Daunorubicin induces GLI1­dependent apoptosis in colorectal cancer cell lines.

Daunorubicin, also known as daunomycin, is a DNA­targeting anticancer drug that is used as chemotherapy, mainly for patients with leukemia. It has also been shown to have anticancer effects in monotherapy or combination therapy in solid tumors, but at present it has not been adequately studied in colorectal cancer (CRC). In the present study, from a screening using an FDA­approved drug library, it was found that daunorubicin suppresses GLI­dependent luciferase reporter activity. Daunorubicin also increased p53 levels, which contributed to both GLI1 suppression and apoptosis. The current detailed investigation showed that daunorubicin promoted the ß­TrCP­mediated ubiquitination and proteasomal degradation of GLI1. Moreover, a competition experiment using BODIPY­cyclopamine, a well­known Smo inhibitor, suggested that daunorubicin does not bind to Smo in HCT116 cells. Administration of daunorubicin (2 mg/kg, ip, qod, 15 days) into HCT116 xenograft mice profoundly suppressed tumor progress and the GLI1 level in tumor tissues. Taken together, the present results revealed that daunorubicin suppresses canonical Hedgehog pathways in CRC. Ultimately, the present study discloses a new mechanism of daunorubicin's anticancer effect and might provide a rationale for expanding the clinical application of daunorubicin.

Patterns of δ15N in forest soils and tree foliage and rings between climate zones in relation to atmospheric nitrogen deposition: A review.

The stable nitrogen (N) isotope ratio (δ15N) of forest samples (soils, tree foliage, and tree rings) has been used as a powerful indicator to explore the responses of forest N cycling to atmospheric N deposition. This review investigated the patterns of δ15N in forest samples between climate zones in relation to N deposition. Forest samples exhibited distinctive δ15N patterns between climate zones due to differences in site conditions (i.e., N availability and retention capacity) and the atmospheric N deposition characteristics (i.e., N deposition rate, N species, and δ15N of deposited N). For example, the δ15N of soil and foliage was higher for tropical forests than for other forests by >1.2 ‰ and 4 ‰, respectively due to the site conditions favoring N losses coupled with relatively low N deposition for tropical forests. This was further supported by the unchanged or increased δ15N of tree rings in tropical forests, which contrasts with other climate zones that exhibited a decreased wood δ15N since the 1920s. Subtropical forests under a high deposition of reduced N (NHy) had a lower δ15N by 2-5 ‰ in the organic layer compared with the other forests, reflecting high retention of 15N-depleted NHy deposition. At severely polluted sites in East Asia, the decreased δ15N in wood also reflected the consistent deposition of 15N-depleted NHy. Though our data analysis represents only a subset of global forest sites where atmospheric N deposition is of interest, the results suggest that the direction and magnitude of the changes in the δ15N of forest samples are related to both atmospheric N and site conditions particularly for tropical vs. subtropical forests. Site-specific information on the atmospheric N deposition characteristics would allow more accurate assessment of the variations in the δ15N of forest samples in relation to N deposition.

Nomogram for predicting the overall survival of underweight patients with colorectal cancer: a clinical study.

