Uricase sensitizes hepatocellular carcinoma cells to 5-fluorouracil through uricase-uric acid-UMP synthase axis

Conventional chemotherapy plays a key role in hepatocellular carcinoma (HCC) treatment, however, with intrinsic or acquired chemoresistance being a major constraint. Here, we aimed to identify potential target to reverse such chemoresistance. In the present study, we found significant difference in uridine monophosphate synthetase (UMPS) expression between 5-FU resistant and sensitive HCC cell lines and the overexpression or downregulation of UMPS impacted 5-FU response in HCC cells. We further found that inhibition of UMPS activity with uric acid at concentration present in human plasma decreased the 5-FU sensitivity of HCC cells, while reduction of uric acid levels with uricase improved the 5-FU sensitivity of HCC cells as well as colorectal cancer cells. In vivo studies also suggested that modulation of uric acid levels did affect 5-FU sensitivity of tumors. These data indicated that UMPS was correlated with the 5-FU resistance in HCC cells and uricase sensitized cancer cells to 5-FU through uricase-uric acid-UMP synthase axis, which provided a potential strategy to improve the efficacy of 5-FU-based chemotherapy for human cancers. (AU)

Uricase sensitizes hepatocellular carcinoma cells to 5-fluorouracil through uricase-uric acid-UMP synthase axis.

Conventional chemotherapy plays a key role in hepatocellular carcinoma (HCC) treatment, however, with intrinsic or acquired chemoresistance being a major constraint. Here, we aimed to identify potential target to reverse such chemoresistance. In the present study, we found significant difference in uridine monophosphate synthetase (UMPS) expression between 5-FU resistant and sensitive HCC cell lines and the overexpression or downregulation of UMPS impacted 5-FU response in HCC cells. We further found that inhibition of UMPS activity with uric acid at concentration present in human plasma decreased the 5-FU sensitivity of HCC cells, while reduction of uric acid levels with uricase improved the 5-FU sensitivity of HCC cells as well as colorectal cancer cells. In vivo studies also suggested that modulation of uric acid levels did affect 5-FU sensitivity of tumors. These data indicated that UMPS was correlated with the 5-FU resistance in HCC cells and uricase sensitized cancer cells to 5-FU through uricase-uric acid-UMP synthase axis, which provided a potential strategy to improve the efficacy of 5-FU-based chemotherapy for human cancers.

Anticoagulation Effect and Safety Observation of Regional Citrate Anticoagulation for Double-Filtration Plasmapheresis in Critical Patients.

INTRODUCTION: Double-filtration plasmapheresis (DFPP) is a semi-selective blood purification method based on dual filtration system. Regional citrate anticoagulation (RCA) is an appealing anticoagulation alternative in DFPP. However, there are still few reports on the safety of RCA in DFPP treatment. OBJECTIVE: To investigate the anticoagulation effect and safety of RCA for DFPP in critical patients. METHODS: A total of 34 critical patients treated with DFPP were retrospectively studied. The incidence of coagulation during extracorporeal circulation after single treatment was compared before and after treatment. Heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure, blood routine indexes, blood gas analysis, peripheral ionic calcium (iCa), total peripheral calcium (TCa), TCa/iCa, and complications before and after single treatment were compared. The changes of transmembrane pressure, pressure drop were measured, and the indexes of coagulation before and after treatment were compared. RESULTS: The blood coagulation 0.05). Level of TCa was significantly decreased at 5 min after treatment (p < 0.05), but there was no statistically significant difference at 6 and 24 h (p > 0.05). No treatment-related serious complications were observed in any of the patients. CONCLUSIONS: For critical patients who underwent DFPP procedure, RCA is safety and had significant anticoagulation effects, which is worthy of clinical application.