Non-genotoxic anti-neoplastic effects of ellipticine derivative NSC176327 in p53-deficient human colon carcinoma cells involve stimulation of p73.
We previously performed a high-throughput screen using real-time noninvasive bioluminescence imaging of p53 transcriptional activity and identified a group of small molecules that trigger p53-like transcriptional responses in p53-deficient tumor cells. Here we further examined the anti-tumor effects of selected compounds in vitro and showed that NSC176327, a derivative of the cytotoxic plant alkaloid ellipticine, exhibited strong anti-neoplastic effect sin wild-type p53, p53-mutant or p53-deficient human colon cancer cells. NSC176327 was more potent at inhibiting tumor cell growth as compared to chemotherapeutic drugs and other ellipticine derivatives and induced cell cycle arrest and apoptosis. Surprisingly, unlike what is observed with the parent compound ellipticine, a DNA damage signaling response was not observed with NSC176327 as evidenced by lack of phosphorylated histone H2AX foci in NSC176327-treated tumor cells. NSC176327 treatment caused a significant increase in p53-activated reporter signal in HCT116, SW620 and HCT116 p53-/- cells and upregulated DR5 and p21 protein expression. NSC176327 treatment also resulted in increased p73 protein expression and knockdown of transactivating isoforms of p73 in HCT116 p53-/- cells showed significant resistance to drug treatment. These results demonstrate an important role of p73 in the anti-tumor effects of NSC176327,and suggest that a close analogue of ellipticine may act by a non-genotoxic mechanism targeting the p53/p73 pathway as compared to the original parent compound that targets the same pathway.
Lu
Chao
C
Laboratory of Molecular Oncology and Cell Cycle Regulation, The Institute for Translational Medicine and Therapeutics, The Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Wang
Wenge
W
El-Deiry
Wafik S
WS
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004611:Ellipticines / Q000627:therapeutic use*; D006801:Humans; D009687:Nuclear Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*; D025521:Tumor Suppressor Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
C541380:3-(9-methoxy-5,11-dimethylpyrido(4,3-b)carbazol-6-yl)propan-1-amine; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004611:Ellipticines; D009687:Nuclear Proteins; C495901:TP53 protein, human; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C034192:ellipticine