nitrophenols and Ovarian-Neoplasms

Ovarian cancer represents the first cause of mortality from gynecologic malignancies due to frequent chemoresistance occurrence. Increasing the [BH3-only Bim, Puma, Noxa proapoptotic]/[Bcl-x

Topics: Apoptosis Regulatory Proteins; bcl-X Protein; Biphenyl Compounds; Female; Humans; Mitogen-Activated Protein Kinase Kinases; Naphthalenes; Nitrophenols; Ovarian Neoplasms; Piperazines; Pyridones; Pyrimidinones; Sulfonamides; Up-Regulation

Compared to normal cells, tumor cells maintain higher concentrations of reactive oxygen species (ROS) to support proliferation, invasion, and metastasis. Chemotherapeutic drugs often induce tumor cell apoptosis by increasing intracellular ROS concentrations to highly toxic levels. ABT737, which inhibits the apoptosis regulator B cell lymphoma 2 (Bcl2), increases the sensitivity of ovarian cancer cells to chemotherapeutic drugs by regulating the glucose metabolism, but the underlying mechanisms remain unclear. Therefore, we aimed to determine whether ABT737 promoted H. SKOV3 ovarian cancer cells were treated with H. ABT737 downregulated proteins associated with glucose uptake (GLUT1) and glycolysis (LHDA, PKM2 and HK2) via the Sirt3-HIF1α axis, reducing glucose uptake and lactate secretion in SKOV3 cells. This reversed glycolysis in the tumor cells, and promoted H. The Bcl2 inhibitor ABT737 enhanced the anti-tumor effect of oxidative stress by reversing the Warburg effect in ovarian cancer cells, providing powerful theoretical support for further clinical applications of Bcl2 inhibitors.

Topics: Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Cell Proliferation; Cell Survival; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Membrane Potential, Mitochondrial; Nitrophenols; Ovarian Neoplasms; Oxidative Stress; Piperazines; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Sirtuin 3; Sulfonamides

The poor prognosis of ovarian cancer is mainly caused by chemotherapy resistance. Studies show that the Bcl-2 inhibitor ABT737 can significantly improve the effect of cisplatin and induce mitochondrial pathway apoptosis. However, the mechanism of ABT737 increases sensitivity to cisplatin by regulating mitochondrial function remains unclear in ovarian cancer cells. Sirt3, as a histone deacetylase, is involved in the regulation of mitochondrial function in cancers. In this study, we intend to explore the mechanistic link between Sirt3 and mitochondrial dysfunction induced by ABT737 and cisplatin in ovarian cancer cells.. Apoptosis was examined by flow cytometry following Annexin V and PI staining. Sirt3 activity was assessed using Sirt3 deacetylase fluorometric assay. The mitochondrial membrane potential was examined by flow cytometry following JC-1 staining. Overexpression and knock-down of Sirt3 were confirmed by western blot analysis. Mitochondrial fission/fusion dynamics were detected by immunofluorescence staining or western blot analysis.. Cisplatin accompanied with ABT737 promoted apoptosis and decreased mitochondrial membrane potential. ABT737 enhanced the sensitivity of ovarian cancer cells to cisplatin, which was partly achieved by activating Sirt3 to regulate the mitochondrial fission process.. This study identified the activation of Sirt3 played an important role in increasing sensitivity of ovarian cancer cells to cisplatin induced by ABT737. Furthermore, Sirt3 might represent a potential therapeutic target for ovarian cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biphenyl Compounds; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cell Survival; Cisplatin; Female; Humans; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Dynamics; Nitrophenols; Ovarian Neoplasms; Ovary; Piperazines; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Signal Transduction; Sirtuin 3; Sulfonamides

