title: Preclinical assessment of JNJ-26854165 (Serdemetan), a novel tryptamine compound with radiosensitizing activity in vitro and in tumor xenografts.
abstract: Serdemetan (JNJ-26854165) is a novel tryptamine compound with antiproliferative activity in various p53 wild-type (WT) tumor cell lines. We investigated its potential as radiosensitizer using four human cancer cell lines: H460, A549, p53-WT-HCT116, and p53-null-HCT116. Serdemetan inhibited clonogenic survival in all cell lines, but in a lower extent in p53-null-HCT116. In the combination studies, Serdemetan treatment at 0.25μM in H460 and at 5μM in A549 cells resulted in a sensitivity-enhancement ratio of 1.18 and 1.36, respectively. At 2Gy, surviving fractions were 0.72 and 0.97 for p53-WT HCT116 and p53-null cells exposed to 0.5μM of Serdemetan, respectively (p<0.05). Radiosensitization of H460 and A549 cells was associated with G2/M cell cycle arrest and with an increased expression of p53 and p21. In vivo, Serdemetan caused a greater than additive increase in tumor growth delay. The dose enhancement factor was 1.9 and 1.6 for H460 and A549 tumors, respectively. Serdemetan inhibited proliferation, capillary tube formation and migration of HMEC-1 cells. These effects were more marked concurrently with irradiation. These results in tumor and endothelial cells suggest that Serdemetan has potential as a radiosensitizer. Further investigations are warranted with regard to the molecular mechanisms underlying its actions and its dependency regarding p53 status.
authors.affiliation: Radiothérapie moléculaire, Université Paris XI, Institut Gustave Roussy, Villejuif, France.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Chargari
authors.forename: Celine
authors.initials: C
authors.lastname: Leteur
authors.forename: Eric
authors.initials: E
authors.lastname: Angevin
authors.forename: Tarig
authors.initials: T
authors.lastname: Bashir
authors.forename: Bruno
authors.initials: B
authors.lastname: Schoentjes
authors.forename: Janine
authors.initials: J
authors.lastname: Arts
authors.forename: Michel
authors.initials: M
authors.lastname: Janicot
authors.forename: Jean
authors.initials: J
authors.lastname: Bourhis
authors.forename: Eric
authors.initials: E
authors.lastname: Deutsch
mesh_terms: D015153:Blotting, Western; D002453:Cell Cycle; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D066298:In Vitro Techniques; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014363:Tryptamines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011838:Radiation-Sensitizing Agents; D014363:Tryptamines; D016159:Tumor Suppressor Protein p53; C568210:JNJ 26854165