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.

This study investigated the prognostic effects of venous thromboembolism (VTE)-related factors in patients with metastatic pancreatic cancer receiving palliative chemotherapy. Predictive factors for VTE were also investigated. A total of 216 patients diagnosed with metastatic pancreatic cancer who received gemcitabine-based palliative chemotherapy at our institution were retrospectively evaluated. VTE occurred in 51 (23.6%) patients during treatment and did not affect survival. However, patients who were diagnosed with VTE at the beginning of chemotherapy showed poor prognosis compared with patients diagnosed with VTE during chemotherapy: all patients (hazard ratio [HR] 1.897, p = 0.008); patients diagnosed with VTE (HR = 3.768, p = 0.001). Low serum sodium (Na) (< 135 mmol/L) and high Khorana score (≥3) were strong predictive factors of early VTE (odds ratio [OR] 5.109; 95% confidence interval [95% CI] = 1.010–25.845; p = 0.049 for Khorana score, OR 10.304; 95% CI = 1.036–102.466; p = 0.047) for hyponatremia). Our study demonstrated that occurrence and detection of VTE in the early period of chemotherapy was the most significant VTE-related prognostic factor in patients with metastatic pancreatic cancer receiving chemotherapy. Prediction using the Khorana score and serum Na levels would be helpful in early diagnosis of VTE.

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.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known to behave as an attractive anti-cancer agent in various cancers. Despite its promise TRAIL has limitations such as short half-life and rapid development of resistance. In this regard, approaches to sensitizers of TRAIL that can overcome the limitations of TRAIL are necessary. However, the molecular targets and mechanisms underlying sensitization to TRAIL-induced apoptosis are not fully understood. Here, we propose that reactive oxygen species modulator-1 (Romo1) as an attractive sensitizer of TRAIL. Romo1 is a mitochondrial inner membrane channel protein that controls reactive oxygen species (ROS) production, and its expression is highly upregulated in various cancers, including colorectal cancer. In the present study, we demonstrated that Romo1 inhibition significantly increased TRAIL-induced apoptosis of colorectal cancer cells, but not of normal colon cells. The combined effect of TRAIL and Romo1 inhibition was correlated with the activation of mitochondrial apoptosis pathways. Romo1 silencing elevated the protein levels of BCL-2-associated X protein (Bax) by downregulating the ubiquitin proteasome system (UPS). Romo1 inhibition downregulated the interaction between Bax and Parkin. Furthermore, Romo1 knockdown triggered the mitochondrial dysfunction and ROS generation. We validated the effect of combination in tumor xenograft model in vivo. In conclusion, our study demonstrates that Romo1 inhibition induces TRAIL-mediated apoptosis by identifying the novel mechanism associated with the Bax/Parkin interaction. We suggest that targeting of Romo1 is essential for the treatment of colorectal cancer and may be a new therapeutic approach in the future and contribute to the drug discovery.

Despite the importance of radiation therapy, there are few radiation-related markers available for use in clinical practice. A larger catalog of such biomarkers is required to help clinicians decide when radiotherapy should be replaced with a patient-specific treatment. Arachidonate 15-lipoxygenase (15-LOX-1) enzyme is involved in polyunsaturated fatty acid metabolism. When colorectal cancer (CRC) cells were exposed to radiation, 15-LOX-1 was upregulated. To verify whether 15-LOX-1 protects against or induces DNA damage, we irradiated sh15-LOX-1 stable cells. We found that low 15-LOX-1 is correlated with radioresistance in CRC cells. These data suggest that the presence of 15-LOX-1 can be used as a marker for radiation-induced DNA damage. Consistent with this observation, gene-set-enrichment analysis based on microarray experiments showed that UV_RESPONSE was decreased in sh15-LOX-1 cells compared to shCon cells. Moreover, we discovered that the expression of the histone H2A variant macroH2A2 was sevenfold lower in sh15-LOX-1 cells. Overall, our findings present mechanistic evidence that macroH2A2 is transcriptionally regulated by 15-LOX-1 and suppresses the DNA damage response in irradiated cells by delaying H2AX activation.

Background: Lenvatinib, a novel multi-target tyrosine kinase inhibitor, has been approved for treating differentiated thyroid cancer. Herein, we describe a rare case of acute pancreatitis that developed during lenvatinib treatment in a 65-year-old man with recurrent thyroid cancer. Case Presentation: The patient was admitted to our department following a complaint of acute-onset epigastric pain and indigestion. He had been receiving lenvatinib since 34 days. Although his serum amylase and lipase levels were normal, he had acute-onset persistent epigastric pain and typical computed tomography findings, which were consistent with those of acute pancreatitis. As other common etiologies were excluded, it was concluded that the patient had lenvatinib-induced acute pancreatitis. On admission day 14, he could consume food orally, after conservative care, including drug cessation, intravenous hydration, and pain control. Conclusion: Physicians should consider acute pancreatitis as a differential diagnosis for patients complaining of abdominal pain while on lenvatinib, regardless of hyperamylasemia or hyperlipasemia. Systematic collection of data on acute pancreatitis development during lenvatinib treatment should be considered, and further research is warranted to identify the mechanism of acute pancreatitis associated with multi-target tyrosine kinase inhibitors such as lenvatinib.