The poor prognosis and high mortality of patients with ovarian cancer result in part from their poor response to platinum-based chemotherapy. However, the precise mechanism behind cisplatin resistance is still not fully understood. In the present study, the authors explored the mechanism of resistance to cisplatin from the perspective of glucose metabolism in human ovarian cancer. The experiments using genetically matched ovarian cancer cell lines SKOV3 (cisplatin-sensitive) and SKOV3/DDP (cisplatin-resistant) in the present study provided some important findings. First, in comparison to SKOV3 cells, SKOV3/DDP cells exhibited decreased dependence on aerobic glycolysis and an increased demand for glucose. Secondly, the stable overexpression of Bcl‑2 and ability to shift metabolism towards oxidative phosphorylation (OXPHOS) in SKOV3/DDP cells were associated with increased oxygen consumption. Furthermore, the metabolic characteristic of elevated OXPHOS primarily comprised most mitochondrial‑derived reactive oxygen species (ROS) and, at least in part, contributed to the slight pro-oxidant state of SKOV3/DDP cells in turn. Thirdly, SKOV3/DDP cells reset the redox balance by overexpressing the key enzyme glucose 6-phosphate dehydrogenase (G6PD) of the pentose phosphate pathway to eliminate the cytotoxicity of highly elevated ROS. Furthermore, the inhibition of Bcl‑2 reduced the OXPHOS and sensitivity of SKOV3/DDP cells to cisplatin in a selective manner. Furthermore, when combined with 2-deoxyglucose (2-DG), the anticancer effect of the Bcl‑2 inhibitor ABT737 was greatly potentiated and hypoxia-inducible factor 1α (HIF‑1α) appeared to be closely associated with Bcl‑2 family members in the regulation of glucose metabolism. These results suggested that the special glucose metabolism in SKOV3/DDP cells might be selectively targeted by disrupting Bcl‑2-dependent OXPHOS.

Topics: Antimetabolites; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cisplatin; Deoxyglucose; Drug Resistance, Neoplasm; Drug Synergism; Female; Glucose; Glycolysis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mitochondria; Nitrophenols; Ovarian Neoplasms; Oxidative Phosphorylation; Piperazines; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Sulfonamides

The anti-apoptotic BCL2 family of proteins elicits a broad cell survival program mainly by promoting cell migration, invasion, and metastasis. High expression level of BCL2 family proteins is a characteristic feature of cancer cells, especially in cisplatin-resistant cancer cells. Recent studies have shown that BCL2 family proteins play a housekeeping role in modulating mitochondrial dynamics. However, it is not clear whether BCL2 family proteins are relevant to mitochondrial fission and fusion in cisplatin-resistant ovarian cancer cells. Here, we report that the BCL2/BCLXL inhibitor ABT737 induced apoptosis more potently in cisplatin-resistant SKOV3/DDP ovarian cancer cells than in cisplatin-sensitive SKOV3 ovarian cancer cells. ABT737 significantly increased levels of DRP1 in mitochondria and increased rates of mitochondrial fission, and then induced cytochrome C release from mitochondria and mitophagy in SKOV3/DDP cells. Mdivi-1, a selective inhibitor of DRP1, weakened ABT737-induced mitochondrial fission, intrinsic apoptotic pathways, and mitophagy in SKOV3/DDP cells. Taken together, these results demonstrate a novel function of ABT737 in inducing DRP1-dependent apoptotic mitochondrial fission and highlight that targeting anti-apoptotic BCL2 family proteins may be an emerging therapeutic strategy for patients with cisplatin-resistant ovarian cancer.

Topics: Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Dose-Response Relationship, Drug; Dynamins; Female; GTP Phosphohydrolases; Humans; Microtubule-Associated Proteins; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Mitophagy; Nitrophenols; Ovarian Neoplasms; Piperazines; Sulfonamides

The aberrant proliferation of tumor cells necessitates compensatory changes in tumor metabolic processes. Previous studies on tumor growth and metabolism have established a relationship between nutrient stress and Bcl-2 anti-apoptotic proteins, although the mechanisms connecting these processes remain unclear. We induced nutrient deprivation in human ovarian cancer SKOV3 cells by culturing cells in Earle's balanced salt solution (EBSS) as a starvation model. We used EBSS treatment with the BH3 domain of Bcl-2 family proteins (BH3) mimetic ABT737, which targets Bcl-2/Bcl-xL, to examine mitochondrial dynamics and the interactive regulatory mechanisms between nutrition and Bcl-2 proteins. We found that EBSS combined with ABT737 can promote SKOV3 cells to undergo apoptosis and convert tubular mitochondria into small, fragmented morphologies. Bcl-2 family proteins participated in the regulation of mitochondrial fusion and fission through apoptosis, and the decrease of Mcl-1 expression was the key to ABT737 sensitization. Our findings showed that nutrient stress could sensitize SKOV3 cells to ABT737 via regulation of the mitochondrial dynamic balance and interaction of Bcl-2 family proteins. Our data suggest that nutrient starvation combined with the BH3 mimetic ABT737 could reduce the required effective dose of ABT737, and that inhibition of Bcl-2 and Mcl-1 together with nutrient starvation could serve as an effective strategy for the treatment of human ovarian cancer. Anat Rec, 300:326-339, 2017. © 2016 Wiley Periodicals, Inc.

