Antitumoral effect of novel synthetic 8-hydroxy-2-((4-nitrophenyl)thio)naphthalene-1,4-dione (CNN16) via ROS-mediated DNA damage, apoptosis and anti-migratory effect in colon cancer cell line

Toxicol Appl Pharmacol. 2022 Dec 1:456:116256. doi: 10.1016/j.taap.2022.116256. Epub 2022 Oct 5.

Abstract

Colorectal cancer (CRC) is estimated as the third most incident cancer and second in mortality worldwide. Moreover, CRC metastasis reduces patients' survival rates. Thus, the study and identification of new compounds with anticancer activity selectively to tumor cells are encouraged in the CRC treatment. Naphtoquinones are compounds with several pharmacologic activities, including antitumoral properties. Therefore, this study aimed to investigate the anticancer mechanism of synthetic 8-Hydroxy-2-(P-Nitrothiophenol)-1,4-Naphthoquinone (CNN16) in colon cancer cell line HCT-116. CNN16 showed an IC50 of 5.32 μM in HCT-116, and 9.36, 10.77, and 24.57 μM in the non-cancerous cells MRC-5, MNP-01, and PMBC, respectively, evaluated by the MTT assay. CNN16 showed an anticlonogenic effect in HCT-116 and induced cell fragmentation identified by flow cytometry analysis. Furthermore, we observed that CNN16 presented genotoxicity and induces reactive oxygen species (ROS) after 3 h of treatment visualized by alkaline comet assay and DCFH-DA dye fluorescence, respectively. Furthermore, CNN16 caused cellular membrane disruption, reduction in the mitochondrial membrane polarization, and the presence of apoptotic bodies and chromatin condensation was visualized by differential stained (HO/FD/PI) in fluorescent microscopy along with PARP1, TP53, BCL-2, and BAX analyzed by RT-qPCR. Results also evidenced inhibition in the migratory process analyzed by wound healing assay. Therefore, CNN16 can be considered as a potential new leader molecule for CRC treatment, although further studies are still necessary to comprehend the effects of CNN16 in in vivo models to evaluate the anti-migratory effect, and toxicology and assure compound safety and selectively.

Keywords: Apoptotic mechanism; DNA damage; Selectively; Synthetic naphthoquinone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / pharmacology
  • Apoptosis
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival
  • Colonic Neoplasms* / drug therapy
  • Colonic Neoplasms* / metabolism
  • DNA Damage
  • Humans
  • Membrane Potential, Mitochondrial
  • Naphthalenes / pharmacology
  • Reactive Oxygen Species / metabolism

Substances

  • Reactive Oxygen Species
  • 4-nitrophenyl
  • Antineoplastic Agents
  • Naphthalenes