Challenging metastatic breast cancer with the natural defensinPvD₁

Abstract

Metastatic breast cancer is a very serious life threatening condition that poses many challenges for the pharmaceutical development of effective chemotherapeutics. As the therapeutics targeted to the localized masses in breast improve, metastatic lesions in the brain slowly increase in their incidence compromising successful treatment outcomes overall. The blood-brain-barrier (BBB) is one important obstacle for the management of breast cancer brain metastases. New therapeutic approaches are in demand for overcoming the BBB's breaching by breast tumor cells. In this work we demonstrate the potential dual role of a natural antimicrobial plant defensin, PvD: it interferes with the formation of solid tumors in the breast and concomitantly controls adhesion of breast cancer cells to human brain endothelial cells. We have used a combination of techniques that probe PvD's effect at the single cell level and reveal that this peptide can effectively damage breast tumor cells, leaving healthy breast and brain cells unaffected. Results suggest that PvD1 quickly internalizes in cancer cells but remains located in the membrane of normal cells with no significant damage to its structure and biomechanical properties. These interactions in turn modulate cell adhesiveness between tumor and BBB cells. PvD is a potential template for the design of innovative pharmacological approaches for metastatic breast cancer treatment: the manipulation of the biomechanical properties of tumor cells that ultimately prevent their attachment to the BBB.

Improved smallest peptides based on positive charge increase of the &gamma;-core motif from <em>P&nu;</em>D₁ and their mechanism of action against <em>Candida</em> species

“…PvD 1 is an isolated defensin from Phaseolus vulgaris seeds with antifungal properties, 14,15,18 anti-Leishmania activity, 24 and anticancer activity. 25 Additionally, knowing that the charge, length, and hydrophobicity influence the activity of antimicrobial peptides, 26 we made rational substitutions of negatively charged amino acid residues with positively charged ones, as well as the reduction in length in the selected PvD 1 defensin γ-core sequence to verify whether the increased net positive charge and the shortened length are related to the increase in antifungal activity. In addition, some tests were carried out to better understand the mechanism of action of the peptides derived from the γ-core region of PvD 1 defensin.…”

Plant defensin PvD1 modulates the membrane composition of breast tumour-derived exosomes

“…Recently, our group has unraveled the multifaceted anticancer action of the plant defensin PvD 1 . 27 The peptide attacks breast tumour cells at the primary site but also modulates the cells' membrane properties and abrogates the adhesion of breast tumour cells to endothelial cells from the human blood-brain barrier (BBB). Therefore, this natural peptide is a promising template for undergoing further pharmacological development.…”

“…As previously reported, PvD 1 shows high toxicity toward the invasive MDA-MB-231 breast cancer cell line with no significant impact on the viability of the non-malignant MCF 10A cell line. 27 In the present study we have used an estrogen positive, luminal A molecular subtype human breast cancer cell line, MCF-7. 48,49 MCF-7 is a non-invasive cancer cell line and is a well described and consecrated model system of breast cancer.…”

Human β-Defensin 2 (HBD-2) Displays Oncolytic Activity but Does Not Affect Tumour Cell Migration

“…In addition, defensins can also prevent tumour cell migration via the disruption of cytoskeleton dynamics. For example, PvD1 defensin (from common bean Phaseolus vulgaris ) effectively disturbs the cytoskeleton of breast cancer cells, thus perturbing cell-to-cell adhesion and tumour cell migration [ 13 ]. Human β-defensins HBD-1 and HBD-3 also exhibit modulatory activity against actin regulators such as Rho family proteins, vascular endothelial growth factor (VEGF) and metastasis-associated 1 family member 2 (MTA2), resulting in anti-migratory effects against oral squamous cell carcinoma [ 14 , 15 ], head and neck [ 16 ] and colon cancer cells [ 17 ].…”