Topics: Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Female; Humans; Mitochondria; Mitochondrial Dynamics; Nitrophenols; Ovarian Neoplasms; Piperazines; Proto-Oncogene Proteins c-bcl-2; Stress, Physiological; Sulfonamides

BH3 mimetics are a class of drugs that antagonize the Bcl-2 family of apoptosis inhibitors. We have previously shown that these compounds can potentiate the activity of carboplatin against several ovarian cancer cell lines. However, recent clinical studies have highlighted that BH3 mimetics which antagonise Bcl-XL are associated with significant thrombocytopenia. This has led to the development of ABT-199 which specifically inhibits Bcl-2. Unfortunately, Bcl-XL appears to be more frequently deregulated in ovarian cancer than Bcl-2. We therefore compared the ability of ABT-199, and the Bcl-XL selective compound WEHI-539, to potentiate the activity of carboplatin in ovarian cancer cell lines.. WEHI-539, ABT-737 and ABT-199 were tested in combination with carboplatin using a panel of 6 ovarian cancer cell lines. The activity of the drugs was evaluated using cell growth assays, staining with trypan bue and measurement of apoptosis by measuring caspase 3/7 activity, PARP cleavage and annexin-V/propidium iodide staining.. We found that WEHI-539 and ABT-737, but not ABT-199, were synergistic with carboplatin in cell growth assays and potentiated cell death when assessed by trypan blue staining. Furthermore, WEHI-539 and ABT-737 augmented carboplatin induced caspase 3/7 activity, PARP cleavage and annexin V labelling, but ABT-199 failed to do so.. These observations suggest that compounds which target Bcl-XL are necessary if BH3 mimetics are to be successfully used to treat patients with ovarian cancer and this highlights the need to develop strategies to minimize thrombocytopenia induced by such compounds.

Topics: Antineoplastic Agents; bcl-X Protein; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Carboplatin; Cell Line, Tumor; Cell Survival; Drug Screening Assays, Antitumor; Drug Synergism; Female; Humans; Inhibitory Concentration 50; Molecular Mimicry; Nitrophenols; Ovarian Neoplasms; Piperazines; Protein Interaction Domains and Motifs; Sulfonamides

Bcl-2, which belongs to the Bcl-2 family, is frequently overexpressed in various types of cancer cells and contributes to drug resistance. However, the function of Bcl-2 in cisplatin resistance in human ovarian cancer cells is not fully understood. In this study, we found that the pharmacological inhibitor ABT737 or genetic knockdown of Bcl-2 increased cisplatin cytotoxicity in cisplatin-resistant ovarian cancer cells. Additionally, treatment with ABT737 or Bcl-2 siRNA increased cisplatin-induced free Ca2+ levels in the cytosol and mitochondria, which increased endoplasmic reticulum (ER)-associated and mitochondria-mediated apoptosis. In addition, ABT737 or Bcl-2 siRNA increased the ER-mitochondria contact sites induced by cisplatin in cisplatin-resistant SKOV3/DDP ovarian cancer cells. Consistently with the in vitro results, ABT737 potently synergized with cisplatin in inhibiting the growth of human ovarian cancer xenografts in nude mice. Collectively, these results indicate that pharmacological inhibitors or genetic knockdown of Bcl-2 may be a potential strategy for improving cisplatin treatment of ovarian cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Calcium; Cell Line, Tumor; Cell Survival; Cisplatin; Cytosol; Drug Resistance, Neoplasm; Endoplasmic Reticulum; Female; Heterografts; Humans; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Mice, Nude; Mitochondria; Neoplasm Transplantation; Nitrophenols; Ovarian Neoplasms; Piperazines; Proto-Oncogene Proteins c-bcl-2; RNA Interference; RNA, Small Interfering; Signal Transduction; Sulfonamides

