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Simple Summary: Antiestrogen hormonal therapy is a relatively low side effect, orally administered cancer treatment option, yet response rates have been limited in epithelial ovarian cancer despite estrogen receptor expression in many tumors. This suggests that other pathways impact estrogen response. Cytokine signaling from the tumor microenvironment promotes ovarian cancer growth, and crosstalk between cytokine signaling and estrogen signaling has been reported in other tumor types. We therefore aimed to investigate whether cytokine signaling impacts estrogen signaling in high-grade serous ovarian cancer. We demonstrated crosstalk between these two pathways in patient-derived samples, in vitro and in animal studies. We found that inhibiting interleukin-6/leukemia inhibitory factor (IL6/LIF) cytokine signaling activates estrogen signaling and blocking both pathways was synergistic in inhibiting tumor cell growth. These results suggest a potential role for combination therapy for epithelial ovarian cancer patients. Antiestrogen therapy (AET) is an alternative to cytotoxic chemotherapy for recurrent ovarian cancer, yet the often short duration of response suggests mechanisms of resistance. We previously demonstrated that tumor microenvironment interleukin-6/leukemia inhibitory factor (IL6/LIF) cytokines induce tumor cell JAK-STAT signaling to promote cancer growth. Crosstalk between estrogen signaling and cytokine signaling has been reported. Therefore, we sought to characterize the impact of IL6/LIF signaling on estrogen signaling in epithelial ovarian cancer and investigate the efficacy of combination therapy. We first assessed patient tumors for cytokine expression and compared it with response to AET to determine clinical relevance. In vitro, we determined the effect of IL6/LIF on estrogen receptor expression and signaling. Cell viability assays were used to determine the efficacy and potential synergy of cytokine blockade and AET. We then extended studies to animal models, incorporating patient-derived stromal cells. Our results demonstrated shorter progression-free interval on AET in patients with stromal IL6/LIF expression. In vitro, IL6/LIF increased tumor cell estrogen receptor expression and signaling, and combination cytokine blockade and AET resulted in synergistic inhibition of tumor cell growth. The anticancer effect was verified in a mouse model. In conclusion, due to crosstalk between IL6/LIF cytokine signaling and estrogen signaling, dual blockade is a potential new treatment approach for ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: Resveratrol inhibits the growth of ovarian carcinoma cells in vitro through the inhibition of glucose metabolism and the induction of both autophagy and apoptosis. In the current study, we investigated the metabolic and therapeutic effects of resveratrol in vivo.Methods: A fluorescent xenograft mouse model of ovarian cancer was used. Mice were treated with cisplatin, resveratrol, or vehicle alone. Tumor burden was assessed using whole-body imaging. The effect of resveratrol on glucose uptake in vivo was determined using micro-positron emission tomography scanning. To determine whether resveratrol could inhibit tumor regrowth, tumor-bearing mice were treated with cisplatin followed by either daily resveratrol or vehicle. Autophagic response in resected tumors taken from mice treated with resveratrol was examined by transmission electron microscopy. Glycolysis and mitochondrial respiration in ovarian tumor cells after treatment with resveratrol was assessed.Results: Mice treated with resveratrol and cisplatin were found to have a significantly reduced tumor burden compared with control animals (P<.001). Resveratrol-treated mice demonstrated a marked decrease in tumor uptake of glucose compared with controls. After treatment with cisplatin, "maintenance" resveratrol resulted in the suppression of tumor regrowth compared with mice receiving vehicle alone (P<.01). Tumors resected from mice treated with resveratrol exhibited autophagosomes consistent with the induction of autophagy. Treatment with resveratrol inhibited glycolytic response in ovarian tumor cells with high baseline glycolytic rates.Conclusions: Treatment with resveratrol inhibits glucose uptake and has a significant antineoplastic effect in a preclinical mouse model of ovarian cancer. Resveratrol treatment suppresses tumor regrowth after therapy with cisplatin, suggesting that this agent has the potential to prolong disease-free survival. Cancer 2016;122:722-729. © 2015 American Cancer Society. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Upregulation of glycolysis has been demonstrated in multiple tumor types. Glucose deprivation results in diminished intracellular ATP; this is counteracted by AMPK activation during energy deficiency to restore ATP levels. We sought to determine whether glucose deprivation could induce cytotoxicity in ovarian cancer cells through activation of AMPK, and whether AMPK activators could mimic glucose deprivation induced cytotoxicity. Methods: Sensitivity to 2DG induced cytotoxicity and glucose deprivation was determined in a panel of ovarian cancer cells. Cellular growth rate, rate of glucose uptake, and response to glucose deprivation were determined. Expression of Glut-1, HIF1-α, AMPK and Akt was determined by immunoblotting. Results: Incubation of ovarian cancer cells with glucose-free media, 2-DG and AMPK activators resulted in cell death. The glycolytic phenotype of ovarian cancer cells was present in both normoxic and hypoxic conditions, and did not correlate with HIF1-α expression levels. Sensitivity to glucose deprivation was independent of growth rate, rate of glucose uptake, and appeared to be dependent upon constitutive activation of Akt. Glucose deprivation resulted in activation of AMPK and inhibition of Akt phosphorylation. Treatment with AMPK activators resulted in AMPK activation, Akt inhibition, and induced cell death in ovarian cancer cells. Conclusions: Ovarian cancer cells are glycolytic as compared to normal, untransformed cells, and are sensitive to glucose deprivation. Because ovarian cancer cells are dependent upon glucose for growth and survival, treatment with AMPK activators that mimic glucose deprivation may result in broad clinical benefits to ovarian cancer patients. [Copyright &y& Elsevier]

