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Peptide Fibrillar Assemblies Exhibit Membranolytic Effects and Antimetastatic Activity on Lung Cancer Cells
Yu-Fon Chen1, Chien-Hsiang Chang1, Ming-Wei Hsu1
1Department of Chemical Engineering, National Cheng Kung University, No. 1 University Road, Tainan 70101 Taiwan.
Abstract:
Cancer 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.
Insights
Drug-free peptide assemblies target cancer cell mitochondria, inducing apoptosis and suppressing metastasis. This novel approach shows significant antimetastatic activity in vitro and in vivo, offering a promising new cancer therapy.
Area of Science:
- Oncology
- Biomaterials
- Nanotechnology
Background:
- Cancer metastasis is a major cause of cancer-related mortality.
- Mitochondrial dysfunction plays a critical role in cancer progression and metastasis.
- Targeting mitochondria presents a promising therapeutic strategy for cancer treatment.
Purpose of the Study:
- To investigate the antimetastatic potential of drug-free, cationic peptide fibrillar assemblies (PFAs).
- To evaluate the efficacy of PFAs in targeting cancer cell mitochondria and inducing apoptosis.
- To assess the therapeutic effect of PFAs on lung metastasis and tumor growth in a preclinical model.
Main Methods:
- Fabrication of poly(L-Lysine)-block-poly(L-Threonine) (Lys-b-Thr) based PFAs.
- In vitro studies using lung cancer cells to assess membranolysis, mitochondrial damage, and apoptosis induction.
- In vivo studies using a metastatic xenograft mouse model to evaluate antimetastatic efficacy and safety.
Main Results:
- PFAs induced membranolysis of cancer cell and mitochondrial membranes via electrostatic interactions.
- Mitochondrial release of apoptosis-inducing factors (cytochrome c, endonuclease G, apoptosis-inducing factor) was observed, triggering both caspase-dependent and independent pathways.
- PFAs significantly suppressed lung metastasis and tumor growth in mice with no significant body weight loss or mortality, and inhibited cancer cell migration and clonogenesis in vitro.
Conclusions:
- Cationic PFAs effectively target and damage cancer cell mitochondria, leading to apoptosis.
- PFAs demonstrate significant antimetastatic activity and tumor growth inhibition.
- These findings suggest PFAs are a promising drug-free therapeutic strategy for combating cancer metastasis.
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