Abstract
Direct-acting anticancer (DAA) peptides are cytolytic peptides that show promise as novel anticancer agents. DAA peptides bind to anionic molecules that are abundant on cancer cells relative to normal healthy cells, which results in preferential killing of cancer cells. Due to the mechanism by which DAA peptides kill cancer cells, it was thought that resistance would be difficult to achieve. Here, we describe the generation and characterization of two MDA-MB-231 breast cancer cell-line variants with reduced susceptibility to pleurocidin-family and mastoparan DAA peptides. Peptide resistance correlated with deficiencies in peptide binding to cell-surface structures, suggesting that resistance was due to altered composition of the cell membrane. Peptide-resistant MDA-MB-231 cells were phenotypically distinct yet remained susceptible to chemotherapy. Surprisingly, neither of the peptide-resistant breast cancer cell lines was able to establish tumors in immune-deficient mice. Histological analysis and RNA sequencing suggested that tumorigenicity was impacted by alternations in angiogenesis and extracellular matrix composition in the peptide-resistant MDA-MB-231 variants. Collectively, these data further support the therapeutic potential of DAA peptides as adjunctive treatments for cancer.
Highlights
Cancer cell resistance to chemotherapeutic drugs, including targeted therapies, remains an obstacle to the eradication of disseminated tumors
We report that prolonged exposure of MDA-MB-231 breast cancer cells to increasing concentrations of two different Direct-acting anticancer (DAA) peptides, the pleurocidins NRC-03 and NRC-07, resulted in the generation of MDA-MB-231 variants that were refractory to the pleurocidins NRC-03 and NRC-07, as well as mastoparan
To generate NRC-03-resistant and NRC-07-resistant breast cancer cells, MDA-MB-231 cells were continuously cultured in the presence of increasing concentrations of the peptides NRC-03 or NRC-07
Summary
Cancer cell resistance to chemotherapeutic drugs, including targeted therapies, remains an obstacle to the eradication of disseminated tumors. There remains an unmet need for alternative therapeutic agents for the treatment of cancer. Such an agent would target cancer cells by a mechanism that differs from that of chemotherapeutic drugs currently on the market. Direct-acting anticancer (DAA) peptides represent an as-yet untapped reservoir of such novel anticancer agents. DAA peptides kill cells by causing irreparable membrane damage and cell lysis whereas indirect-acting anticancer peptides enter the cytoplasm and cause cell death via the induction of apoptosis [4]
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