P53 tumor suppressor is required for efficient execution of the death program following treatment with a cytotoxic limonoid obtained from Melia azedarach

JORAY, MARIANA BELÉN; CRESPO, MARÍA INÉS; BOCCO, JOSÉ LUIS; GONZÁLEZ, MARÍA LAURA; PALACIOS, SARA MARÍA; CARPINELLA, MARÍA CECILIA; VILLAFAÑEZ, FLORENCIA; LAIOLO, JERÓNIMO; SORIA, GASTÓN

FOOD AND CHEMICAL TOXICOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2017

0278-6915

This work examines the antitumor activity of an isomeric mixture (1), composed of the limonoidsmeliartenin and its interchangeable isomer 12-hydroxyamoorastatin. The results obtained showed that 1displayed outstanding cytotoxic activity against CCRF-CEM, K562, A549 and HCT116 cells, with a highlyselective effect on the latter, with an IC50 value of 0.2 mM. Based on this finding, HCT116 cells wereselected to study the mechanism of action of 1. Cell cycle analysis revealed that 1 induced sustainedarrest in the S-phase, which was followed by the triggering of apoptotic cell death and reduced clonogeniccapacity. This cytotoxicity was seen to be preceded by the upregulation of the tumor suppressorp53 and its target effector p21. In addition, it was found that p53 expressionwas required for efficient celldeath induction, and thus that the toxicity of 1 relies mainly on p53-dependent mechanisms. Takentogether, these findings position 1 as a potent antitumor agent, with potential for the development ofnovel chemotherapeutic drugs based on the induction of S-phase arrest.