BACKGROUND: An underweight individual is defined as one whose Body Mass Index (BMI) is < 18.5 kg/m2. Currently, the prognosis in patients with colorectal cancer (CRC) who are also underweight is unclear. METHODS: Information on South Korean patients who underwent curative resection for CRC without distant metastasis was collected from health insurance registry data between January 2014 and December 2016. We compared the overall survival (OS) of underweight and non-underweight (BMI ≥ 18.5 kg/m2) patients after adjusting for confounders using propensity score matching. A nomogram to predict OS in the underweight group was constructed using the significant risk factors identified in multivariate analysis. The predictive and discriminative capabilities of the nomogram for predicting 3- and 5-year OS in the underweight group were validated and compared with those of the tumor, node, and metastasis (TNM) staging system in the training and validation sets. RESULTS: A total of 23,803 (93.6%) and 1,644 (6.4%) patients were assigned to the non-underweight and underweight groups, respectively. OS was significantly worse in the underweight group than in the non-underweight group for each pathological stage (non-underweight vs. underweight: stage I, 90.1% vs. 77.1%; stage IIA, 85.3% vs. 67.3%; stage IIB/C, 74.9% vs. 52.1%; and stage III, 73.2% vs. 59.4%, P < 0.001). The calibration plots demonstrated that the nomogram exhibited satisfactory consistency with the actual results. The concordance index (C-index) and area under the receiver operating characteristic curve (AUC) of the nomogram exhibited better discriminatory capability than those of the TNM staging system (C-index, nomogram versus TNM staging system: training set, 0.713 versus 0.564, P < 0.001; validation set, 0.691 versus 0.548, P < 0.001; AUC for 3- and 5- year OS, nomogram versus TNM staging system: training set, 0.748 and 0.741 versus 0.610 and 0.601; validation set, 0.715 and 0.753 versus 0.586 and 0.579, respectively). CONCLUSIONS: Underweight patients had worse OS than non-underweight patients for all stages of CRC. Our nomogram can guide prognostic predictions and the treatment plan for underweight patients with CRC.

Long-term oncologic outcome of D3 lymph node dissection for clinical stage 2/3 right-sided colon cancer.

PURPOSE: To investigate oncologic outcomes including overall survival and disease-free survival depending on the extent of lymphadenectomy (D3 versus D2) by comparing D3 and D2 lymphadenectomy in patients with clinical stage 2/3 right colon cancer. METHODS: Consecutive series of patients who underwent radical resection for right colon cancer at our three hospitals between January 2015 and June 2018 were retrospectively analyzed. Study cohorts were divided into two groups: D3 group and D2 group. Oncologic, pathologic, and perioperative outcomes of the two groups were compared. RESULTS: A total of 295 patients (167 in the D2 group and 128 in the D3 group) were included in this study. Patients' characteristics showed no significant difference between the two groups. The median number of harvested lymph nodes was significantly higher in the D3 group than in the D2 group. The rate of complications was not significantly different between the two groups except for chyle leakage, which was more frequent in the D3 group. Five-year disease-free survival was 90.2% (95% CI: 84.8-95.9%) in the D3 group, which was significantly (p = 0.028) higher than that (80.5%, 95% CI: 74-87.5%) in the D2 group. There was no significant difference in overall survival between the two groups. CONCLUSION: Our results indicate that D3 lymphadenectomy is associated with more favorable 5-year disease-free survival than D2 lymphadenectomy for patients with stage 2/3 right-sided colon cancer. D3 lymphadenectomy might improve oncologic outcomes in consideration of the recurrence rate.

Prognosis and Sensitivity of Adjuvant Chemotherapy in Mucinous Colorectal Adenocarcinoma without Distant Metastasis.

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.

Treatment outcomes of patients with involved resection margin after rectal cancer surgery: A nationwide population-based cohort study in South Korea.

BACKGROUND: The involvement of resection margins after rectal cancer surgery by malignant tumors is a negative prognostic factor. Therefore, it is important to analyze treatment outcomes and establish adjuvant therapy. METHODS: The Health Insurance Review and Assessment Service collects data from medical institutions in South Korea. We reviewed the database of this prospectively collected cohort for patients who underwent curative resection for rectal cancer. RESULTS: Of the 5,620 patients, 113 (2.0%) were diagnosed with resection margin involvement after surgery. The resection margins of patients with mid-rectal cancer, pathologic stage III, mucinous/signet ring cell carcinoma, and undergoing emergency surgery were more frequently involved. Neoadjuvant chemoradiotherapy was a significant preventive factor for resection margin involvement (odds ratio = 0.53; 95% confidence interval [CI], 0.32-0.87; p = 0.012). The OS of patients with adjuvant treatment was better than that of patients without adjuvant treatment (5-year overall survival [OS]: 62.8% vs. 46.3%, p = 0.02). The administration of chemoradiotherapy was also significantly associated with better OS (hazard ratio = 0.36; 95% CI, 0.17-0.77; p = 0.009). CONCLUSION: Efforts to acquire wider resection margins are necessary for patients with mid-rectal cancer, pathologic stage III, mucinous/signet ring cell carcinoma, and emergency surgery. Neoadjuvant chemoradiotherapy was a significant preventive factor for involved resection margin. Patients with resection margin involvement showed better OS after adjuvant treatment than those without adjuvant treatment. The adjuvant chemoradiotherapy was helpful to prevent the worse prognosis of these patients.

