Fighting Cancer Cells, Host Defense Guards Have Potential

Chemotherapy for most cancers targets rapidly proliferating cells with little distinction between cancerous and normally proliferating cells. This makes chemotherapy a series of side effects, such as nausea, vomiting, bone marrow suppression and thrombocytopenia.

Chemotherapy had little effect on dormant cells and slower-growing cancer cells. In addition, cancer cells rapidly develop resistance to anticancer drugs, mainly through the overexpression of drug transporters and resistance to apoptosis mechanisms. Many HDPs can kill cancer cells in vitro, including melittin, limulusin Ⅱ and LL-37

However, these peptides have no anticancer activity in vivo because the peptides are inactivated in serum. Interestingly, however, peptides composed of D-amino acids significantly inhibited the growth of human prostate and breast cancers in xenografts and in ACID/NCr mice, respectively.

It has been hypothesized that peptides with anticancer activity are bacteriolytic, and that they differentially target the cell membranes of cancer cells and normal cells. Due to the overexpression of some negative macromolecules, many cancer cells have a network of negatively charged layers outside the membrane, such as: phosphatidylserine, O-glycosylated mucin, gangliosides and heparin. In addition, cancer cells often form microvilli to increase the surface area, thereby increasing the permeability of anticancer drugs to the membrane. While normal host cells have neutral zwitterionic phospholipids and sterols. In fact, it is thought that the presence of cholesterol may protect normal cells from the interaction of cationic peptides.

Despite these findings, little research has been done on the mechanisms underlying the anticancer activity of HDPs. Many HDPs can readily enter mammalian cells. Indeed, entry into cells and interaction with their internal receptors are the main basis for the immunomodulatory activity of HDPs. It is likely that the peptide triggers apoptosis or other programmed or unprogrammed cell death in a receptor-regulated manner.

LL-37 can trigger apoptosis in epithelial cells at physiological concentrations of 25-50 μg/ml, while the opposite is true in neutrophils. In addition, some HDPs can also target mitochondrial membranes. For example, buforin IIb isolated from solder mask white H2A can pass through 62 human tumor cell lines without destroying the membrane structure, and can induce mitochondria-dependent apoptosis; After in vivo in mice, it still inhibits its growth. Whether HDPs can differentiate between normal cells and how cancerous cells can be differentiated to trigger apoptosis is currently unknown. However, researchers can take advantage of the physiological differences between cancer cells and normal cells to design synthetic HDPs that specifically target cancer cells with low cytotoxicity to normal cells.

Multifunctional cationic host Defense Peptides and Their Clinical Application consists of 12 chapters. The selected sections of this article is Chapter 4 --Fighting cancer cells, Host defense guards have potential