Branched α-helical peptides enhanced antitumor efficacy and selectivity

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Chemotherapy drug resistance is a major obstacle in cancer treatment.
• Cationic antimicrobial peptides (CAPs) are being explored as alternative anticancer agents.
• Repurposing CAPs offers a strategy to overcome existing resistance mechanisms.

Purpose of the Study:

• To investigate the potential of synthetic α-helical cationic antimicrobial peptides (CAPs) as anticancer agents.
• To evaluate the efficacy of de novo designed branched CAPs against drug-resistant cancer cells.
• To compare the anticancer activity and selectivity of linear versus branched CAP structures.

Main Methods:

• Systematic screening of de novo designed synthetic α-helical CAPs in various cancer cell lines.
• Comparative analysis of 2-arm and 4-arm branched CAPs against their linear counterparts.
• Apoptotic pathway analysis to elucidate the mechanism of cancer cell death.
• In vivo efficacy and toxicity studies in mice bearing breast tumors.

Main Results:

• The 4-arm branched peptide {[(LLKK)2]2κC}2 demonstrated superior selectivity and efficacy compared to linear and 2-arm branched peptides.
• This 4-arm branched peptide effectively countered drug resistance and eradicated multiple drug-resistant cancer cells.
• Mechanism studies confirmed cancer cell death induction via the apoptotic pathway.
• In vivo studies showed significant tumor growth inhibition and favorable retention at tumor sites with minimal organ toxicity.

Conclusions:

• Synthetic α-helical branched CAPs, particularly the 4-arm variant, represent a promising therapeutic strategy against drug-resistant cancers.
• These peptides induce cancer cell death through apoptosis and exhibit favorable pharmacokinetic properties in vivo.
• The 4-arm branched peptide shows potential for development into a novel anticancer therapy with reduced side effects.