Abstract: Objective. : Curcumin, the active component of turmeric (Curcuma longa), exhibits growth inhibitory activity against prostate, colon, and breast cancer; however, the effect of curcumin on ovarian cancer cells is not known. We hypothesized that curcumin could induce cell death in ovarian cancer cells, and enhance apoptosis induced by tumor necrosis factor-related apoptosis inducing Apo2 ligand/TRAIL. Methods. : Chemoresistant ovarian cancer cell lines SKOV3 and ES-2 were used. The cytotoxic effect of curcumin, Apo2L/TRAIL, and curcumin+Apo2L/TRAIL in combination was determined by sulforhodamine assay. Apoptotic fraction was determined by staining cells with propidium iodide followed by analysis of the sub-G0 DNA content of cells by flow cytometry. Caspase activation was determined by immunoblotting. Results. : Curcumin alone had a cytotoxic effect in cisplatin-resistant cells at 25 μM. Curcumin at low doses (5–15 μM) or Apo2L/TRAIL alone was not significantly cytotoxic to the cell lines tested. Preincubating cells with curcumin at low doses prior to treating with Apo2L/TRAIL resulted in markedly enhanced cell death. The combined treatment of curcumin and Apo2L/TRAIL resulted in activation of both the extrinsic, receptor-mediated apoptotic pathway (cleavage of caspase-8) and the intrinsic, mitochondria-mediated apoptotic pathway (cleavage of caspase-9). Conclusions. : Combined curcumin and Apo2L/TRAIL treatment results in enhanced induction of apoptotic cell death. Because curcumin and Apo2L/TRAIL together can activate both the extrinsic and intrinsic pathways of apoptosis, they may circumvent chemoresistance to conventional chemotherapeutic agents. [Copyright &y& Elsevier]

Abstract: Objective. : Genistein, a naturally occurring isoflavenoid abundant in soy products, has anti-neoplastic activity in multiple tumor types. There are several mechanisms reported for genistein''s anti-neoplastic activity. In the present study, we studied the mechanism of genistein-induced cell death in ovarian cancer cells. Methods. : The effect of genistein on the induction of apoptosis, autophagy, and inhibition of glucose uptake in ovarian cancer cells was determined. The effect of genistein on the expression of phosphorylated Akt was determined by immunoblotting. Results. : Genistein is cytotoxic to ovarian cancer cells. The mechanism of genistein-induced cell death includes both apoptosis and autophagy. Because autophagy is typically an adaptive response to nutrient starvation, we hypothesized that genistein could induce a starvation-like signaling response. We show here that genistein treatment results in caspase-independent cell death with hallmarks of autophagy. Genistein treatment dramatically inhibits glucose uptake in ovarian cancer cells, and methyl pyruvate, a cell-permeable 3-carbon substrate for oxidative phosphorylation and fatty acid synthesis, rescues cells from genistein-induced autophagy. In addition, genistein treatment results in reduced levels of phosphorylated Akt, which may contribute towards a mechanism to limit glucose utilization. Conclusions. : Most conventional chemotherapeutic agents induce apoptotic cell death. Because genistein can induce both apoptotic and autophagic cell death, it has the potential to circumvent chemoresistance due to alterations in apoptotic signaling. [Copyright &y& Elsevier]

Abstract: Objectives.: Resveratrol is a phytoalexin found in grapes that inhibits the in vitro growth of multiple tumor cell types. We showed previously that resveratrol induces autophagic cell death in ovarian cancer cells. Because autophagy is typically an adaptive response to nutrient starvation, we hypothesized that autophagy would also be triggered when ovarian cancer cells are nutrient deprived and that resveratrol could in fact be acting by inducing a starvation-like signaling response. Methods.: Ovarian cancer cells were incubated with normal media, media containing resveratrol, glucose free media, or media lacking amino acids. Growth inhibition was determined using the sulforhodamine assay. Cells were evaluated for autophagocytosis by analyzing cleavage of LC3. Glucose uptake, lactate production, and activation of glycolytic regulators pAkt and pmTOR were analyzed following resveratrol treatment. Results.: We show here that epithelial ovarian cancer cells are highly sensitive to glucose-deprivation-induced cell death and like resveratrol, glucose deprivation induces caspase-independent cell death with hallmarks of autophagy. Consistent with the hypothesis that resveratrol treatment results in biochemical conditions that mirror a nutrient deprived state, we found that resveratrol dramatically reduces glucose uptake and lactate production. Moreover, resveratrol reduces the levels of phosphorylated Akt and mTOR, two signals that increase glucose uptake and the rate limiting steps in glycolysis. Conclusions.: Our findings are consistent with the hypothesis that resveratrol-induced changes in glucose utilization comprise the mechanism that underlies resveratrol-induced autophagocytosis in ovarian cancer. Inhibition of glycolysis in ovarian cancer with resveratrol or other compounds may be effective therapy for ovarian cancer. [Copyright &y& Elsevier]