Cannabidiol Suppresses Angiogenesis and Stemness of Breast Cancer Cells by Downregulation of Hypoxia-Inducible Factors-1α.

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.

Biochar-induced reduction of N2O emission from East Asian soils under aerobic conditions: Review and data analysis.

Global meta-analyses showed that biochar application can reduce N2O emission. However, no relevant review study is available for East Asian countries which are responsible for 70% of gaseous N losses from croplands globally. This review analyzed data of the biochar-induced N2O mitigation affected by experimental conditions, including experimental types, biochar types and application rates, soil properties, and chemical forms and application rates of N fertilizer for East Asian countries. The magnitude of biochar-induced N2O mitigation was evaluated by calculating N2O reduction index (Rindex, percentage reduction of N2O by biochar relative to control). The Rindex was further standardized against biochar application rate by calculating Rindex per unit of biochar application rate (ton ha-1) (Unit Rindex). The Rindex averaged across different experimental types (n = 196) was -21.1 ± 2.4%. Incubation and pot experiments showed greater Rindex than column and field experiments due to higher biochar application rate and shorter experiment duration. Feedstock type and pyrolysis temperature also affected Rindex; either bamboo feedstock or pyrolysis at > 400 °C resulted in a greater Rindex. The magnitude of Rindex also increased with increasing biochar rate. Soil properties did not affect Rindex when evaluated across all experimental types, but there was an indication that biochar decreased N2O emission more at a lower soil moisture level in field experiments. The magnitude of Rindex increased with increasing N fertilizer rate up to 500-600 kg N ha-1, but it decreased thereafter. The Unit Rindex averaged across experimental types was -1.2 ± 0.9%, and it was rarely affected by experimental type and conditions but diminished with increasing biochar rate. Our results highlight that since N2O mitigation by biochar is affected by biochar application rate, Rindex needs to be carefully evaluated by standardizing against biochar application rate to suggest the best conditions for biochar usage in East Asia.

Clinical characteristics of rectal cancer patients with neoadjuvant chemoradiotherapy: a nationwide population-based cohort study in South Korea.

PURPOSE: Neoadjuvant chemoradiotherapy has been accepted as a standard treatment for stage II-III rectal cancer. This study aimed to evaluate the clinical characteristics of patients who underwent neoadjuvant chemoradiotherapy for rectal cancer and effects on overall survival (OS) of neoadjuvant chemoradiotherapy in South Korea. METHODS: Patients who underwent curative resection for rectal cancer from 2014 to 2016 were retrospectively reviewed from the database of the National Quality Assessment program in South Korea. Patients were categorized into the upfront surgery group and neoadjuvant chemoradiotherapy group. We evaluated factors associated with the administration of neoadjuvant chemoradiotherapy and its effects on OS. Inverse probability of treatment weighting was performed to account for baseline differences between subgroups. RESULTS: A total of 6,141 patients were categorized into the upfront surgery group (n = 4,237) and neoadjuvant chemoradiotherapy group (n = 1,904). The neoadjuvant chemoradiotherapy was more frequently administered to male, midrectal cancer, and younger patients. In the neoadjuvant chemoradiotherapy group, old age, underweight, and pathologic stage were significant risk factors of OS, and male sex, the level of tumor and clinical stages were not associated with OS. After adjustment, the OS of the neoadjuvant chemoradiotherapy group followed the OS of the upfront surgery group of the same pathologic stage. CONCLUSION: Male sex and the level of tumor were not related to the OS of rectal cancer patients with neoadjuvant chemoradiotherapy. The OS of patients who underwent neoadjuvant chemoradiotherapy was decided by their pathologic stages regardless of clinical stages.

