Improved tumor-suppressive effect of OZ-001 combined with cisplatin mediated by mTOR/p70S6K and STAT3 inactivation in A549 human lung cancer cells

• Published in: Biomedicine & pharmacotherapy 2021-10, Vol.142, p.111961-111961, Article 111961
• Main Authors: Lee, Jeong-Hun, Chung, Kyung-Sook, Lee, Hwi-Ho, Ko, Dohyeong, Kang, Minji, Yoo, Ho, Ahn, JooHoon, Lee, Jae Yeol, Lee, Kyung-Tae
• Format: Article
• Language: English
• Subjects: A549 Cells; Animals; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis; Cisplatin - administration & dosage; Cisplatin - pharmacology; Combined therapy; Drug Synergism; Humans; In Situ Nick-End Labeling; Lung Neoplasms - drug therapy; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Non-small cell lung cancer; OZ-001; P70S6K; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; STAT3 Transcription Factor - metabolism; TOR Serine-Threonine Kinases - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2021.111961

We previously reported the anticancer activity of 4-(4-fluorobenzylcarbamoylmethyl)-3-(4-cyclohexylphenyl)-2-[3-(N,N-dimethylureido)-N′-methylpropylamino]-3,4-dihydroquinazoline (OZ-001), a T-type calcium channel (TTCC) blocker, against non-small cell lung cancer (NSCLC) in vitro and in vivo. Here, we evaluated the synergistic effect of OZ-001 and cisplatin on A549 human lung cancer cells and A549 xenograft mice. Our study demonstrated that treatment with OZ-001 and cisplatin sensitized A549 cells to cisplatin and significantly inhibited cell growth, increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, and induced poly (ADP-ribose) polymerase (PARP) cleavage in A549 cells and an A549 xenograft tumor mouse model. Moreover, our findings showed that mechanistic target of rapamycin (mTOR), ribosomal protein S6 kinase (p70S6K), and signal transducer and activator of transcription (STAT3) inactivation was required for apoptosis induced by the combination of OZ-001 and cisplatin in in vitro and in vivo experiments. Our results suggest that combined treatment with OZ-001 and cisplatin could potentiate antiproliferative effects via suppression of the mTOR/p70S6K and STAT3 pathways and may be considered a potential therapeutic agent for NSCLC.