Cannabidiol Overcomes Oxaliplatin Resistance by Enhancing NOS3-and SOD2-Induced Autophagy in Human Colorectal Cancer Cells

被引：45

作者：

Jeong, Soyeon ^{[1
]}

Kim, Bu Gyeom ^{[2
]}

Kim, Dae Yeong ^{[2
]}

Kim, Bo Ram ^{[1
]}

Kim, Jung Lim ^{[1
]}

Park, Seong Hye ^{[2
]}

Na, Yoo Jin ^{[2
]}

Jo, Min Jee ^{[2
]}

Yun, Hye Kyeong ^{[2
]}

Jeong, Yoon A. ^{[2
]}

Kim, Hong Jun ^{[3
]}

Lee, Sun Il ^{[4
]}

Kim, Han Do ^{[5
]}

Kim, Dae Hyun ^{[5
]}

Oh, Sang Cheul ^{[1
,2
]}

Lee, Dae-Hee ^{[1
,2
]}

机构：

[1] Korea Univ, Dept Internal Med, Div Oncol Hematol, Guro Hosp, 148 Gurodong Gil, Seoul 08308, South Korea

[2] Korea Univ, Coll Med, Grad Sch Med, Seoul 08308, South Korea

[3] Kyung Hee Univ, Dept Internal Med, Div Oncol, Sch Med, 23 Kyung Hee Dae Ro, Seoul 02447, South Korea

[4] Korea Univ, Coll Med, Dept Surg, Guro Hosp, Seoul 08308, South Korea

[5] Kaiyon Bio Tech Co Ltd, 226 Gamasan Ro, Seoul 08308, South Korea

来源：

CANCERS | 2019年 / 11卷 / 06期

基金：

新加坡国家研究基金会;

关键词：

oxaliplatin resistance; colorectal cancer; CBD; NOS3; autophagy; mitochondrial dysfunction; NITRIC-OXIDE SYNTHASE; MECHANISMS; STRESS; GROWTH;

D O I：

10.3390/cancers11060781

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页数：18

共 42 条

[1] Platinum-DNA Interactions and Subsequent Cellular Processes Controlling Sensitivity to Anticancer Platinum Complexes [J].