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

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.

• Authors: Wensong Yao, Zhen Lin, Peiying Shi, Bing Chen, Gang Wang, Jianyong Huang, Yuxia Sui, Qicai Liu, Shaoguang Li, Xinhua Lin, Qicai Liu, Hong Yao
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 171 Pg. 113680 (01 2020) ISSN: 1873-2968 [Electronic] England
• PMID: 31669234 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Biflavonoids (chemistry, pharmacology)
• Colorectal Neoplasms (drug therapy, metabolism, 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, 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)