Verapamil enhances the sensitivity of oxaliplatin to tumor cells by influencing the PARP pathway.

PARP is a DNA damage-modifying enzyme present in most eukaryotic cells. In this study, reverse docking showed that verapamil (Vera), which can effectively bind PARP1/2, could significantly inhibit PARP1/2 activity inside and outside the system. Moreover, it could enhance the sensitivity of oxaliplatin to low-expression P-glycoprotein (P-gP) tumor cells and strengthen its apoptosis-inducing effect on tumor cells under the reverse drug resistance concentration of tumor cells. Vera, which can reverse chemotherapy resistance of tumor cells, showed no simple correlations with oxaliplatin drug resistance or P-gP expression and could enhance the anti-tumor effect of platinum chemotherapeutic agents by influencing the PARP pathway.

Famotidine promotes inflammation by triggering cell pyroptosis in gastric cancer cells.

BACKGROUND: Cell pyroptosis has been characterized by cell swelling and pro-inflammatory factors release to aggravate inflammatory reaction., such as interlukin-1 beta (IL-1ß) and interlukin18 (IL-18). However, the function of famotidine, an antagonist of histamine H2-receptor antagonists, in cell pyroptosis remained unknown. METHODS: Real-time quantitative PCR (qPCR), western blotting (WB), LDH release assay and enzyme linked immunosorbent assay (Elisa) combined with inhibitor were performed to analyze the effect of famotidine on cell pyroptosis-related gene expression. RESULTS: In this study, we found that famotidine (300 µm) treatment led to a phenomenon of cell pyroptosis as confirmed by LDH assay. Further results showed that famotidine triggered cell pyroptosis in gastric cancer cells by activation of NLPR3 inflammasomes including ASC, Caspase-1 and NLRP, leading to enhanced IL-18, not IL-1ß, mature and secretion. What's more, the results also showed GSDME, not GSDMD, was increased in response to famotidine stimulation in BGC823 and AGS cells. Mechanically, phosphorylation of ERK1/2 was drastically enhanced in present with famotidine treatment, while inhibition of ERK1/2 activity by U0126 could reverse the promotion of famotidine in IL-18 secretion. CONCLUSION: These findings revealed a novel role of famotidine in cell pyroptosis in patients with gastric cancer, a comprehensive consideration is needed in treatment of gastric cancer.

[Effect of axial stress stimulation on tibial and fibular open fractures healing after Taylor space stent fixation].

Objective: To investigate the effect of axial stress stimulation on tibial and fibular open fractures healing after Taylor space stent fixation. Methods: The data of 45 cases with tibial and fibular open fractures treated by Taylor space stent fixation who meet the selection criteria between January 2015 and June 2016 were retrospectively analysed. The patients were divided into trial group (23 cases) and control group (22 cases) according to whether the axial stress stimulation was performed after operation. There was no significant difference in gender, age, affected side, cause of injury, type of fracture, and interval time from injury to operation between 2 groups ( P>0.05). The axial stress stimulation was performed in trial group after operation. The axial load sharing ratio was tested, and when the value was less than 10%, the external fixator was removed. The fracture healing time, full weight-bearing time, and external fixator removal time were recorded and compared. After 6 months of external fixator removal, the function of the limb was assessed by Johner-Wruhs criteria for evaluation of final effectiveness of treatment of tibial shaft fractures. Results: There were 2 and 3 cases of needle foreign body reaction in trial group and control group, respectively, and healed after symptomatic anti allergic treatment. All the patients were followed up 8-12 months with an average of 10 months. All the fractures reached clinical healing, no complication such as delayed union, nonunion, or osteomyelitis occurred. The fracture healing time, full weight-bearing time, and external fixator removal time in trial group were significantly shorter than those in control group ( P<0.05). After 6 months of external fixator removal, the function of the limb was excellent in 13 cases, good in 6 cases, fair in 3 cases, and poor in 1 case in trial group, with an excellent and good rate of 82.6%; and was excellent in 5 cases, good in 10 cases, fair in 4 cases, and poor in 3 cases in control group, with an excellent and good rate of 68.2%, showing significant difference between 2 groups ( Z=-2.146, P=0.032). Conclusion: The axial stress stimulation of Taylor space stent fixation can promote the healing of tibial and fibular open fractures and promote local bone formation at fracture site.

CDKN2B is critical for verapamil-mediated reversal of doxorubicin resistance in hepatocellular carcinoma.

In this study, we explored the function and mechanism of CDKN2B genes in verapamil (VER)-induced reversal of resistance to doxorubicin (ADM) chemotherapy in hepatocellular carcinoma (HCC). We examined 4 HCC cell lines and found that the expression levels of CDKN2B genes correlated with the level of apoptosis induced by ADM+VER. Overexpression of CDKN2B genes promoted apoptosis in cells treated with VER+ADM. CDKN2B knockdown using siRNA weakened the effect of ADM+VER, indicating that ADM+VER promotes HCC cell apoptosis and that CDKN2B genes participate in VER-mediated promotion in tumor cell apoptosis. Future research will further explore the functional mechanism, and the associated signal transduction pathways via which CDKN2B affects HCC drug resistance.

