Amyloid-like aggregates of short self-assembly peptide selectively induce melanoma cell apoptosis

Area of Science:

• Biomedical Engineering
• Materials Science
• Oncology

Background:

• Melanoma incidence is rising globally, necessitating novel anti-melanoma drugs.
• Existing treatments face challenges with drug resistance and selectivity.
• Amyloid protein aggregates are known to be toxic to cells.

Purpose of the Study:

• To design a tyrosinase-responsive peptide for targeted melanoma therapy.
• To investigate the self-assembly and anti-melanoma activity of the designed peptide.
• To explore a novel drug design strategy utilizing enzyme-triggered aggregate formation.

Main Methods:

• Rational design of a peptide (I4K2Y*) responsive to tyrosinase.
• In vitro self-assembly of the peptide into nanofibers and amyloid-like aggregates.
• In vitro assessment of cytotoxicity and cell cycle effects on melanoma cells.
• In vivo evaluation of the peptide's efficacy in a melanoma mouse model.

Main Results:

• The peptide I4K2Y* self-assembled into nanofibers extracellularly.
• Tyrosinase in melanoma cells catalyzed peptide aggregation, leading to nuclear accumulation.
• Aggregates induced melanoma cell apoptosis via cell cycle arrest and mitochondrial dysfunction.
• I4K2Y* significantly inhibited B16 melanoma tumor growth in mice with low toxicity.

Conclusions:

• Tyrosinase-responsive peptide self-assembly into toxic aggregates is a viable anti-melanoma strategy.
• This approach demonstrates high selectivity for melanoma cells.
• Targeting intracellular aggregation offers a promising avenue for developing new anti-cancer drugs.