Ovarian cancers are addicted to Bcl-xL and Mcl-1, antiapoptotic members of the Bcl-2 family. Bcl-xL can be inhibited by the BH3-mimetic ABT-737. In vitro, ABT-737 can induce apoptosis of cancer cells, and its activity is potentiated by Mcl-1 inactivation. Herein, we assessed the sensitivity of human ovarian tumor nodes to ABT-737 when combined with carboplatin, which can indirectly inhibit Mcl-1. Fresh samples from 25 patients with high-grade serous ovarian cancer (HGSOC) who were chemo-naïve and had undergone surgery were prospectively exposed ex vivo to ABT-737 ± carboplatin. The treatment effect was studied on sliced tumor nodes by assessment of cleaved-caspase 3 immunostaining. We also studied the association between baseline Bcl-2 family protein expression (via immunohistochemistry) and the response of nodes to treatment. ABT-737 induced apoptosis as a single agent but its efficacy was not improved by the addition of carboplatin. Bim was frequently expressed (20/25) and its absence or low expression was associated with the absence of response to ABT-737, p value = 0.019 by Fisher's test and sensitivity = 93%, (95% confidence interval, 66-100). Moreover, we observed that in tumors in which Bim was expressed, a low expression of phospho-Erk1/2 or Mcl-1 improved the proportion of responses. This pilot study showed that ABT-737 has promise as monotherapy for HGSOC in a specific subgroup of tumors. Bim, Mcl-1, and phospho-Erk1/2 appeared to be relevant biomarkers that could be used for the selection of patients in the design of clinical trials using Navitoclax (an orally available compound related to ABT-737).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Biomarkers, Tumor; Biphenyl Compounds; Carboplatin; Combined Modality Therapy; Cystadenocarcinoma, Serous; Extracellular Signal-Regulated MAP Kinases; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Membrane Proteins; Middle Aged; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Grading; Neoplasm Staging; Nitrophenols; Ovarian Neoplasms; Piperazines; Prognosis; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Platinum drug-resistance in ovarian cancers mediated by anti-apoptotic proteins such as Bcl-xL is a major factor contributing to the chemotherapeutic resistance of recurrent disease. Consequently, concurrent inhibition of Bcl-xL in combination with chemotherapy may improve treatment outcomes for patients. Here, we develop a mathematical model to investigate the potential of combination therapy with ABT-737, a small molecule inhibitor of Bcl-xL, and carboplatin, a platinum-based drug, on a simulated tumor xenograft. The model is calibrated against in vivo experimental data, wherein xenografts established in mice were treated with ABT-737 and/or carboplatin on a fixed periodic schedule. The validated model is used to predict the minimum drug load that will achieve a predetermined level of tumor growth inhibition, thereby maximizing the synergy between the two drugs. Our simulations suggest that the infusion-duration of each carboplatin dose is a critical parameter, with an 8-hour infusion of carboplatin given weekly combined with a daily bolus dose of ABT-737 predicted to minimize residual disease. The potential of combination therapy to prevent or delay the onset of carboplatin-resistance is also investigated. When resistance is acquired as a result of aberrant DNA-damage repair in cells treated with carboplatin, drug delivery schedules that induce tumor remission with even low doses of combination therapy can be identified. Intrinsic resistance due to pre-existing cohorts of resistant cells precludes tumor regression, but dosing strategies that extend disease-free survival periods can still be identified. These results highlight the potential of our model to accelerate the development of novel therapeutics such as BH3 mimetics.

Topics: Algorithms; Animals; Biphenyl Compounds; Carboplatin; Cell Line, Tumor; Computer Simulation; Disease Models, Animal; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Mice; Models, Biological; Nitrophenols; Ovarian Neoplasms; Piperazines; Sulfonamides; Xenograft Model Antitumor Assays

