Delicaflavone induces ROS-mediated apoptosis and inhibits PI3K/AKT/mTOR and Ras/MEK/Erk signaling pathways in colorectal cancer cells

Biochem Pharmacol. 2020 Jan:171:113680. doi: 10.1016/j.bcp.2019.113680. Epub 2019 Oct 25.

Abstract

Colorectal cancer (CRC) is one of the most common malignant tumors worldwide and tends to have drug resistance. Delicaflavone (DLF), a novel anticancer agent of biflavonoid from Selaginella doederleinii Hieron, showed strong anti-CRC activities, which has not yet been reported. In this study, we investigated the effects and possible anti-CRC mechanism of DLF in vitro and in vivo. It was shown that DLF significantly inhibited the cells viability and induced G2/M phase arrest, apoptosis, the loss of mitochondrial membrane potential (Δψm), generation of ROS and increase of intracellular Ca2+ in HT29 and HCT116 cells by MTT assay, TEM, flow cytometry and inverted fluorescence microscope. Western blot and qPCR assays results further confirmed DLF induced caspase-dependent apoptosis and inhibited PI3K/AKT/mTOR and Ras/MEK/Erk signaling pathways in CRC cells. Meanwhile, DLF significantly suppressed the tumor growth via activation of Caspase-9 and Caspase-3 protein and decrease of ki67 and CD34 protein without apparent side effects in vivo. In summary, these results indicated DLF induced ROS-mediated cell cycle arrest and apoptosis through ER stress and mitochondrial pathway accompanying with the inhibition of PI3K/AKT/mTOR and Ras/MEK/Erk signaling cascade. Thus DLF could be a potential therapeutic agent for CRC.

Keywords: Apoptosis; Biflavonoids; G2/M; PI3K/AKT/mTOR and Ras/Mek/Erk; ROS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Biflavonoids / chemistry
  • Biflavonoids / pharmacology*
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Enzymes / metabolism*
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • MAP Kinase Signaling System / drug effects*
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Phosphatidylinositol 3-Kinases / metabolism
  • Plant Preparations / chemistry
  • Plant Preparations / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reactive Oxygen Species / metabolism*
  • Selaginellaceae / chemistry
  • Signal Transduction / drug effects*
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays / methods
  • ras Proteins / metabolism

Substances

  • Antineoplastic Agents
  • Biflavonoids
  • Enzymes
  • Plant Preparations
  • Reactive Oxygen Species
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • ras Proteins