Antitumor activity of a membrane lytic peptide cyclized with a linker sensitive to membrane type 1-matrix metalloproteinase.
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.
Zhong
Jieying
J
Department of Chemical and Biomolecular Engineering, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.
Chau
Ying
Y
D000595:Amino Acid Sequence; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism*; D048430:Cell Shape / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D011817:Rabbits; D012967:Sodium Dodecyl Sulfate; D014867:Water
D010456:Peptides, Cyclic; D014867:Water; D012967:Sodium Dodecyl Sulfate; D053511:Matrix Metalloproteinase 14