Guidelines for accreditation of endoscopy units: quality measures from the Korean Society of Coloproctology.

PURPOSE: Colonoscopy is an effective method of screening for colorectal cancer (CRC), and it can prevent CRC by detection and removal of precancerous lesions. The most important considerations when performing colonoscopy screening are the safety and satisfaction of the patient and the diagnostic accuracy. Accordingly, the Korean Society of Coloproctology (KSCP) herein proposes an optimal level of standard performance to be used in endoscopy units and by individual colonoscopists for screening colonoscopy. These guidelines establish specific criteria for assessment of safety and quality in screening colonoscopy. METHODS: The Colonoscopy Committee of the KSCP commissioned this Position Statement. Expert gastrointestinal surgeons representing the KSCP reviewed the published evidence to identify acceptable quality indicators and indicators that lacked sufficient evidence. RESULTS: The KSCP recommends an optimal standard list for quality control of screening colonoscopy in the following 6 categories: training and competency of the colonoscopist, procedural quality, facilities and equipment, performance indicators and auditable outcomes, disinfection of equipment, and sedation and recovery of the patient. CONCLUSION: The KSCP recommends that endoscopy units performing CRC screening evaluate 6 key performance measures during daily practice.

Impact of D3 lymph node dissection on upstaging and short-term survival in clinical stage I right-sided colon cancer.

BACKGROUND: D3 lymph node dissection is becoming the standard procedure for the treatment of advanced right colon cancer and has shown increasing evidence of its oncologic benefit. However, a clear indication for its application is lacking and data on this topic is unsatisfactory. Thus, the necessity for D3 lymph node dissection in clinical stage I right colon cancer remains controversial. METHODS: We retrospectively analyzed data from clinical stage I right colon cancer patients who underwent radical surgery at three hospitals of Korea university medical center between January 2015 and June 2018. We compared surgical complications and short-term oncologic outcomes between D2 and D3 lymph node dissections in these patients. RESULTS: Among 512 patients, 122 (23.8%) were clinical stage I. Of these, 88 and 34 patients received D2 and D3 lymph node dissection, respectively. There were no statistically significant differences in clinicopathologic variables and surgical outcomes between the two groups. Upstaging occurred in 16 patients (47.1%) in the D3 group and 23 patients (26.1%) in the D2 group. There were four recurrences in the D2 group but no recurrence in the D3 group. Log-rank tests showed no statistically significant difference in disease-free survival rates between the two groups (p = 0.210). CONCLUSION: There was no significant difference in disease-free survival rates between D2 and D3 lymph node dissection in clinical stage I right colon cancer patients. However, recurrence occurred in the D2 group. Efforts to improve the accuracy of clinical staging are required and more studies with better quality are needed.

Effects of the proximity of metastasis to the central vessels of the liver on surgical outcomes and survival in colorectal cancer with liver metastasis.

BACKGROUND: Resectability of liver metastasis is important to establish a treatment strategy for patients with colorectal cancer. We aimed to evaluate the effect of the distance from metastasis to the centre of the liver on surgical outcomes and survival after hepatectomy. METHODS: The clinical data of a total of 155 patients who underwent hepatectomy for colorectal cancer with liver metastasis were retrospectively reviewed. We measured the minimal length from metastasis to the bifurcation of the portal vein at the primary branch of the Glissonean tree and defined it as 'centrality'. The postoperative outcomes and survival among the patients were then analysed. RESULTS: Anatomic resections were more frequently performed, and the operative time was longer in the patients with high centrality (≤1.5 cm) than in the patients with low centrality (>1.5 cm). A size of ≥5 cm for the largest lesion, a number of lesions of ≥3 and centrality of ≤1.5 cm were found to be the independent risk factors of a positive resection margin after hepatectomy. The patients with high centrality showed worse recurrence-free survival than those with low centrality; however, there was no significant difference found in the overall survival. In the multivariate analysis, high centrality was not found to be associated with worse recurrence-free and overall survival. CONCLUSION: Centrality significantly affected the surgical outcomes and treatment strategy for liver metastasis but did not influence the survival of the patients with colorectal cancer. Active efforts through surgical resections are important to treat liver metastasis of high centrality.

