The Application of Cationic Antimicrobial Peptides in Cancer Treatment: Laboratory Investigations and Clinical Potential

Hilchie, Ashley L.

doi:10.1002/9780470626528.ch14

Cited by 10 publications

(10 citation statements)

References 87 publications

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“…ACPs kill cells by a direct (i.e., lytic) or indirect (i.e., apoptosis-inducing) mechanisms[7]. Mastoparan triggered lactate dehydrogenase release from leukemia cells in a time-dependent manner (Figure 2), suggesting that Mastoparan functions as a direct-acting ACP.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast to normal cell membranes, which are largely charge neutral, cancer cell membranes carry a net negative charge due to an abundance of anionic phospholipids (e.g., phosphatidylserine)[3], proteoglycans (e.g., heparan sulfate proteoglycans)[4], O-glycosylated mucins[5], and sialoglycoproteins[6]. Following membrane binding, ACPs kill the cancer cell by causing irreparable membrane damage followed by cell lysis (i.e., direct-acting ACPs), or by initiating a cell death pathway that results in death by apoptosis (i.e., indirect-acting ACPs)[7]. Unlike conventional chemotherapeutic agents, ACPs do not only target rapidly dividing cells; therefore, certain ACPs are also toxic to slow growing cancers[8].…”

Section: Introductionmentioning

confidence: 99%

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Mastoparan is a membranolytic anti-cancer peptide that works synergistically with gemcitabine in a mouse model of mammary carcinoma

Hilchie

Sharon

Haney

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Anti-cancer peptides (ACPs) are small cationic and hydrophobic peptides that are more toxic to cancer cells than normal cells. ACPs kill cancer cells by causing irreparable membrane damage and cell lysis, or by inducing apoptosis. Direct-acting ACPs do not bind to a unique receptor, but are rather attracted to several different molecules on the surface of cancer cells. Here we report that an amidated wasp venom peptide, Mastoparan, exhibited potent anti-cancer activities toward leukemia (IC50 ~8-9.2 μM), myeloma (IC50 ~11 μM), and breast cancer cells (IC50 ~20–24 μM), including multidrug resistant and slow growing cancer cells. Importantly, the potency and mechanism of cancer cell killing was related to the amidation of the C-terminal carboxyl group. Mastoparan was less toxic to normal cells than it was to cancer cells (e.g., IC50 to PBMC = 48 μM). Mastoparan killed cancer cells by a lytic mechanism. Moreover, Mastoparan enhanced etoposide-induced cell death in vitro. Our data also suggests that Mastoparan and gemcitabine work synergistically in a mouse model of mammary carcinoma. Collectively, these data demonstrate that Mastoparan is a broad-spectrum, direct-acting ACP that warrants additional study as a new therapeutic agent for the treatment of various cancers.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mastoparan is a membranolytic anti-cancer peptide that works synergistically with gemcitabine in a mouse model of mammary carcinoma

Hilchie

Sharon

Haney

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…A necrosis triggered by severe membrane damage is often regarded as direct way of AMPs attack [62]. Carpet, barrel-stave or torodial pore models are often observed in this straight forward way of killing.…”

Section: Necrosis Apoptosis and Death Pathways Of Cells Triggered Bymentioning

confidence: 99%

“…To date, no AMP has been found to be capable of acting to all cancer cell lines [3,4]. The toxic effects on healthy cells, instability in serum, degradation by proteases and cost for AMPs production are the drawbacks of therapeutic application of many anticancer AMPs [3,4,21,62]. Phase I clinical trials regarding to some membrane lytic AMP also suggest that the short half-life of peptide is the main obstacle that hinders the efficiency of peptide-based therapies [62].…”

Section: Open Questions On Anticancer Activity Of Ampsmentioning

confidence: 99%

Mechanism of Anticancer Effects of Antimicrobial Peptides

et al. 2015

JFBI

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Antimicrobial Peptides (AMPs) were first known as a group of innate immune products that mainly targets on the invading pathogens among multiple species. The essential mechanisms of action of AMPs toward microbial cells have been reported as electrostatic attraction and hydrophobic interaction between AMPs (cationic AMPs) and microbial cell membranes. These effects also contribute to the potential mechanism of anticancer activities of AMPs as well. The membrane difference between cancer cells and normal cells are believed to play significant roles in AMPs orienting process. Membrane selective targeting properties make AMPs promising candidates for alternative approach to solve the problems from anticancer drug resistance.

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“…Unlike the cell membranes of normal healthy cells, cancer cell membranes carry a net negative charge due to an abundance of anionic phospholipids and proteoglycans [ 3 ], which are thought to lead to the selective attraction of anticancer peptides to cancer cell membranes. Following membrane binding, 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 ].…”

Section: Introductionmentioning

confidence: 99%

MDA-MB-231 Breast Cancer Cells Resistant to Pleurocidin-Family Lytic Peptides Are Chemosensitive and Exhibit Reduced Tumor-Forming Capacity

et al. 2020

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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.

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The Application of Cationic Antimicrobial Peptides in Cancer Treatment: Laboratory Investigations and Clinical Potential

Cited by 10 publications

References 87 publications

Mastoparan is a membranolytic anti-cancer peptide that works synergistically with gemcitabine in a mouse model of mammary carcinoma

Mastoparan is a membranolytic anti-cancer peptide that works synergistically with gemcitabine in a mouse model of mammary carcinoma

Mechanism of Anticancer Effects of Antimicrobial Peptides

MDA-MB-231 Breast Cancer Cells Resistant to Pleurocidin-Family Lytic Peptides Are Chemosensitive and Exhibit Reduced Tumor-Forming Capacity

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