3-5-bis(2-fluorobenzylidene)piperidin-4-one and Ovarian-Neoplasms

Cancer cells require glucose to support their rapid growth through a process known as aerobic glycolysis, or the Warburg effect. As in ovarian cancer cells, increased metabolic activity and glucose concentration has been linked to aggressiveness of cancer. However, it is unclear as to whether targeting the glycolytic pathway may kill the malignant cells and likely have broad therapeutic implications against ovarian cancer metastasis. In the present research, we found that EF24, a HIF-1α inhibitor, could significantly block glucose uptake, the rate of glycolysis, and lactate production compared with vehicle treatment in SKOV-3, A2780 and OVCAR-3 cells. These results might possibly contribute to the further observation that EF24 could inhibit ovarian cancer cell migration and invasion from wound healing and Transwell assays. Furthermore, as an important mediator of glucose metabolism, glucose transporter 1 (Glut1) was found to contribute to the function of EF24 in both energy metabolism and metastasis. To examine the effect of EF24 and the mediated role of Glut1 in vivo in a xenograph subcutaneous tumor model, intraperitoneal metastasis and lung metastasis model were introduced. Our results indicated that EF24 treatment could inhibit tumor growth, intraperitoneal metastasis and lung metastasis of SKOV-3 cells, and Glut1 is a possible mediator for the role of EF24. In conclusion, our results highlight that an anti-cancer reagent with an inhibiting effect on energy metabolism could inhibit metastasis, and EF24 is a possible candidate for anti-metastasis therapeutic applications for ovarian cancer.

Topics: Animals; Benzylidene Compounds; Biological Transport; Cell Line, Tumor; Cell Movement; Cell Proliferation; Energy Metabolism; Female; Glucose; Glucose Transporter Type 1; Glycolysis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lactic Acid; Lung Neoplasms; Mice; Mice, Inbred BALB C; Neoplasm Invasiveness; Neoplasm Transplantation; Ovarian Neoplasms; Peritoneal Neoplasms; Piperidones

Curcumin, a component of turmeric, has been reported to exhibit potential antitumor activities. This study assessed the effects of a novel synthetic curcumin analog, EF24, on proliferation, apoptosis, and vascular endothelial growth factor (VEGF) regulation in platinum-sensitive (IGROV1) and platinum-resistant (SK-OV-3) human ovarian cancer cells. EF24 time- and dose-dependently suppressed the growth of both cell lines and synergized with cisplatin to induce apoptosis. Although treatment with EF24 had no significant effect on VEGF messenger RNA (mRNA) expression,VEGF protein secretion into conditioned media was dose-dependently reduced with EF24 demonstrating ∼8-fold greater potency than curcumin (P < .05). EF24 significantly inhibited hydrogen peroxide (H(2)O(2))-induced VEGF expression, as did the phenolic antioxidant tert-butylhydroquinone (t-BHQ). EF24 upregulated cellular antioxidant responses as observed by the suppression of reactive oxygen species (ROS) generation and activation of antioxidant response element (ARE)-dependent gene transcription. Given its high potency, EF24 is an excellent lead candidate for further development as an adjuvant therapeutic agent in preclinical models of ovarian cancer.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Benzylidene Compounds; Cell Line, Tumor; Cell Proliferation; Female; Humans; Ovarian Neoplasms; Piperidones; Reverse Transcriptase Polymerase Chain Reaction; RNA; Vascular Endothelial Growth Factor A

We report that EF24, a synthetic compound 3,5-bis(2-flurobenzylidene)piperidin-4-one, greatly inhibits cisplatin-resistant (CR) human ovarian cancer cell proliferation. The inhibitory effect of EF24 on cell proliferation is associated with G(2)/M phase cell cycle arrest and increased G(2)/M checkpoint protein (pp53, p53, and p21) levels. Within 24 h following treatment, EF24 induced apoptosis in CR cells. The apoptosis was partially blocked by the general caspase inhibitor z-VAD. Within 12 h, EF24 induced a membranous FasL expression, consistent with a substantial decrease in the Ser(473) and Thr(308) phosphorylation of Akt, a known negative regulator of FasL transcription. Also, EF24 activated the phosphorylated PTEN and marginally up-regulated total PTEN expression through the inhibition of ubiquitin-mediated PTEN degradation. Suppression of PTEN expression with siRNA significantly reduced the p53 and p21 levels and activated Akt phosphorylation at Ser(473) and Thr(308), resulting in decreased apoptosis and increased cell survival. On the other hand, overexpression of PTEN markedly induced apoptosis. Our results clearly suggested that EF24 induced significant increase in PTEN expression. The up-regulation of PTEN inhibited Akt and MDM2, which enhanced the level of p53, thereby inducing G(2)/M arrest and apoptosis. Therefore, EF24 appears to have a potential therapeutic role in human ovarian cancer through the activation of PTEN.

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzylidene Compounds; Caspase Inhibitors; Caspases; Cell Division; Cell Survival; Cisplatin; Cysteine Proteinase Inhibitors; Drug Resistance, Neoplasm; Fas Ligand Protein; Female; G2 Phase; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Nude; Ovarian Neoplasms; Phosphorylation; Piperidones; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-mdm2; PTEN Phosphohydrolase; RNA, Small Interfering; Time Factors; Tumor Suppressor Protein p53; Ubiquitin; Up-Regulation; Xenograft Model Antitumor Assays