CT‑1042, a novel anticancer agent, exhibits effects by activating p53 and inhibiting survivin

Abstract

A novel small molecular compound, 4‑ethyl‑8‑fluoro‑hydroxy‑9‑methoxy‑11‑methyl‑1,12‑dihydro‑4H‑2‑oxa‑6,12a‑diaza‑dibenzo[b,h]fluorene‑3,13‑dione (CT‑1042) exhibits potent antitumor activity against many tumor cells in vitro. However, the effects and underlying mechanisms of CT‑1042 in non‑small cell lung cancer (NSCLC) remain unclear. The present study was designed to determine the anticancer properties and underlying molecular mechanisms of CT‑1042 in NCI‑H460 NSCLC cells. A thiazolyl blue tetrazolium bromide assay (MTT) was performed to evaluate cell viability and flow cytometry was used to analyze apoptosis, mitochondrial membrane potential (MMP) and cell cycle. Real‑time quantitative PCR and western blotting were conducted to determine relative mRNA and protein levels. A tumor xenograft experiment was performed to investigate the effects of CT‑1042 on tumor growth in vivo. CT‑1042 markedly inhibited the proliferation of twelve cancer cell lines, decreased MMP in subject cells and increased caspase‑3 activity. Cell cycle analysis indicated that CT‑1042 delayed the cell cycle progression during the G2/M phase in a dose‑dependent manner. In addition, CT‑1042 induced mitochondrial‑mediated apoptosis by activating p53 and Bax, as well as inhibiting Bcl‑2 and survivin. Finally, CT‑1042 significantly suppressed NCI‑H460 xenograft tumor growth in vivo, with low systemic toxicity. Collectively, these results revealed that CT‑1042 has significant lung anticancer properties.

<p>The effects and mechanisms of a biosynthetic ginsenoside 3β,12β-Di-O-Glc-PPD on non-small cell lung cancer</p>

“…Furthermore, C 3 C 12 PPD had little systemic toxicity at dose of 10.0 mg/kg in Lewis and A549 xenograft models, without decreasing the body weight of mice, or altering the hematological index, which are important indexes for the initial evaluation of drug safety 38,39. Taken together, these results suggest that C 3 C 12 PPD may serve as a potent candidate compound for the treatment of NSCLC.…”

Tumor Suppressor Protein p53 and Inhibitor of Apoptosis Proteins in Colorectal Cancer—A Promising Signaling Network for Therapeutic Interventions

“…Other preclinical approaches are mainly concentrating on targeting the p53/Survivin axis. For that purpose, several drugs including statin Lovastatin, small molecular compound CT-1042 and natural compound Phoyunnanin-E show promising findings particularly on the transcriptional suppression of Survivin, activation of p53 and sensitization of treatment resistant cancer cells to apoptosis [178][179][180] (Table 1).…”