Disulfiram Synergizes with SRC Inhibitors to Suppress the Growth of Pancreatic Ductal Adenocarcinoma Cells in Vitro and in Vivo.

Disulfiram (DSF), an old anti-alcoholism drug, has emerged as a candidate for drug repurposing in oncology. In exploratory studies on its therapeutic effects, we unexpectedly discovered that DSF increased the phosphorylation of SRC, a proto-oncogene tyrosine-protein kinase elevated in 70% of pancreatic ductal adenocarcinoma (PDAC) cases. This serendipitous and novel finding led to our hypothesis for the current study which proposes DSF may synergize with SRC inhibitors in suppressing PDAC. Human PDAC PANC-1 and BXPC-3 cells were incubated with DSF chelated with copper (Cu2+), SRC inhibitors (PP2 and dasatinib), or transfected with lentiviral short hairpin RNA (shRNA), and their proliferation and apoptosis were analyzed. A xenograft model was employed to verify the in vitro results. The expression of key molecules was detected. DSF significantly inhibited cell proliferation and induced cell apoptosis by increasing the cleavage of poly ADP ribose polymerase (PARP), downregulating Bcl-2 and upregulating p27 in concentration- and time-dependent manners. DSF had little effect on signal transducer and activator of transcription 3 (STAT3) expression but inhibited its phosphorylation. DSF did not alter SRC expression but significantly increased its phosphorylation through upregulating actin filament associated protein 1 like 2 (AFAP1L2). DSF exhibited a synergistic effect, as analyzed by drug coefficient interactions, with either PP2, or dasatinib, or SRC depletion in suppressing PDAC cells in vitro and/or in vivo. The present results indicate DSF is a potential therapeutic drug, particularly when it is combined with SRC inhibitors, and warrant further studies on the pharmacological utility of DSF as a promising adjunct therapy for the treatment of PDAC.

Exosomal MiR-4261 mediates calcium overload in RBCs by downregulating the expression of ATP2B4 in multiple myeloma.

Background: Hypercalcemia induced by multiple myeloma (MM) affects the biological functions of excitable and non-excitable cells. However, red blood cells (RBCs) regulatory effect on calcium in hypercalcemia is still not fully understood. Methods: A total of 113 patients with MM osteolytic lesions were studied retrospectively. Flow cytometry and atomic absorption spectroscopy were used to detect calcium content. Immunofluorescence and Western blotting were used to investigate protein expression. GEO and miRNA databases were used to screen miRNAs. Exosomal miR-4261 migration was investigated by Transwell assay. Dual-luciferase assays confirmed the targeting relationship between miR-4261 and ATP2B4. An RBC oxidative stress model was constructed, and Omega-Agatoxin IVA was used to study the role of plasma membrane Ca2+-ATPase 4 (PMCA4) in RBCs. Results: The results showed that MM RBCs had calcium overload, and serum calcium levels increased as the number of RBCs decreased. The expression of PMCA4 in MM RBCs was significantly lower than in normal RBCs. The exosomal miR-4261 produced by MM cells could be transferred to RBCs to downregulate the expression of ATP2B4. Conclusions: Studies have confirmed that RBCs experience calcium overload in MM with osteolytic lesions, which is related to the downregulation of ATP2B4 by MM exosomal miR-4261.

The relationship between diabetic risk factors, diabetic complications and salt intake.

The relationship between salt and hypertension is the focus of a large amount of research, there are few reviews of the relationship between salt and diabetes, despite the increasing incidence of diabetes. By searching PubMed and the Cochrane Library, we summarized the relationships between diabetic risk factors, diabetic complications and salt intake. The pathophysiological mechanisms underlying the effects of salt on diabetes risk factors and diabetic complications are also discussed. Our findings should assist experts and scholars to understand the current research of salt intake and to pay more attention to the prevention and treatment of related diseases caused by excessive salt intake; guide treatment for patients with diabetes mellitus; and provide a reference for government departments to formulate a reasonable salt restriction policy. We also recommend future research directions.