Abstract
Membrane lytic peptides are a novel class of anticancer agents that have the potential to overcome drug resistance. The limited selectivity against cancer cells, however, presents a major hurdle for the application. We aim to exploit the proteolytic activity of tumor-associated matrix metalloproteinases (MMP) to mediate the cytotoxicity of these peptides. We designed a membrane lytic peptide cyclized with a linker cleavable by membrane type 1-MMP (MT1-MMP). We showed that the cyclic peptide could be restored to the linear state on MT1-MMP digestion, and it preferentially killed MMP-overexpressing cells above a threshold concentration. Circular dichroism indicated that cyclization resulted in a more rigid structure, making it more difficult for the lytic peptide to transit from random coil to alpha-helix in a membrane-mimicking environment. Selective membrane activity of the cyclic peptide was shown by comparing cytotoxicity results on RBC and two human breast cancer cell lines of different malignancy and MT1-MMP expression: highly invasive MDA-MB-435 and noninvasive MCF-7. Above a concentration of 5 micromol/L, suppressed activity to MCF-7 and RBC was observed, whereas the toxicity against MDA-MB-435 was maintained. MMP inhibition experiments further showed that the membrane-lysing activity was enzyme dependent.
Highlights
Membrane lytic peptides serve as an innate immune mechanism against pathogens in many species in nature [1, 2]
We aim to show that the newly designed peptide exhibits selectivity against tumor cells with overexpressed MT1-matrix metalloproteinases (MMP)
Concanavalin A (Con A) and recombinant human membrane type 1-MMP (MT1-MMP) catalytic domain were purchased from Calbiochem
Summary
Membrane lytic peptides serve as an innate immune mechanism against pathogens in many species in nature [1, 2]. These peptides have a simple structure yet rapid and potent activity against a broad spectrum of microbes. Due to the growing drug resistance against conventional antibiotics, these peptides have become candidates of a new class of antibiotics [3, 4]. Peptides insert into and disturb the cell membrane and cause cell death due to membrane disintegration. This process can be completed in minutes at a micromolar level. As the potency does not rely on cellular internalization, lytic peptides circumvent the problems of multidrug resistance, which causes inefficient drug uptake and presents a predominant hindrance to conventional chemotherapy [13]
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