strychnine and Carcinoma--Non-Small-Cell-Lung

To study the molecular mechanism of cyclooxygenase-2 (COX-2), one of effective ingredient of brucine, in inducing non-small cell lung cancer cell apoptosis.. COX-2 promoter, transcription factor deletion mutants and COX-2 mRNA 3'-UTR-containing report plasmids were transfected with Renillia to non-small cell lung cancer A549 cell, in order to detect the activity of report gene luciferase and minimum cis-acting element of COX-2 promoter inhibited by brucine. The influence of brucine on IkappaB phosphorylation and the nuclear translocation of p65 were detected by immunoblotting assay.. Brucine significantly suppressed LPS-induced COX-2 promoter activation, but revealed minor impact on COX-2 mRNA stability. NF-kappaB in the vicinity of COX-2 promoter-262 was an important cis-acting element of brucine for inhibiting the activity of COX-2 promoter. Brucine was found to inhibit the phosphorylation of IkappaBalpha as well as the nuclear translocation of p65.. Brucine can improve A549 cells apoptosis by inhibiting the activity of NF-kappaB and the subsequent COX-2 gene expression.

Topics: Biological Transport; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cyclooxygenase 2; Humans; NF-kappa B; Phosphorylation; Promoter Regions, Genetic; RNA Stability; Strychnine

Isostrychnopentamine (ISP) is an indolomonoter-penic alkaloid that is present in the leaves of Strychnos usambarensis, an East African small tree. We have reported previously pro-apoptotic effects induced in vitro by ISP in the human HCT-116 colon cancer cell line, a model that displays relative sensitivity to apoptosis. In the present study, we observed that the in vitro growth inhibitory activities of ISP are similar in cancer cells that display sensitivity versus resistance to apoptosis. We made use of the U373 glioblastoma and the A549 non-small cell lung cancer (NSCLC) cell lines as models relatively resistant to apoptosis, and the human PC-3 prostate cancer cell line as a model relatively sensitive to apoptosis. While ISP induced transient decreases in [ATP]i and apoptosis in human U373 GBM cells, it did not provoke such features in A549 NSCLC cells. It thus seems that ISP-induced anti-cancer activity can lead to pro-apoptotic effects as a consequence, while apoptosis seems not to be the main cause by which ISP induces cancer cell death. ISP is a compound that merits further investigations in order to: i) identify the mechanism(s) of action by which it kills cancer cells, and ii) hemisynthesize novel ISP derivatives aiming to overcome, at least partly, the resistance of metastatic cancers to apoptosis.

Topics: Adenosine Triphosphate; Antineoplastic Agents, Phytogenic; Apoptosis; Brain Neoplasms; Breast Neoplasms; Carbolines; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Glioblastoma; Humans; Inhibitory Concentration 50; Lung Neoplasms; Male; Neoplasms; Plant Leaves; Prostatic Neoplasms; Strychnos; Time Factors