Prognostic implication of systemic inflammatory markers in young patients with resectable colorectal cancer.

PURPOSE: The prognosis of young colorectal cancer (CRC) patients has not fully been addressed. The prognostic significance of systemic inflammatory markers was examined in those patients. METHODS: A total of 965 patients with resectable CRC were divided into young (≤ 50 years, n = 101) and old groups (> 51 years, n = 864). Neutrophil-to-lymphocyte ratio (NLR) > 5, derived NLR (dNLR) > 3, lymphocyte-to-monocyte ratio (LMR) < 2, platelet-to-lymphocyte ratio (PLR) > 150, and prognostic nutritional index (PNI) < 45 were analyzed for prognosis. Overall survival (OS) and progression-free survival (PFS) were compared using the log-rank test. A multivariate analysis was performed using a Cox proportional hazards regression model. RESULTS: In the young group, NLR > 5, LMR < 2, and PNI < 45 were significantly associated with OS with univariate analyses. dNLR > 3 and those markers showed significance for PFS. LMR < 2 was a significant marker for poor PFS (hazard ratio [HR], 5.81; P = 0.020) in the multivariate analysis. In the old group, all inflammatory markers were significantly associated with OS and PFS with univariate analyses. LMR < 2 (HR, 2.66; P = 0.016) and PNI < 45 (HR, 2.14; P = 0.016) were independently associated with OS in multivariate analyses. PLR > 150 (HR, 1.45; P = 0.036) and PNI < 45 (HR, 1.73; P = 0.002) were significant markers for PFS. CONCLUSION: Systemic inflammation might be one of biologic factors that influence on prognosis of young CRC.

The Effect of Epidermal Growth Factor Receptor Mutation on Intracranial Progression-Free Survival of Non-Small Cell Lung Cancer Patients with Brain Metastasis Underwent Gamma Knife Radiosurgery.

BACKGROUND: The aim of this study was to survey prognostic factors, particularly those focusing on epidermal growth factor receptor (EGFR) mutations, of patients with non-small cell lung cancer (NSCLC) after Gamma Knife Radiosurgery (GKRS) for metastatic brain tumors. METHODS: We retrospectively reviewed the medical records of 98 patients with NSCLC who underwent GKRS for brain metastases from August 2010 to July 2017. The primary endpoint was progression-free survival (PFS) of the intracranial disease. We analyzed variables such as age, sex, Karnofsky Performance Status, recursive partitioning analysis (RPA) class, smoking status, primary cancer pathology, EGFR mutations, and time to brain metastases as prognostic factors. RESULTS: The median overall survival (OS) of the patients was 16 months [95% confidence interval (CI), 13-21 months]. Median systemic PFS and intracranial PFS were 9 months (95% CI, 8-11 months) and 11 months (95% CI, 7-14 months), respectively. Kaplan-Meier survival analysis revealed that the patients with EGFR mutations had longer intracranial PFS than those without EGFR mutation (median intracranial PFS: 19 vs. 10 months with p=0.01) while they had no benefits in OS and systemic PFS. Furthermore, the patients harboring adenocarcinoma had longer OS (p<0.01) and intracranial PFS (p<0.01) and the patients with lower RPA class had longer OS (p=0.02) and intracranial PFS (p=0.03). CONCLUSION: EGFR mutations, primary cancer pathology, and RPA class may be proposed as prognostic factors for intracranial PFS in NSCLC patients after GKRS for brain metastasis in this study.

Development and validation of novel scoring system for the prediction of disease recurrence following resection of colorectal liver metastasis.