We previously showed that Bcl-xL and Mcl-1 cooperatively protect platinum-resistant ovarian cancer cells from apoptosis. Here we assessed the anticancer potential of combining ABT-737-induced inhibition of Bcl-xL with Mcl-1 inhibition via PI3K/Akt/mTOR pathway disruption using NVP-BEZ235. NVP-BEZ235 inhibited cell proliferation without inducing apoptosis. It strongly repressed Mcl-1 expression and induced Puma expression in both cell lines tested while differentially modulating Bim between the two. Interestingly, NVP-BEZ235 efficiently sensitized ovarian carcinoma cells to ABT-737, provided that Bim expression was induced. Moreover, inhibiting the ERK1/2 pathway restored Bim expression and sensitized low Bim-expressing cancer cells to the BEZ235/ABT-737 treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; bcl-X Protein; Biphenyl Compounds; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases; Female; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Membrane Proteins; Myeloid Cell Leukemia Sequence 1 Protein; Nitrophenols; Ovarian Neoplasms; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Quinolines; RNA Interference; Signal Transduction; Sulfonamides; Time Factors; TOR Serine-Threonine Kinases; Transfection

Ovarian cancer is the leading cause of death from gynecological cancer. The anti-apoptotic protein Bcl-x(L) is frequently overexpressed in ovarian carcinoma which correlates with chemotherapy resistance. It has been demonstrated that Bcl-x(L) cooperates with another anti-apoptotic protein, Mcl-1, to protect ovarian cancer cells against apoptosis, and that their concomitant inhibition induces massive cell death. Here, we examined the interest of ABT-737, a potent BH3-mimetic molecule targeting Bcl-x(L), both alone and in combination with Mcl-1 modulators, in ovarian cancer cell lines. As a single agent, ABT-737 was ineffective at promoting cell death in the four cell lines we tested in vitro. However, the specific inhibition of Mcl-1 by siRNA dramatically increased the sensitivity of chemoresistant cells to ABT-737. Platinum compounds also sensitize to ABT-737 by dose-dependently decreasing Mcl-1 expression or by increasing the expression of pro-apoptotic BH3-only proteins Noxa and, to a lower extent, Bim. Furthermore, we demonstrated that Noxa accumulation was involved in apoptosis occurring in response to the combination of ABT-737 and platinum compounds, since cells were protected from apoptosis by its silencing. Moreover, the combination was also highly cytotoxic ex vivo in sliced SKOV3 tumor nodes. However we observed in these slices a strong basal expression of Noxa and apoptotic cell death in response to ABT-737 alone. Therefore, we have revealed that the modulation of the Mcl-1/Noxa axis by platinum compounds results in a strong sensitization of chemoresistant ovarian carcinoma cells to ABT-737, which could constitute a promising therapeutic in these cancers.

Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; bcl-X Protein; Biphenyl Compounds; Carboplatin; Cell Line, Tumor; Cisplatin; Drug Synergism; Female; Humans; Membrane Proteins; Mice; Mice, Nude; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Transplantation; Nitrophenols; Ovarian Neoplasms; Piperazines; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; RNA Interference; RNA, Small Interfering; Sulfonamides; Xenograft Model Antitumor Assays

Resistance to standard chemotherapy (carboplatin + paclitaxel) is one of the leading causes of therapeutic failure in ovarian carcinomas. Emergence of chemoresistance has been shown to be mediated in part by members of the Bcl family of proteins including the antiapoptotic protein Bcl-x(L), whose expression is correlated with shorter disease-free intervals in recurrent disease. ABT-737 is an example of one of the first small-molecule inhibitors of Bcl-2/Bcl-x(L) that has been shown to increase the sensitivity of ovarian cancer cells to carboplatin. To exploit the therapeutic potential of these two drugs and predict optimal doses and dose scheduling, it is essential to understand the molecular basis of their synergistic action. Here, we build and calibrate a mathematical model of ABT-737 and carboplatin action on an ovarian cancer cell line (IGROV-1). The model suggests that carboplatin treatment primes cells for ABT-737 therapy because of an increased dependence of cells with DNA damage on Bcl-x(L) for survival. Numerical simulations predict the existence of a threshold of Bcl-x(L) below which these cells are unable to recover. Furthermore, co- plus posttreatment of ABT-737 with carboplatin is predicted to be the best strategy to maximize synergism between these two drugs. A critical challenge in chemotherapy is to strike a balance between maximizing cell-kill while minimizing patient drug load. We show that the model can be used to compute minimal doses required for any desired fraction of cell kill. These results underscore the potential of the modeling work presented here as a valuable quantitative tool to aid in the translation of novel drugs such as ABT-737 from the experimental to clinical setting and highlight the need for close collaboration between modelers and experimental scientists.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-X Protein; Biphenyl Compounds; Carboplatin; DNA Damage; Drug Administration Schedule; Drug Synergism; Female; Humans; Mice; Models, Biological; Molecular Targeted Therapy; Nitrophenols; Ovarian Neoplasms; Piperazines; Sulfonamides

