No abstract

In the absence of proper immunity, such as in the case of acquired immune deficiency syndrome (AIDS) patients, Candida albicans, the most common human fungal pathogen, may cause mucosal and even life-threatening systemic infections. P-113 (AKRHHGYKRKFH), an antimicrobial peptide (AMP) derived from the human salivary protein histatin 5, shows good safety and efficacy profiles in gingivitis and human immunodeficiency virus (HIV) patients with oral candidiasis. However, little is known about how P-113 interacts with Candida albicans or its degradation by Candida-secreted proteases that contribute to the fungi’s resistance. Here, we use solution nuclear magnetic resonance (NMR) methods to elucidate the molecular mechanism of interactions between P-113 and living Candida albicans cells. Furthermore, we found that proteolytic cleavage of the C-terminus prevents the entry of P-113 into cells and that increasing the hydrophobicity of the peptide can significantly increase its antifungal activity. These results could help in the design of novel antimicrobial peptides that have enhanced stability in vivo and that can have potential therapeutic applications.

PurposeLung cancer and other solid tumors contain not only tumor cells but various types of stromal cells, such as fibroblasts and endothelial cells. In addition, tumors are infiltrated by inflammatory cells (neutrophils, macrophages, and lymphocytes). Tumor cells, stromal cells, and the tumor-associated leukocytes are responsible for the production of chemokines inside the tumor and the maintenance of systemic circulating chemokine levels. CXCL8 and its receptors, CXCR1 and CXCR2, were found to play important roles in tumor proliferation, migration, survival, and growth. We have developed a novel ELR-CXC chemokine antagonist CXCL8-IP10 based on the structure of CXCL8 and IP10.Patients and methodsWe assessed the anticancer efficacies of the blockade of CXCL8-CXCR1/2 axis in the Lewis lung carcinoma (LL/2) model using CXCL8-IP10.ResultsWe found that CXCL8-IP10 markedly reduced LL/2 cell anchorage-independent growth and invasion. Moreover, we demonstrated that CXCL8-IP10 could significantly suppress tumor growth and improve survival rate as well as lifespan of C57BL/6 mice inoculated with LL/2 cells.ConclusionOur results suggest that ELR-CXC chemokine antagonism would potentially be a useful therapeutic approach in patients with lung cancer.