G1 phase cell cycle arrest in NSCLC in response to LZ-106, an analog of enoxacin, is orchestrated through ROS overproduction in a P53-dependent manner

Abstract

LZ-106, a newly synthetized analog of quinolone, has been shown to be highly effective in NSCLC in both cultured cells and xenograft mouse model with low toxicity, yet the molecular mechanisms still requires exploration. Here, we substantiated the involvement of P53 activation in intracellular ROS generation upon LZ-106 treatment, and related P53 to the ROS-induced viability inhibition and apoptosis, which was exhibited in the previous research. P53 was shown to play an indispensable role in the elevated levels of intracellular ROS in LZ-106-treated NSCLC cells through ROS detection. We further identified the anti-proliferation effect of LZ-106 in NSCLC cells through G1 phase cell cycle arrest by cell cycle analysis, with the expression analysis of the key proteins, and discovered that the cell cycle arrest effect is also mediated by induction of ROS in a P53-dependent manner. In addition, the tumor suppression effect exhibited in vivo was demonstrated to be similar to that in vitro, which requires the participation of P53. Thus, LZ-106 is a potent antitumor drug possessing potent proliferation inhibition and apoptosis induction ability through the P53-dependent ROS modulation both in vitro and in vivo.

Anti-tumor effects of an ID antagonist with no observed acquired resistance

“…Nonetheless, our findings are consistent with a recent report where siRNA-mediated ID1 and ID3 inhibition was associated with increased ROS levels 55 and indicate that a main mechanism of AGX51-mediated cell killing is ROS-mediated. We also suggest that the G0/G1 arrest we see prior to cell death may in fact be ROS-mediated as has been observed in other systems 52 , 53 .…”

“…2h ) and 4T1 cells (data not shown), suggesting that the cell cycle arrest is secondary to ROS production. ROS leading to cell cycle arrest has been previously reported 52 , 53 . Interestingly, other free radical scavengers such as N-acetyl cysteine (NAC), MnTBAP, MitoQ, MitoTEMPO, Apocynin, and Catalase did not rescue the AGX51-induced phenotypes (Supplementary Fig.…”

Transcription Factor p53 Suppresses Tumor Growth by Prompting Pyroptosis in Non-Small-Cell Lung Cancer

“…Transcription factor p53 is considered to regulate cell cycle and inhibit cell carcinogenesis [31]. However, the mutation of p53 not only loses the function of tumor suppressor but also regains the function of oncogene to promote malignant transformation of cells [32].…”

Involvement of p53 Acetylation in Growth Suppression of Cutaneous T-Cell Lymphomas Induced by HDAC Inhibition

“…For transfection, cells were seeded in 6-well plates. Then, the plasmid was introduced into the cells with Lipofectamine 2000 (Invitrogen, OR) according to the manufacturer's instructions (Yang et al, 2019).…”