The effective treatment of ovarian cancer is hampered by the development of drug resistance, which may be mediated by members of the Bcl-2 family of apoptosis regulators. ABT-737 is a recently described inhibitor of members of this family. We investigated whether this compound could sensitize ovarian cancer cells to chemotherapeutic agents.. The sensitivity of ovarian cancer cell lines to ABT-737 in combination with either carboplatin or paclitaxel was tested either in vitro by assessing cell growth/survival and apoptosis or in xenograft studies.. As a single agent, ABT-737 inhibited the growth of eight ovarian cancer cell lines, although with relatively poor potency. However, ABT-737, but not a less active enantiomer, increased the sensitivity of several cell lines to carboplatin. The increased sensitivity to carboplatin was accompanied by a decrease in time at which apoptosis was observed when assessed according to the number of attached cells, PARP cleavage, and nucleosome formation. ABT-737 was more effective at sensitizing IGROV-1 cells when ABT-737 was administered after carboplatin. In addition, ABT-737 significantly enhanced the activity of carboplatin in one of three primary cultures derived directly from ascitic tumor cells in patients recently treated with chemotherapy. Small interfering RNA directed to Bcl-X(L) also increased the sensitivity of ovarian cancer cell lines to carboplatin. ABT-737 was also able to augment the inhibition of IGROV-1 tumor xenograft growth beyond that obtained with carboplatin alone.. These data suggest that ABT-737, in combination with carboplatin, may find utility in the treatment of patients with ovarian cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-X Protein; Biphenyl Compounds; Carboplatin; Cell Line, Tumor; Drug Administration Schedule; Drug Synergism; Female; Humans; Mice; Nitrophenols; Ovarian Neoplasms; Paclitaxel; Piperazines; Proto-Oncogene Proteins c-bcl-2; RNA Interference; RNA, Small Interfering; Sulfonamides; Xenograft Model Antitumor Assays

A vitamin E derivative, vitamin E succinate (VES; RRR-alpha-tocopheryl succinate), and a vitamin E analogue, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxy acetic acid (alpha-TEA), induce human breast, prostate, colon, lung, cervical, and endometrial tumor cells in culture to undergo apoptosis but not normal human mammary epithelial cells, immortalized, nontumorigenic breast cells, or normal human prostate epithelial cells. Human ovarian and cervical cancer cell lines are exceptions, with alpha-TEA exhibiting greater proapoptotic effects. Although both VES and alpha-TEA can induce A2780 and subline A2780/cp70 ovarian cancer cells to undergo DNA synthesis arrest within 24 h of treatment, only alpha-TEA is an effective inducer of apoptosis. VES or alpha-TEA treatment of cp70 cells with 5, 10, or 20 microg/ml for 3 days induced 5, 6, and 19% versus 9, 36, and 71% apoptosis, respectively. Colony formation data provide additional evidence that cp70 cells are more sensitive to growth inhibition by alpha-TEA than VES. Differences in stability of the ester-linked succinate moiety of VES versus the ether-linked acetic acid moiety of alpha-TEA were demonstrated by high-performance liquid chromatography analyses that showed alpha-TEA to remain intact, whereas VES was hydrolyzed to the free phenol, RRR-alpha-tocopherol. Pretreatment of cp70 cells with bis-(p-nitrophenyl) phosphate, an esterase inhibitor, before VES treatment, resulted in increased levels of intact VES and apoptosis. Taken together, these data show alpha-TEA to be a potent and stable proapoptotic agent for human ovarian tumor cells and suggest that endogenous ovarian esterases can hydrolyze the succinate moiety of VES, yielding RRR-alpha-tocopherol, an ineffective apoptotic-inducing agent.

Topics: Apoptosis; Cell Division; Cell Line, Tumor; DNA, Neoplasm; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Esterases; Female; Humans; Neoplastic Stem Cells; Nitrophenols; Ovarian Neoplasms; Tocopherols; Uterine Cervical Neoplasms; Vitamin E