Pharmacologically active compounds from ticks and other arthropods and their potential use in anticancer therapy

Abstract

Arthropods represent a rich source of various biologically and pharmacologically active molecules and were also shown to possess cytotoxic and cytolytic effects on tumor cell lines as well as anti-angiogenic activities. Cytotoxic and apoptosis-inducing factors were found, e.g., in some butterflies, beetles and saprophagous flies, however, venomous and blood feeding animals contain the widest array of pharmacologically active compounds. Antitumor and anti-angiogenic compounds have been detected in saliva of ticks and blood feeding insects quite recently. For example, an antigen 5-like protein (tabRTS) containing the RTS-disintegrin motif with anti-angiogenic properties was isolated from horsefly salivary glands. However, and in contrast to blood feeding dipterans (e.g., horseflies or mosquitoes), hard ticks (Ixodida) as a distinct group of blood feeding arthropods remain attached to their hosts for several days to weeks. Tick salivary compounds are secreted into the host during feeding and are involved in the modulation of host haemostasis and immune responses and thus are essential for completion of the feeding process and tick survival. During the extended feeding period, expression of new proteins is switched on in salivary glands of hard ticks. By exploring the proteins expressed in tick salivary glands (sialome), novel sequences with similarities to disintegrin metalloproteases and thrombospondin were discovered, suggesting that tick salivary peptides can be involved in disruption of platelet aggregation, cell-matrix interactions and/or inhibition of angiogenesis. These findings suggest that tick saliva modulates negatively angiogenesis-dependent wound healing and tissue repair, allowing ticks to feed for prolonged periods. Antihemostatic factors in tick saliva represent another source of promising anticancer therapeutics. Ixolaris, a tissue factor inhibitor from ticks blocks tumor growth and angiogenesis in a glioblastoma model. The inhibitory effect of ixolaris is most probably due to downregulation of the vascular endothelial growth factor and reduced tumor vascularization. Amblyomin-X, a tick Kunitz-type serine protease inhibitor induces tumor mass regression and decreased number of metastatic processes in a murine melanoma model, indicating that the compound selectively acts on tumor cells by inducing apoptosis. Generally, the diversity of arthropod bioactive molecules is very wide and needs further extensive exploration with the perspective to discover novel compounds with potential use as pharmaceuticals in anticancer therapy.