Cannabidiol overcomes oxaliplatin resistance by enhancing NOS3- and SOD2-Induced autophagy in human colorectal cancer cells

Soyeon Jeong, Bu Gyeom Kim, Dae Yeong Kim, Bo Ram Kim, Jung Lim Kim, Seong Hye Park, Yoo Jin Na, Min Jee Jo, Hye Kyeong Yun, Yoon A. Jeong, Hong Jun Kim, Sun Il Lee, Han Do Kim, Dae Hyun Kim, Sang Cheul Oh, Dae Hee Lee

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

Abstract

Although oxaliplatin is an effective chemotherapeutic drug for colorectal cancer (CRC) treatment, patients often develop resistance to it. Therefore, a new strategy for CRC treatment is needed. The purpose of this study was to determine the effect of cannabidiol (CBD), one of the components of the cannabis plant, in overcoming oxaliplatin resistance in CRC cells. We established oxaliplatin-resistant cell lines, DLD-1 R and colo205 R, in CRC DLD-1 and colo205 cells. Autophagic cell death was induced when oxaliplatin-resistant cells were treated with both oxaliplatin and CBD. Additionally, phosphorylation of nitric oxide synthase 3 (NOS3) was increased in oxaliplatin-resistant cells compared to that in parent cells. Combined treatment with oxaliplatin and CBD reduced phospho-NOS3 levels and nitric oxide (NO) production and resulted in the production of reactive oxygen species (ROS) by reducing the levels of superoxide dismutase 2, an antioxidant present in the mitochondria, causing mitochondrial dysfunction. Taken together, these results suggest that elevated phosphorylation of NOS3 is essential for oxaliplatin resistance. The combination of oxaliplatin and CBD decreased NOS3 phosphorylation, which resulted in autophagy, by inducing the overproduction of ROS through mitochondrial dysfunction, thus overcoming oxaliplatin resistance.

Original languageEnglish
Article number781
JournalCancers
Volume11
Issue number6
DOIs
Publication statusPublished - 2019 Jun

Keywords

  • Autophagy
  • CBD
  • Colorectal cancer
  • Mitochondrial dysfunction
  • NOS3
  • Oxaliplatin resistance

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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