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.
Highlights
Colorectal cancer (CRC) is the third most common cancer in both men and women [1]
To determine whether the increased death of oxaliplatin and CBD-treated cells was due to autophagy, DLD-1 R and colo205 R cells were treated with oxaliplatin and CBD and autophagic changes were assessed
Levels were decreased by combined oxaliplatin and CBD treatment. These results show that nitric oxide synthase 3 (NOS3) plays an important role in oxaliplatin resistance, as well as autophagic cell death induced by CBD and nitric oxide (NO) production
Summary
The standard treatment for CRC is chemotherapy following colon resection by surgery [2]. FOLFOX (5-fluorouracil and leucovorin with oxaliplatin) or FOLFIRI (5-fluorouracil, leucovorin with irrinotecan) combined with bevacizumab is mainly used [3]. Despite advances in treatment strategies for CRC, the prognosis remains poor because of the high rates of metastasis [4]. Oxaliplatin is the first platinum-based drug to demonstrate clinical effectiveness against CRC, and it remains one of the most effective chemotherapeutic drug for CRC treatment along with 5-fluorouracil and leucovorin [4,5]. There is a need to explore new strategies to improve the efficiency of CRC treatment by identifying molecules and mechanisms associated with oxaliplatin resistance
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