Growth inhibitory role of the p53 activator SCH 529074 in non‑small cell lung cancer cells expressing mutant p53.

Mutations of p53 occur in approximately 50% of advanced non‑small cell lung cancer (NSCLC) cases, leading to loss of tumor suppressive function and/or gain of p53 oncogenic activity. Reactivation of mutant p53 and consequently induction of apoptosis in cancer cells is the goal of p53‑targeted therapy. Recently, several p53 mutant reactivating compounds were discovered including SCH 529074. However, the role of SCH 529074 in NSCLC has not been fully explored. In the present study, the effects of this compound on cell survival, cell cycle progression, induction of apoptosis and modulation of cell signaling in p53 mutant NSCLC cells (H1975, H322 and H157) and p53 wild‑type NSCLC cells (A549), was investigated. Cell‑based functional assays, real‑time RT‑qPCR and western blot assays were used. HCT116 [p53 wild‑type (WT)] and HCT116 p53‑/‑ (p53 null) were used as control cells. The results demonstrated that SCH 529074 treatment caused significant reduction in cell viability and colony formation activity in p53 mutant, p53 WT and p53‑deficient cells. The treatment of NSCLC cells with SCH 529074 resulted in a dose‑dependent induction of apoptosis and G0/G1 cell cycle arrest, which was associated with the activation of caspases (3 and 7), p53‑independent upregulation of p21 and PUMA as well as increased LC3II, a biomarker of autophagy. The combination treatment with the autophagy inhibitor chloroquine (CQ) and SCH 529074 led to decreased cell viability, colony formation and increased induction of apoptosis. The data indicated that SCH 529074 may exert its growth inhibitory function in a p53‑independent manner in NSCLC cells.