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.

To assess the effect of Cannabidiol (CBD) on the angiogenesis and stemness of breast cancer cells as well as proliferation. Methods: mRNA level and the amount of protein of vascular endothelial growth factor (VEGF) were determined by qRT-PCR and ELISA. The angiogenic potential of breast cancer cells under hypoxic conditions was identified by the HUVEC tube formation assay. The degradation of HIF-1α by CBD and the Src/von Hippel–Lindau tumor suppressor protein (VHL) interaction were assessed by a co-immunoprecipitation assay and Western blotting. To identify the stemness of mamospheres, they were evaluated by the sphere-forming assay and flow cytometry. Results: CBD can suppress angiogenesis and stem cell-like properties of breast cancer through Src/VHL/HIF-1α signaling. CBD may potentially be utilized in the treatment of refractory or recurrent breast cancer.

In colorectal cancer, whereas mucinous adenocarcinoma (MAC) has several poor clinical prognostic factors compared to adenocarcinoma (AC), the prognosis of MAC remains controversial. We evaluated the prognosis of MAC without distant metastasis and the effects of adjuvant chemotherapy using health insurance registry data managed by South Korea. Patients with colorectal cancer between January 2014 and December 2016 were included (AC, 22,050 [96.8%]; MAC, 729 [3.2%]). We observed no difference in overall survival (OS) between AC and MAC in stages I and II. However, MAC showed a worse OS than AC in stage III disease, especially in patients administered chemotherapy (p < 0.001). These findings persisted after propensity score matching of clinical characteristics between AC and MAC. In addition, transcriptome analysis of The Cancer Genome Atlas (TCGA) data showed increased chemoresistance-associated pathways in MAC compared to AC. In consensus molecular subtypes (CMS) classification, unlike in AC, CMSs 1, 3, and 4 comprised most of MAC and the proportions of CMSs 3 and 4 increased with stage progression. These results suggest clues to overcome resistance to chemotherapy and develop targeted treatments in MAC.

Objectives: The primary aim of this study was to investigate the beneficial effect of exercise on completion rates of adjuvant treatment, which is one of the major prognostic factors among patients with locally advanced colorectal cancer after undergoing curative resection followed by adjuvant treatment. Design: Prospective pilot study Methods: We assigned patients who were scheduled to undergo adjuvant treatment (N=39) to the exercise group or the control group in a 2:1 ratio in the order of enrollment. Patients completed questionnaires and underwent assessment of the outcome variables at the start of chemotherapy and upon completion of treatment. Results: A fivefold lower possibility of dose adjustment in the exercise group compared to the control group was demonstrated (OR, 0.188; p=0.023; 95% CI, 0.044–0.793). A significantly smaller proportion of the exercise group had grade 3 or 4 nausea (p=0.018) and neurotoxicity (P=0.024) symptoms. Muscle to fat ratios were significantly reduced in the control group (p=0.039), but not in the exercise group (p=0.742). Serum levels of leptin were significantly increased in the control group (p=0.038), but not in the exercise group (p=0.073). Serum levels of adiponectin were significantly increased in the exercise group (p=0.026) but tended to be decreased in the control group with no statistical significance (p=0.418). Conclusions: Exercise training among patients with colorectal cancer was found to have a beneficial impact on adjuvant treatment completion rates and treatment-associated toxicities. This program was also shown to be beneficial to patients’ body compositions and serum levels of adipokines.

The treatment of patients with triple-negative breast cancer (TNBC) relies on cytotoxic therapy. Currently, atezolizumab and chemotherapy can be combined in patients with TNBC. However, this approach is not effective for all patients, with many tumors showing low responsiveness to atezolizumab. As there is a lack of alternative treatment options, new anticancer drugs are urgently needed to enhance atezolizumab activity against TNBC. Recent strategies have focused on regulating the expression of programmed cell death ligand 1 (PD-L1) or enhancing immune response activation by combining anticancer drugs with immune checkpoint inhibitors. Cannabidiol (CBD), a cannabinoid component derived from the cannabis plant, has been reported to have anticancer therapeutic potential because of its capacity to induce apoptotic cell death in tumor cells while avoiding cytotoxicity in normal cells. Previous studies have demonstrated the effects of CBD on apoptosis in various cancer cell types. However, the potential role of CBD as an immune modulator in the regulation of PD-L1 expression and anticancer immune responses remains to be explored. In this study, we found that CBD stimulated PD-L1 expression in TNBC cells and that this occurred downstream of CBD-mediated cyclic guanosine monophosphate-adenosine monophosphate synthase–stimulator of interferon genes (cGAS–STING) pathway activation. Taken together, we have demonstrated that the combination of CBD and anti–PD-L1 enhances the anticancer immune responses in in vitro and in vivo experiments. Our findings identified the mechanism of PD-L1 regulation by CBD in TNBC cells and suggested that CBD could be a potential candidate for the development of new combinatorial strategies with immune checkpoint inhibitors in patients with TNBC.

Lee SY, et al. Ann Surg Treat Res. 2021 Jan;100(1):25-32. https://doi.org/10.4174/astr.2021.100.1.25