bms345541 and Lung-Neoplasms

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

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

Smac mimetics target cancer cells in a TNFalpha-dependent manner, partly via proteasome degradation of cellular inhibitor of apoptosis 1 (cIAP1) and cIAP2. Degradation of cIAPs triggers the release of receptor interacting protein kinase (RIPK1) from TNF receptor I (TNFR1) to form a caspase-8 activating complex together with the adaptor protein Fas-associated death domain (FADD). We report here a means through which cancer cells mediate resistance to Smac mimetic/TNFalpha-induced apoptosis and corresponding strategies to overcome such resistance. These human cancer cell lines evades Smac mimetic-induced apoptosis by up-regulation of cIAP2, which although initially degraded, rebounds and is refractory to subsequent degradation. cIAP2 is induced by TNFalpha via NF-kappaB and modulation of the NF-kappaB signal renders otherwise resistant cells sensitive to Smac mimetics. In addition, other signaling pathways, including phosphatidyl inositol-3 kinase (PI3K), have the potential to concurrently regulate cIAP2. Using the PI3K inhibitor, LY294002, cIAP2 up-regulation was suppressed and resistance to Smac mimetics-induced apoptosis was also overcome.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Baculoviral IAP Repeat-Containing 3 Protein; Base Sequence; Biomimetic Materials; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Chromones; Drug Resistance, Neoplasm; Humans; I-kappa B Kinase; Imidazoles; Inhibitor of Apoptosis Proteins; Intracellular Signaling Peptides and Proteins; Lung Neoplasms; Mitochondrial Proteins; Morpholines; NF-kappa B; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Quinoxalines; Receptor-Interacting Protein Serine-Threonine Kinases; RNA, Small Interfering; Tumor Necrosis Factor-alpha; Ubiquitin-Protein Ligases; Up-Regulation