Studies on assessment methods of malignant ascites residue and changes of verapamil concentration in intraperitoneal perfusion chemotherapy.

PURPOSE: To establish a simple method for estimating residual peritoneal ascites in order to determine the optimum verapamil (VRP) initial concentration in the intraperitoneal perfusion chemotherapy. METHODS: (1) Pelvic size of adults was assessed by measuring distance from the superior margin of pubic symphysis to the connecting line of two anterior superior spine (SL) and to the midpoint of the line (SM) in 172 adults; (2) 35 postoperative gastric or colon cancer patients with indications for use of preventive intraperitoneal chemotherapy were infused with 1,000-1,250 mL 0.9 % normal saline solution for about 15 min and used for perfusate detection by moving along the midpoint of connecting line of two anterior superior spine after 5 min of infusion; (3) The VRP concentration in ascites was detected by liquid chromatography. RESULTS: The distance between two anterior superior spines for adult were 29.6 ± 2.6 cm and the distance from the superior margin of pubic symphysis to the midpoint between two anterior superior spines was 10.6 ± 1.9 cm. When the total intraperitoneal infusion fluid was 1,000-1,250 mL, it could be detected by B-mode ultrasonic device at 0.1-0.3 cm directly below the midpoint of two anterior superior spines. The VRP reversal concentration of drug resistance could maintain for 90 min when the residual ascites volume was within the range of 1,000-1,250 mL. CONCLUSIONS: Detection of liquid at the position directly below or above the midpoint of two anterior superior spines by B-mode ultrasonic device in patients in erect position could be a simple method for estimation of ascites volume (liquid found at 0.1-0.3 cm directly below the midpoint of two anterior superior spines suggested that ascites volume was smaller than 1,000-1,250 mL). The method could be used for determination of VRP initial concentration for IPC treatment.

Treatment of malignant ascites with a combination of chemotherapy drugs and intraperitoneal perfusion of verapamil.

PURPOSE: This study was designed to evaluate efficacy, toxicity, and adverse effects of combination of chemotherapy drugs and intraperitoneal perfusion of verapamil in the treatment of malignant ascites. METHODS: Seventy-two patients with malignant ascites were divided into two study groups. Patients in control group (31 cases) received conventional chemotherapy, whereas patients in the combined treatment group (41 cases) were given verapamil intraperitoneally in addition to chemotherapy drugs. Thirty days after the treatment, efficacy, toxicity, and adverse effects were assessed in both study groups. RESULTS: The treatment of control group led to 1 case of complete remission and 2 cases of partial remission, making the rate of efficacy (complete + partial remission) of 9.7 %. The combined treatment group demonstrated 13 cases of complete remission and 22 cases of partial remission. Thus, the rate of efficacy was significantly higher in the combined treatment group (85.36 %; p < 0.05 vs. control group). Using KPS scores, changes in quality of life were compared before and after the treatment. The quality of life improved in control group by 13.7 %, while combined treatment group showed improvement of 83.5 % (p < 0.05 vs. control group). Further, cumulative survival rate was also significantly higher in the combined treatment group. Treatment toxicity and the rate of adverse effects and intestinal adhesion were not significantly different between study groups. CONCLUSIONS: Intraperitoneal perfusion of verapamil enhances the efficacy of chemotherapy drugs, prolongs survival, and improves the quality of life. Intraperitoneal administration limits cardiotoxicity of verapamil.

Clinical evaluation of targeted arterial perfusion of verapamil and chemotherapeutic drugs in interventional therapy of advanced lung cancer.

PURPOSE: To assess the clinical efficacy of targeted arterial perfusion of verapamil and chemotherapeutic agents in the interventional therapy of lung cancer. METHODS: Forty patients with advanced lung cancer underwent treatment with targeted arterial perfusion of verapamil and chemotherapeutic agents using Seldinger technique. Interventional therapy was performed once a month, and each subject received interventional treatment for 2 or more cycles. The therapeutic efficacy was evaluated 2 months post-treatment. RESULTS: Out of 40 patients with advanced lung cancer, 5 cases achieved complete remission (CR) and 29 cases achieved partial remission (PR), with a total effectiveness (CR + PR) rate of 85 %. Besides, 32 cases achieved significantly alleviated clinical symptoms, and 29 cases had decreased clinical tumor stage. All subjects had stable karnofsky performance status score and body weight. Among the 40 patients, 13 cases had leucopenia, 10 cases had gastrointestinal reactions, 3 cases presented with elevated alanine aminotransferase/aspartate aminotransferase ratio, and 3 cases had fever. However, all these side effects relieved quickly. No elevation of BUN/Cr ratio and allergic reactions was observed. No significant changes in cardiac function and electrocardiogram were noticed after the treatment. CONCLUSIONS: Targeted arterial perfusion of verapamil and chemotherapeutic drugs can improve the clinical symptoms of patients with advanced lung cancer and increase the efficacy of chemotherapeutic agents, thereby providing an opportunity for radiotherapy or surgical treatment for advanced lung cancer.