Securinine inhibits the tumor growth of human bladder cancer cells by suppressing Wnt/ß-catenin signaling pathway and activating p38 and JNK signaling pathways.

Bladder cancer (BC) is the most common malignant tumor in urinary system. Although chemotherapy is one of the most important adjuvant treatments for BC, drug resistance, non-specific toxicity and severe side effects are the major obstacles to BC chemotherapy. Natural products have always been a leading resource of antitumor drug discovery, with the advantages of excellent effectiveness, low toxicity, multi-targeting potency and easy availability. In this study, we evaluated the potential anti-tumor effect of securinine (SEC), a natural alkaloid from Securinega suffruticosa, on BC cells in vitro and in vivo, and delineated the underlying mechanism. We found that SEC inhibited the proliferation, migration and invasion, induced the apoptosis of BC cells in vitro, and retarded the xenograft tumor growth of BC cell in vivo. Notably, SEC had a promising safety profile because it presented no or low toxicity on normal cells and mice. Mechanistically, SEC inactivated Wnt/ß-catenin signaling pathway while activated p38 and JNK signaling pathway. Moreover, ß-catenin overexpression, the p38 inhibitor SB203580 and the JNK inhibitor SP600125 both mitigated the inhibitory effect of SEC on BC cells. Furthermore, we demonstrated a synergistic inhibitory effect of SEC and gemcitabine (GEM) on BC cells in vitro and in vivo. Taken together, our findings suggest that SEC may exert anti-BC cell effect at least through the activation of p38 and JNK signaling pathways, and the inhibition of Wnt/ß-catenin signaling pathway. More meaningfully, the findings indicate that GEM-induced BC cell killing can be enhanced by combining with SEC.

Inhibition of Macropinocytosis Enhances the Sensitivity of Osteosarcoma Cells to Benzethonium Chloride.

Osteosarcoma (OS) is a primary malignant tumor of bone. Chemotherapy is one of the crucial approaches to prevent its metastasis and improve prognosis. Despite continuous improvements in the clinical treatment of OS, tumor resistance and metastasis remain dominant clinical challenges. Macropinocytosis, a form of non-selective nutrient endocytosis, has received increasing attention as a novel target for cancer therapy, yet its role in OS cells remains obscure. Benzethonium chloride (BZN) is an FDA-approved antiseptic and bactericide with broad-spectrum anticancer effects. Here, we described that BZN suppressed the proliferation, migration, and invasion of OS cells in vitro and in vivo, but simultaneously promoted the massive accumulation of cytoplasmic vacuoles as well. Mechanistically, BZN repressed the ERK1/2 signaling pathway, and the ERK1/2 activator partially neutralized the inhibitory effect of BZN on OS cells. Subsequently, we demonstrated that vacuoles originated from macropinocytosis and indicated that OS cells might employ macropinocytosis as a compensatory survival mechanism in response to BZN. Remarkably, macropinocytosis inhibitors enhanced the anti-OS effect of BZN in vitro and in vivo. In conclusion, our results suggest that BZN may inhibit OS cells by repressing the ERK1/2 signaling pathway and propose a potential strategy to enhance the BZN-induced inhibitory effect by suppressing macropinocytosis.

Assessment of a high-avidity IgG ANAs for the diagnosis and activity prediction of systemic lupus erythematosus.

OBJECTIVES: Our aim was to investigate the prevalence value of a high-avidity antinuclear antibody (ANA) of the IgG isotype (HA IgG ANA) compared with that of ANAs of other isotypes in patients with systemic lupus erythematosus (SLE) and to assess the associations of HA IgG ANA with the activity of SLE and lupus nephritis. METHODS: We retrospectively analyzed clinical and laboratory data from subjects. Blood samples were acquired from 101 SLE patients, 67 patients with other autoimmune diseases, and 65 healthy donors. The levels of HA IgG ANA and other isotype ANAs were measured by indirect immunofluorescence (IIF). The prevalence and diagnosis value of HA IgG ANA and other antibodies in SLE patient were tested. The advantage of HA IgG ANA compared with HA anti-dsDNA antibodies IgG (HA dsDNA IgG) was verified by ELISA. We monitored the relative avidity indexes (RAIs) of HA IgG ANA and HA dsDNA IgG at 3 time points after the start of treatment in the same individuals with SLE. RESULTS: The prevalence of HA IgG ANA was significantly higher in active cases than in inactive cases of SLE and LN, which is consistent with data for IgG ANAs, anti-dsDNA IgG antibodies, low C3 levels, low C4 levels, and anti-C1q antibodies. HA IgG ANA showed moderate sensitivity and specificity (80% and 81.3%) for discriminating active and inactive SLE cases. However, HA IgG ANA showed no significant differences among the different clinical manifestations of SLE. Compared with that of HA dsDNA IgG, the RAI of HA IgG ANA was positively related to SLEDAI scores after treatment at 0, 1, and 3 months (r = 0.6813, p = 0.0026; r = 0.5972, p = 0.0114; r = 0.4817, p = 0.0474). CONCLUSIONS: First, we demonstrated that HA IgG ANA was a reliable diagnostic tool in SLE patients. Furthermore, HA IgG ANA was supposed to be more appropriate for identifying the activity of SLE compared with HA dsDNA IgG. In summary, HA IgG ANA may be a new biomarker for diagnosing SLE and identifying SLE activity. Key Points • We first introduced the concept of a "high-avidity IgG ANA (HA IgG ANA)" that could distinguish between the early stage of SLE and SLE that had been active for some time. • The relative avidity indexes (RAIs) of HA IgG ANA and HA dsDNA IgG were presented and applied here to evaluate the avidities of antibodies involved in SLE. • In our study, we confirmed the value of HA IgG ANA in diagnosing SLE. In addition, HA IgG ANA was more appropriate for identifying the activity of SLE than was HA dsDNA IgG. • In conclusion, HA IgG ANA could be a potential biomarker for the assessment of the prognosis of SLE activity.