The combination of arsenic and cryptotanshinone induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in breast cancer cells.

Arsenic trioxide has been successfully used for the treatment of patients with acute promyelocytic leukemia (APL) worldwide. Recently, it has also been further developed to treat solid tumors in clinical trials. However, the therapeutic effects on malignant tumors appeared to be unsatisfactory, as these cells exhibited resistance towards arsenic. In this study, we explored new therapeutic strategies for treatment of human breast cancer MCF-7 cells based on arsenic metabolites. The MCF-7 cells were exposed to three arsenic species, namely, inorganic arsenite (iAs(III)) and its intermediate metabolites monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)) either alone or in combination with cryptotanshinone (CPT) to establish their anticancer effects against MCF-7 cells. Surprisingly, MCF-7 cells were shown to be resistant to both iAs(III) and CPT when used alone; however, they were shown to be relatively sensitive to treatment when exposed to MMA(III) and DMA(III) alone. Conversely, the combination of MMA(III) with CPT showed significantly enhanced anticancer effects on MCF-7 cells at low doses, but no appreciable effect was observed upon exposure to the other two arsenic species with CPT. In addition, remarkable redistribution of pro-apoptosis related proteins Bax and Bak was observed in the mitochondria, together with activation of poly(ADP-ribose) polymerase (PARP) and caspase-9 after exposure to the combination of MMA(III) with CPT. Furthermore, we clearly found that induction of apoptosis in MCF-7 cells was predominantly triggered by endoplasmic reticulum (ER) stress after exposure to the combination of MMA(III) with CPT.

CCL5, CXCL16, and CX3CL1 are associated with Henoch-Schonlein purpura.

Chemokines are involved in the pathogenesis of various vascular inflammations. However, information about chemokines in Henoch-Schonlein purpura (HSP) is limited. Herein, we investigated the serum CCL5, CXCL16, and CX3CL1 levels in HSP patients with controls and the ability of sera from HSP patients on chemokine production in human dermal microvascular endothelial cells. Enzyme-linked immunosorbent assay (ELISA) detected serum CCL5, CXCL16, and CX3CL1 levels in patients with HSP. Human dermal microvascular endothelial cell line (HMEC-1) was treated with sera from patients with HSP at different stages, patients with acute spontaneous urticaria, or controls. Serum levels of CCL5, CXCL16, and CX3CL1 were elevated in HSP patients at acute stage, which correlated with the severity of this disease. Sera from patients with active HSP markedly induced CCL5, CXCL16, and CX3CL1 production at both mRNA and protein levels. In addition, patients' sera-stimulated HMEC-1 supernatants enhanced HL-60 or THP-1 cells migration. Furthermore, patients' sera increased the phosphorylation of inhibitor of κB-α (IκBα) and phosphorylation of extracellular signal-regulated kinase (ERK)1/2 protein levels, upregulated the translocation of nuclear factor-κB (NF-κB) p65 to the nucleus. Taken together, we show firstly that CCL5, CXCL16, and CX3CL1 may be involved in the pathogenesis of HSP. Factors present in sera from patients with active HSP may act as an inducer of inflammatory response in HMEC-1 cells and contribute to chemokine production through NF-κB and ERK 1/2 pathways.

Peoniflorin suppresses tumor necrosis factor-α induced chemokine production in human dermal microvascular endothelial cells by blocking nuclear factor-κB and ERK pathway.

Peoniflorin (PF) extracted from the root of Paeonia lactiflora pall displays anti-inflammation and antioxidant properties in several animal models. Chemokines are vital for directing the movement of circulating leukocytes to the sites of inflammation and are involved in the pathogenesis of various inflammatory skin diseases. Herein, we investigated the effects and potential mechanisms of PF on tumor necrosis factor-α (TNF-α) induced chemokine production in human dermal microvascular endothelial cells. Human dermal microvascular endothelial cell line (HMEC-1) was treated by TNF-α with or without PF. PF markedly attenuated TNF-α-induced chemokines (including CCL2, CCL5, CCL20, CXCL8, CXCL16 and CX3CL1) mRNA expression in HMEC-1. PF also reduced the secretion of these chemokines in culture supernatants. In addition, endothelial activation in the presence of PF markedly blocked the chemotactic activities of TNF-α-stimulated HMEC-1 supernatant on promyelocytic leukemia cell line (HL-60) or the acute mature monocytic leukemia cell line (THP-1) cell migration. Furthermore, Western blot data revealed TNF-α upregulated phosphorylation of inhibitor of κB-α (IκBα) and phosphorylation of extracellular signal-regulated kinase (ERK)1/2, which was almost completely reversed by PF. Finally, PF inhibited nuclear factor-κB (NF-κB) nuclear translocation to the nucleus. Taken together, our data provide the first evidence that PF has an anti-inflammatory ability against TNF-α-induced chemokine production and leukocyte migration, which may be at least partly related to the inhibition of NF-κB and ERK pathway. PF may be a candidate medicine for the treatment of inflammatory skin diseases.