Targeted inhibition of the PI3K/AKT/mTOR pathway by (+)-anthrabenzoxocinone induces cell cycle arrest, apoptosis, and autophagy in non-small cell lung cancer

Cell Mol Biol Lett. 2024 Apr 23;29(1):58. doi: 10.1186/s11658-024-00578-6.

Abstract

Non-small cell lung cancer (NSCLC), characterized by low survival rates and a high recurrence rate, is a major cause of cancer-related mortality. Aberrant activation of the PI3K/AKT/mTOR signaling pathway is a common driver of NSCLC. Within this study, the inhibitory activity of (+)-anthrabenzoxocinone ((+)-ABX), an oxygenated anthrabenzoxocinone compound derived from Streptomyces, against NSCLC is demonstrated for the first time both in vitro and in vivo. Mechanistically, it is confirmed that the PI3K/AKT/mTOR signaling pathway is targeted and suppressed by (+)-ABX, resulting in the induction of S and G2/M phase arrest, apoptosis, and autophagy in NSCLC cells. Additionally, the augmentation of intracellular ROS levels by (+)-ABX is revealed, further contributing to the inhibition of the signaling pathway and exerting inhibitory effects on tumor growth. The findings presented in this study suggest that (+)-ABX possesses the potential to serve as a lead compound for the treatment of NSCLC.

Keywords: Anthrabenzoxocinones; Autophagy; Cell cycle arrest apoptosis; Non-small cell lung cancer; PI3K/AKT/mTOR pathway; ROS.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis* / drug effects
  • Autophagy* / drug effects
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Cell Cycle Checkpoints* / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Phosphatidylinositol 3-Kinases* / metabolism
  • Proto-Oncogene Proteins c-akt* / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction* / drug effects
  • TOR Serine-Threonine Kinases* / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphatidylinositol 3-Kinases
  • MTOR protein, human
  • Reactive Oxygen Species
  • Antineoplastic Agents