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

As NF-κB signaling pathway is constitutively activated in lung cancer, targeting NF-κB has a potential for the treatment. EF24 has been proved to be a NF-κB inhibitor with good antitumor activity, while whose toxicity possibly became one of the obstacles to enter into clinical application. In order to find high efficiency and low toxicity NF-κB inhibitors, EF24 was modified and 13d was screened out. It was proved that 13d possessed an effective combination of inhibiting NF-κB pathway and showing lower cytotoxicity on normal cells as well as less toxicity in acute toxicity experiment compared with the lead compound of EF24. In addition, 13d was found to inhibit cell vitality, arrest cell cycle in G2/M phase, promote cell apoptosis, and suppress the xenograft tumor growth. Furthermore, 13d was elucidated to induce pyroptosis developing from apoptosis, which was associated with the inhibition of NF-κB. Taken together, it was suggested that 13d was a potent antitumor agent.

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzylidene Compounds; Cell Line, Tumor; Cell Survival; Drug Design; G2 Phase Cell Cycle Checkpoints; Humans; Lung Neoplasms; M Phase Cell Cycle Checkpoints; Mice; Mice, Inbred BALB C; Mice, Nude; NF-kappa B; Nitrogen; Piperidones; Pyroptosis; Xenograft Model Antitumor Assays

EF24 and F35 both were effective monocarbonyl curcumin analogues (MCACs) with excellent anti-tumor activity, however, drug defect such as toxicity may limit their further development. To get anti-lung cancer drugs with high efficiency, low toxicity and chemosensitization, a series of analogues based on EF24 and F35 were designed and synthesized. A number of compounds were found to exhibit cytotoxic activities selectively towards lung cancer cells compared to normal cells. Among these compounds, 5B was considered as an optimal anti-tumor agent for lung cancer cells with IC

Topics: A549 Cells; Antineoplastic Agents; Curcumin; Drug Design; Humans; Lung Neoplasms; MAP Kinase Signaling System; NF-kappa B; Reactive Oxygen Species

Chalcone, a natural structure, demonstrates many pharmacological activities including anticancer, and one promising mechanism is to modulate the generation of ROS. It has been known that pyroptosis is associated with anticancer effects, whereas there is fewer researches about ROS-mediated pyroptosis triggered by chemotherapy drugs. Moreover, incorporation of a α,β-unsaturated ketone unit into chalcone may be an effective strategy for development of chemotherapy drugs. Hence, a number of chalcone analogues bearing a α,β-unsaturated ketone were synthesized from chalcone analogues 1 with modest anticancer activities as the lead compound. Structure-activity relationship (SAR) studies confirmed the function of α,β-unsaturated ketone to improve anticancer activity. Notably, compound 8, bearing a α,β-unsaturated ketone, is the most potent inhibitor of cancer, with IC

Topics: Antineoplastic Agents; Cell Proliferation; Chalcone; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Ketones; Lung Neoplasms; Molecular Structure; Pyroptosis; Reactive Oxygen Species; Structure-Activity Relationship; Tumor Cells, Cultured

The nuclear factor-kappa B (NF-κB) signaling pathway has been targeted for the therapy of various cancers, including lung cancer. EF24 was considered as a potent inhibitor of NF-κB signaling pathway. In this study, a series of asymmetric EF24 analogues were synthesized and evaluated for their anti-cancer activity against three lung cancer cell lines (A549, LLC, H1650). Most of the compounds exhibited good anti-tumor activity. Among them, compound 81 showed greater cytotoxicity than EF24. Compound 81 also possessed a potent anti-migration and anti-proliferative ability against A549 cells in a concentration-dependent manner. Moreover, compound 81 induced lung cancer cells death by inhibiting NF-κB signaling pathway, and activated the JNK-mitochondrial apoptotic pathway by increasing reactive oxygen species (ROS) generation resulting in apoptosis. In summary, compound 81 is a valuable candidate for anti-lung cancer therapy.

Topics: Antineoplastic Agents; Apoptosis; Benzylidene Compounds; Cell Line, Tumor; Drug Design; Humans; Lung; Lung Neoplasms; Mitochondria; NF-kappa B; Piperidones; Reactive Oxygen Species; Signal Transduction

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

3,5-Bis(benzylidene)-4-piperidones are being advanced as synthetic analogs of curcumin for anti-cancer and anti-inflammatory properties. We performed structure-activity relationship studies, by testing several synthesized 3,5-bis(benzylidene)-4-piperidones for anti-proliferative activity in lung adenocarcinoma H441 cells. Compared to the lead compound 1, or 3,5-bis(2-fluorobenzylidene)-4-piperidone, five compounds were found to be more potent (IC(50) < 30 microM), and 16 compounds possessed reduced cell-killing efficacy (IC(50) > 50 microM). Based on the observations, we synthesized 4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] (29 or CLEFMA) as a novel analog of 1. CLEFMA was evaluated for anti-proliferative activity in H441 cells, and was found to be several folds more potent than compound 1. We did not find apoptotic cell population in flow cytometry, and the absence of apoptosis was confirmed by the lack of caspase cleavage. The electron microscopy of H441cells indicated that CLEFMA and compound 1 induce autophagic cell death that was inhibited by specific autophagy inhibitor 3-methyladenine. The results suggest that the potent and novel curcuminoid, CLEFMA, offers an alternative mode of cell death in apoptosis-resistant cancers.

Topics: Adenocarcinoma; Antineoplastic Agents; Autophagy; Benzylidene Compounds; Cell Line, Tumor; Cell Proliferation; Humans; Lung Neoplasms; Piperidones; Structure-Activity Relationship

Increasing attention has been given to the anticancer effects of curcumin and the ability of this natural product to inhibit cancer cell proliferation. New curcumin analogs have been developed to optimize the in vitro and in vivo activity of the parent compound yet retain the same safety profile. EF24, a fluorinated synthetic analog, surpasses curcumin in its ability to inhibit cancer cell viability and down-regulate TNFα-induced NF-κB activation. Here we report a critical role of the p38-mediated signaling pathway in the determination of lung cancer cell's sensitivity to EF24. We have found that EF24-induced decease of lung cancer cell viability was accompanied by upregulated mitogen-activated protein kinases (MAPK) as evidenced by increased phosphorylation of ERK1/2, JNK, and p38. Pharmacological investigation led to our suggestion that EF24 triggers a negative feedback loop through p38 activation. In support of this model, inhibition of p38, either by small molecule inhibitors or through an RNAi-mediated knockdown approach, enhanced the EF24-induced apoptotic death of A549 cells. Thus, inhibition of p38 may boost the EF24 anticancer effect. Indeed, a combination of EF24 and SB203580, a p38 inhibitor, synergistically inhibited clonogenic activity of A549 lung cancer cells and induced their apoptosis as reflected by poly(ADP-ribose) polymerase cleavage, the accumulation of the sub-G(1) fraction of cells, and apoptotic cell staining. These studies offer a novel strategy that combines the curcumin analog EF24 with a p38 inhibitor for potentially enhanced therapy in the treatment of lung cancer.

Topics: Antineoplastic Agents; Apoptosis; Benzylidene Compounds; Cell Line, Tumor; Drug Therapy, Combination; Extracellular Signal-Regulated MAP Kinases; Humans; Imidazoles; JNK Mitogen-Activated Protein Kinases; Lung Neoplasms; MAP Kinase Signaling System; p38 Mitogen-Activated Protein Kinases; Piperidones; Pyridines