Isoflavones; Ovarian Neoplasms; Proteins; RNA Interference; Taxoids; Tumor Cells, Cultured; X-Linked Inhibitor of Apoptosis Protein; Zinc Fingers

Interference with the innate apoptotic activity is a hallmark of neoplastic transformation and tumor formation. In this study we characterize the cytotoxic effect of phenoxodiol, a synthetic anticancer drug analog of genestein, and demonstrate the mechanism of action by which phenoxodiol affects the components of the Fas apoptotic pathway on ovarian cancer cells. Primary ovarian cancer cells, isolated from ascitic fluids of ovarian cancer patients, resistant to conventional chemotherapy, undergo apoptosis following phenoxodiol treatment. This effect is dependent upon the activation of the caspase system, inhibiting XIAP, an inhibitor of apoptosis, and disrupting FLICE inhibitory protein (FLIP) expression through the Akt signal transduction pathway. We suggest that phenoxodiol is an efficient inducer of cell death in ovarian cancer cells and sensitizes the cancer cells to Fas-mediated apoptosis. We identified FLIP and XIAP signalling pathways as key factors regulating the survival of ovarian cancer cells. These findings demonstrate a novel nontoxic drug that controls FLIP/XIAP function and has the potential to eliminate tumor cells through Fas-mediated apoptosis.

Topics: Antineoplastic Agents; Apoptosis; Benzopyrans; Carrier Proteins; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspase 8; Caspase 9; Caspases; Cell Line; Drug Resistance, Neoplasm; Fas Ligand Protein; fas Receptor; Female; Humans; Intracellular Signaling Peptides and Proteins; Isoflavones; Membrane Glycoproteins; Ovarian Neoplasms; Phenols; Proteins; Signal Transduction; X-Linked Inhibitor of Apoptosis Protein