Improving anticancer activity towards colon cancer cells with a new p53‐activating agent

• Published in: British journal of pharmacology Vol. 175; no. 20; pp. 3947 - 3962
• Main Authors: Raimundo, Liliana, Espadinha, Margarida, Soares, Joana, Loureiro, Joana B, Alves, Marco G, Santos, Maria M M, Saraiva, Lucília
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.10.2018
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cell Cycle Proteins; Cell Line, Tumor; Cell Movement - drug effects; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Doxorubicin - pharmacology; Drug Resistance, Neoplasm; Humans; Lactams - pharmacology; Lactams - therapeutic use; Nuclear Proteins - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-mdm2 - metabolism; Research Paper; Research Papers; Tryptophan - analogs & derivatives; Tryptophan - pharmacology; Tryptophan - therapeutic use; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.14468

Background and Purpose Impairment of the tumour suppressor p53 pathway is a major event in human cancers, making p53 activation one of the most attractive therapeutic strategies to halt cancer. Here, we have identified a new selective p53 activator and investigated its potential as an anticancer agent. Experimental Approach Anti‐proliferative activity of the (R)‐tryptophanol‐derived bicyclic lactam SYNAP was evaluated in a range of human cancer cells with different p53 status. The anticancer activity and mechanism of action of SYNAP was studied in two‐ and three‐dimensional models of human colon adenocarcinoma HCT116 cells with wild‐type p53 and corresponding p53‐null isogenic derivative cells, alone and in combination with known chemotherapeutic agents. Key Results SYNAP showed anti‐proliferative effect in human cancer cells dependent on p53 status. In HCT116 cells, SYNAP caused p53‐dependent growth inhibition, associated with cell cycle arrest and apoptosis, anti‐migratory activity and regulation of the expression of p53 transcriptional targets. Data also indicated that SYNAP targeted p53, inhibiting its interaction with its endogenous inhibitors, murine double minute (MDM)2 and MDMX. Moreover, SYNAP sensitized colon cancer cells to the cytotoxic effect of known chemotherapeutic agents. SYNAP did not induce acquired or cross‐resistance and re‐sensitized doxorubicin‐resistant colon cancer cells to chemotherapy. Additionally, SYNAP was non‐genotoxic and had low cytotoxicity against normal cells. Conclusion and Implications SYNAP revealed encouraging anticancer activity, either alone or in combination with known chemotherapeutic agents, in colon cancer cells. Apart from its promising application in cancer therapy, SYNAP may provide a starting point for improved p53 activators.