BACKGROUND: The aim of this study was to identify predictive factors for the recurrence of colorectal cancer liver metastasis (CRLM) and then to develop a corresponding novel scoring system that should improve the sensitivity of predicting recurrence in patients with CRLM. METHODS: A total of 295 consecutive CRLM patients were enrolled in our institution between January 2002 and December 2015. Multivariate analyses were performed to identify the variables associated with disease recurrence and established the novel scoring system based on it. RESULTS: The scoring system considered seven variables: synchronosity, CA19-9 level, number of liver metastasis, largest size of liver metastasis, resection margin of hepatic lesion, neutrophil-to-lymphocyte ratio and prognostic nutritional index. The area under the curve of ROC was 0.824 (95% confidence interval 0.767-0.882); the sensitivity of our scoring system was 87.9%, specificity was 66.7%, positive predictive value was 20.6%, and negative predictive value was 20.9%. CONCLUSION: For patients with CRLM undergoing curative hepatic resection, our novel scoring system would improve the sensitivity for prediction of disease recurrence in Case of CRLM patients.

Korean Red Ginseng Extract Increases Apoptosis by Activation of the Noxa Pathway in Colorectal Cancer.

BACKGROUND: Although the anticancer activity of Korean Red Ginseng (KRG) has been known in various cancers, the mechanism of KRG-induced apoptosis is unknown in colorectal cancer (CRC). In our study, we examined whether KRG induces apoptosis in CRC cells. METHODS: In the cell viability assay, the concentration of the appropriate KRG extracts was fixed at 2.5 mg/mL in numerous CRC cells. This fixed concentration was in other experiments, and it was confirmed that the KRG extracts induce apoptosis in CRC cells. RESULTS: We found that KRG induced Noxa activation and apoptosis and increased endoplasmic reticulum stress via reactive oxygen species production. This indicated that KRG efficiently enhanced cell death in CRC cells. CONCLUSION: Our results show that KRG can be used as a possible anticancer drug for patients with CRC.

Exercise during adjuvant treatment for colorectal cancer: treatment completion, treatment-related toxicities, body composition, and serum level of adipokines.

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.

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

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.

Cannabidiol Enhances the Therapeutic Effects of TRAIL by Upregulating DR5 in Colorectal Cancer.

Cannabidiol, a major non-psychotomimetic compound derived from Cannabis sativa, is a potential therapeutic agent for a variety of diseases such as inflammatory diseases, chronic neurodegenerative diseases, and cancers. Here, we found that the combination of cannabidiol and TNF-related apoptosis-inducing ligand (TRAIL) produces synergistic antitumor effects in vitro. However, this synergistic effect was not observed in normal colonic cells. The levels of ER stress-related proteins, including C/EBP homologous protein (CHOP) and phosphorylated protein kinase RNA-like ER kinase (PERK) were increased in treatment of cannabidiol. Cannabidiol enhanced significantly DR5 expression by ER stress. Knockdown of DR5 decreased the combined effect of cannabidiol and TRAIL. Additionally, the combination of TRAIL and cannabidiol decreased tumor growth in xenograft models. Our studies demonstrate that cannabidiol enhances TRAIL-induced apoptosis by upregulating DR5 and suggests that cannabidiol is a novel agent for increasing sensitivity to TRAIL.

Cannabidiol-induced apoptosis is mediated by activation of Noxa in human colorectal cancer cells.

Cannabidiol (CBD), one of the compounds present in the marijuana plant, has anti-tumor properties, but its mechanism is not well known. This study aimed to evaluate the apoptotic action of CBD in colorectal cancer (CRC) cells, and focused on its effects on the novel pro-apoptotic Noxa-reactive oxygen species (ROS) signaling pathway. CBD experiments were performed using the CRC cell lines HCT116 and DLD-1. CBD induced apoptosis by regulating many pro- and anti-apoptotic proteins, of which Noxa showed significantly higher expression. To understand the relationship between Noxa and CBD-induced apoptosis, Noxa levels were downregulated using siRNA, and the expression of apoptosis markers decreased. After ROS production was blocked, the level of Noxa also decreased, suggesting that ROS is involved in the regulation of Noxa, which along with ROS is a well-known pro-apoptotic signaling agents. As a result, CBD induced apoptosis in a Noxa-and-ROS-dependent manner. Taken together, the results obtained in this study re-demonstrated the effects of CBD treatment in vivo, thus confirming its role as a novel, reliable anticancer drug.