Bruton's Tyrosine Kinase Inhibitors (BTKIs): Review of Preclinical Studies and Evaluation of Clinical Trials.

In the last few decades, there has been a growing interest in Bruton's tyrosine kinase (BTK) and the compounds that target it. BTK is a downstream mediator of the B-cell receptor (BCR) signaling pathway and affects B-cell proliferation and differentiation. Evidence demonstrating the expression of BTK on the majority of hematological cells has led to the hypothesis that BTK inhibitors (BTKIs) such as ibrutinib can be an effective treatment for leukemias and lymphomas. However, a growing body of experimental and clinical data has demonstrated the significance of BTK, not just in B-cell malignancies, but also in solid tumors, such as breast, ovarian, colorectal, and prostate cancers. In addition, enhanced BTK activity is correlated with autoimmune disease. This gave rise to the hypothesis that BTK inhibitors can be beneficial in the therapy of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), Sjögren's syndrome (SS), allergies, and asthma. In this review article, we summarize the most recent findings regarding this kinase as well as the most advanced BTK inhibitors that have been developed to date and their clinical applications mainly in cancer and chronic inflammatory disease patients.

The intensification of anticancer activity of LFM-A13 by erythropoietin as a possible option for inhibition of breast cancer.

Recombinant human erythropoietin (Epo) is an effective and convenient treatment for cancer-related anaemia. In our study for the first time, we evaluated the effect of simultaneous use of Epo and Bruton's tyrosine kinase (BTK) inhibitor LFM-A13 on the viability and tumour development of breast cancer cells. The results demonstrated that Epo significantly intensifies the anticancer activity of LFM-A13 in MCF-7 and MDA-MB-231. The featured therapeutic scheme efficiently blocked the tumour development in zebrafish experimental cancer model. Epo and LFM-A13 administered together resulted in effective cell killing, accompanied by attenuation of the BTK signalling pathways, loss of mitochondrial membrane potential (MMP), accumulation of apoptotic breast cancer cells with externalised PS, a slight increase in phase G0/G1 and a reduction in cyclin D1 expression. Simultaneous use of Epo with LFM-A13 inhibited early stages of tumour progression. This therapeutic scheme may be rationale for further possible research.

Erythropoietin Enhances the Cytotoxic Effect of Hydrogen Peroxide on Colon Cancer Cells.

BACKGROUND: Cancer patients treated with alkylating agents and radiotherapy are exposed to high level of reactive oxygen species (ROS) in tissues. ROS can involve superoxide free radicals, peroxynitrite, singlet oxygen, nitric oxide and hydrogen peroxide. It is well documented that increased exposure to oxygen through a high metabolic rate could lead to a shortened life span. Ionizing radiation, use of drugs and the development of cancer can lead to cancer-induced anemia. Recombinant human erythropoietin (Epo) supplementation is one of the methods for treating anemia. Erythropoietin through an increase in the number of erythrocytes, improves oxygenation tissue. The aim of this work was to study the effect of Epo on colon adenocarcinoma cells (DLD-1) given alone or in combination with hydrogen peroxide (H2O2). Cell proliferation and number were measured. METHODS: Expression of EpoR, Bcl-2 and Akt1 protein was assessed by RT-PCR, Western blot, and confocal microscopy. RESULTS: The results show that the coadministration of Epo and H2O2 indicates antitumor action, which occurs via a dose-dependent inhibition of DLD-1 cell growth and proliferation. Moreover, the coadministration of Epo and H2O2 resulted in a decrease of cell numbers, as well as Bcl-2 expression. The incubation of DLD-1 cells with those agents led to a decrease in EpoR and phosphorylated EpoR expression and an increase in Akt1 and phosphorylated Akt expression. The addition of Epo to H2O2 intensified the cytotoxic effect of the latter. CONCLUSION: These preclinical results suggest that Epo during chemotherapy or radiotherapy may possess potential benefits in colon cancer patients.

YKL-40 in hemodialyzed patients with and without cardiovascular complications - the enhancement by the coexistence of the seropositivity against hepatitis C virus infection.

BACKGROUND: YKL-40 is a new biomarker of inflammation, which is expressed by several cell types of the immune system. The aim of the present study was to evaluate plasma YKL-40 levels in hemodialysis (HD) patients and to establish its potential role as a new inflammatory biomarker of cardiovascular disease (CVD) in this population. METHODS: YKL-40 and two other inflammatory markers: high sensitivity C-reactive protein (hsCRP) and neopterin levels were measured in 70 HD patients both with and without CVD and in 38 healthy controls. RESULTS: Median YKL-40, hsCRP and neopterin levels were significantly elevated in HD patients, particularly those with CVD, compared to controls. YKL-40 was no associated with hsCRP, but it is strongly and independently associated with plasma neopterin levels in HD patients. The coexistence of the seropositivity against hepatitis C virus (anti-HCV) infection increased both YKL-40 and neopterin levels in these patients. This effect was particularly seen in subjects with CVD. Moreover, high neopterin levels were exclusively associated with anti-HCV seropositivity, whereas hsCRP values were only associated with the presence of CVD. CONCLUSIONS: This study indicated for the first time that plasma YKL-40 level is increased in HD patients, especially in those with CVD, and it is independently associated with neopterin - an biomarker of monocyte/macrophage activation. There was no association between YKL-40 and hsCRP, the common indicator of an inflammatory state. Moreover, the coexistence of anti-HCV seropositivity had an important impact on plasma YKL-40 levels in HD patients particularly those with cardiovascular complications.