Human CD38 regulates B cell antigen receptor dynamic organization in normal and malignant B cells.

CD38 is a multifunctional protein expressed on the surface of B cells in healthy individuals but also in B cell malignancies. Previous studies have suggested a connection between CD38 and components of the IgM class B cell antigen receptor (IgM-BCR) and its coreceptor complex. Here, we provide evidence that CD38 is closely associated with CD19 in resting B cells and with the IgM-BCR upon engagement. We show that targeting CD38 with an antibody, or removing this molecule with CRISPR/Cas9, inhibits the association of CD19 with the IgM-BCR, impairing BCR signaling in normal and malignant B cells. Together, our data suggest that CD38 is a new member of the BCR coreceptor complex, where it exerts a modulatory effect on B cell activation upon antigen recognition by regulating CD19. Our study also reveals a new mechanism where α-CD38 antibodies could be a valuable option in therapeutic approaches to B cell malignancies driven by aberrant BCR signaling.

Sildenafil enhances cisplatin-induced apoptosis in human breast adenocarcinoma cells.

INTRODUCTION: Cyclic nucleotide phosphodiesterase (PDE) enzymes are a large superfamily of enzymes that catalyze the conversion reaction of cyclic adenosine monophosphate (AMP) and cyclic guanosine monophosphate (GMP) to AMP and GMP, respectively. In some cancer cells, PDE-5 has been shown to be overexpressed in multiple human carcinomas. It seems that the inhibition of PDE-5 may has anticancer effects. Cisplatin is one of the prevalent chemo-agents to treat solid tumors. However, its clinical usefulness is hindered by dose-limiting toxicities, especially on the kidneys (nephrotoxicity) and ears (ototoxicity). In this study, the antitumor activity of the sildenafil as a PDE-5 inhibitor alone and in combination with cisplatin on human mammary adenocarcinomas and MCF-7 and MDA-MB-468 was assessed. MATERIALS AND METHODS: Sildenafil as PDE type 5 (PDE5) inhibitor is the drugs that we combined with the cisplatin (chemotherapeutic agent), in vitro. Human mammary adenocarcinomas and MCF-7 and MDA-MB-468 cell lines were cultured in standard conditions. At time point, following 24 h and 48 h incubation, the cell lines were treated by cisplatin in the presence/absence of sildenafil. Cell viability, apoptosis, and reactive oxygen species (ROS) were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, real-time polymerase chain reaction, and Western blot; and fluorimetric methods, respectively. Statistical analysis was performed using SPSS software SPSS (SPSS Inc., Chicago, IL, USA). RESULTS: In MCF-7 cell line, following 24 h incubation, combinations of sildenafil with cisplatin (P < 0.001) showed decreased cell viability when compared to sildenafil and cisplatin alone. Moreover in MDA-MB-468 cell line, following 24 h incubation, data did not show any significant changes on cell viability when treated with cisplatin, in the presence or absence of sildenafil. However, following 48 h incubation, combinations of cisplatin with sildenafil (P < 0.001) were showed decreased cell viability when compared to cisplatin and sildenafil alone in both MCF-7 and MDA-MB-468 cell lines. Concerning the ROS production and apoptosis, data showed that both processes increase significantly in the presence of the sildenafil in comparison absent it. CONCLUSION: Our data showed that the combination of sildenafil with cisplatin can improve cell toxicity and anticancer effect of cisplatin. And also sildenafil as a PDE-5 inhibitor could be used as additive treatment in combination with cisplatin to make a reduction in cisplatin dosage and its side effects.