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Peptide Fibrillar Assemblies Exhibit Membranolytic Effects and Antimetastatic Activity on Lung Cancer Cells
journal contribution
posted on 2020-08-28, 12:33 authored by Yu-Fon Chen, Chien-Hsiang Chang, Ming-Wei Hsu, Ho-Min Chang, Yi-Cheng Chen, Yi-Sheng Jiang, Jeng-Shiung JanCancer metastasis
is a central oncology concern that worsens patient
conditions and increases mortality in a short period of time. During
metastatic events, mitochondria undergo specific physiological alterations
that have emerged as notable therapeutic targets to counter cancer
progression. In this study, we use drug-free, cationic peptide fibrillar
assemblies (PFAs) formed by poly(L-Lysine)-block-poly(L-Threonine)
(Lys-b-Thr) to target mitochondria. These PFAs interact
with cellular and mitochondrial membranes via electrostatic interactions,
resulting in membranolysis. Charge repulsion and hydrogen-bonding
interactions exerted by Lys and Thr segments dictate the packing of
the peptides and enable the PFAs to display enhanced membranolytic
activity toward cancer cells. Cytochrome c (cyt c), endonuclease G, and apoptosis-inducing factor were released
from mitochondria after treatment of lung cancer cells, subsequently
inducing caspase-dependent and caspase-independent apoptotic pathways.
A metastatic xenograft mouse model was used to show how the PFAs significantly
suppressed lung metastasis and inhibited tumor growth, while avoiding
significant body weight loss and mortality. Antimetastatic activities
of PFAs are also demonstrated by in vitro inhibition of lung cancer
cell migration and clonogenesis. Our results imply that the cationic
PFAs achieved the intended and targeted mitochondrial damage, providing
an efficient antimetastatic therapy.
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Antimetastatic activitiesmitochondrial damagemembranolytic activitycationic PFAslung cancer cell migrationcancer cellscaspase-independent apoptotic pathwaysoncology concerncationic peptide fibrillar assemblieslung metastasisPeptide Fibrillar Assemblies Exhibi...tumor growthcharge repulsionincreases mortalityapoptosis-inducing factorCytochrome clung cancer cellsantimetastatic therapybody weight lossmitochondrial membraneshydrogen-bonding interactionsmetastatic xenograft mouse modelcounter cancer progressiontarget mitochondriaAntimetastatic Activitymetastatic eventspatient conditionsThr segmentsLung Cancer Cells Cancer metastasis
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