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Topical application of temperature-sensitive caerin 1.1 and 1.9 gel inhibits TC-1 tumor growth in mice.

ABSTRACT: Genital warts, which are one of the most common sexually transmitted diseases (STDs), result from persistent infection with human papillomavirus (HPV), especially subtypes 6 or 11. Topical application of 5% imiquimod cream is currently recommended as a first-line treatment choice for genital warts, but the clearance and patient compliance rates remain less than sufficient. In the current study, we developed a temperature-sensitive gel that contains the host-defense peptides caerin 1.1 and 1.9, which were originally isolated from Australian tree frogs of the genus Litoria. Growth of HPV16 E6/E7-transformed TC-1 cells was inhibited in vitro and in vivo following injection of the tumor with the caerin gel in a TC-1 tumor mouse model. Furthermore, when the caerin gel was topically applied, the inhibitory effect remained, and T, NK cells were attracted to the tumor site. In addition, the gel maintained a similar level of bioactivity after incubation at room temperature for 30 days. Our results suggest that this caerin gel, following further optimization, may provide an alternative method for the management of genital warts.

SUBMITTER: Ma B

PROVIDER: S-EPMC7013226 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Topical application of temperature-sensitive caerin 1.1 and 1.9 gel inhibits TC-1 tumor growth in mice.

Ma Bowei B Yuan Jianwei J Chen Shu S Huang Kunsong K Wang Qianbo Q Ma Jianchun J Lin Ruoting R Zhang Lu L Zhou Yingying Y Wang Tianfang T Walton Shelley F SF Pan Xuan X Chen Guoqiang G Wang Yuejian Y Ni Guoying G Liu Xiaosong X

American journal of translational research 20200115 1

Genital warts, which are one of the most common sexually transmitted diseases (STDs), result from persistent infection with human papillomavirus (HPV), especially subtypes 6 or 11. Topical application of 5% imiquimod cream is currently recommended as a first-line treatment choice for genital warts, but the clearance and patient compliance rates remain less than sufficient. In the current study, we developed a temperature-sensitive gel that contains the host-defense peptides caerin 1.1 and 1.9, w ...[more]

PMID: 32051748

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Project description:Host defense caerin 1.1 and 1.9 peptides, isolated from the glandular secretion of Australian tree frogs, the genus Litoria, have been previously shown to have multiple biological activities, including the inhibition of human papillomavirus (HPV) 16 early protein E7 transformed murine as well as human cancerous cell proliferation both in vitro and in vivo. However, the mechanism underlying their anti-proliferative activities against HPV18+ cervical cancer HeLa cells remains unknown. This study comparatively investigated the anti-proliferation on HeLa cells by caerin 1.1, 1.9, and their mixture, followed by confocal microscopy examination to assess the cellular intake of the peptides. Tandem mass tag labeling proteomics was employed to reveal the proteins that were significantly regulated by the peptide treatment in cells and cell growth environment, to elucidate the signaling pathways that were modulated. Western blot was performed to confirm the modulation of the pathways. Both caerin 1.1 and 1.9 highly inhibited HeLa cell proliferation with a significant additive effect compared to untreated and control peptide. They entered the cells with different magnitudes. Intensive protein-protein interaction was detected among significantly upregulated proteins. Translation, folding and localization of proteins and RNA processing, apoptosis process was significantly enriched post the treatments. The apoptotic signaling was suggested as a result of tumor necrosis factor-? (TNF-?) pathway activation, indicated by the dose-dependent elevated levels of caspase 3 and caspase 9. The epidermal growth factor receptor and androgen receptor pathways appeared inhibited by the peptides. Moreover, the activation of T-cell receptor derived from the quantitation results further implies the likelihood of recruiting more T cells to the cell growth environment post the treatment and more sensitive to T cell mediated killing of HeLa cells. Our results indicate that caerin 1.1 and 1.9 mediate apoptotic signals of HeLa cells and may subsequently enhances adaptive T cell immune responses.

Project description:Caerin 1 is a family of host defense peptides with antimicrobial properties originally isolated from the Australian tree frog. Both caerin 1.1 and caerin 1.9 have been demonstrated to inhibit infections caused by multiple antibiotic-resistant bacteria, both in vitro and in vivo. In this current study, we conducted a comparison of the minimum inhibitory concentrations of caerin 1.1 and caerin 1.9 (referred to as caerin 1.1/1.9) with commonly used antibiotics against various bacteria, including Staphylococcus aureus, Copper-Green Pseudomonas aeruginosa, Acinetobacter baumannii, and Streptococcus haemolyticus. Our findings reveal that caerin 1.1/1.9 not only prevent the formation of biofilms by A. baumannii but also exhibit a therapeutic effect on established biofilms. Furthermore, our study demonstrates that caerin 1.1/1.9 significantly inhibit the growth of methicillin-resistant Staphylococcus aureus (MRSA) strains in a murine skin infection model. A quantitative proteomic analysis conducted as part of our study indicates that caerin 1.1/1.9 primarily activate oxidative phosphorylation pathways, along with several pathways associated with tissue repair and growth. These findings were observed in comparison to untreated tissues that were infected with MRSA in mice. In summary, our research outcomes suggest that caerin 1.1/1.9 exhibit the potential to serve as promising drug candidates for treating complicated antibiotic-resistant bacterial infections in humans. IMPORTANCE Caerin 1.1 and caerin 1.9, natural antimicrobial peptides derived from tree frogs, have demonstrated the ability to inhibit the growth of antibiotic-resistant bacteria, comparable to certain widely used antibiotics. Additionally, these peptides exhibit the capacity to prevent or treat biofilms formed by bacteria in conjunction with bodily components. The mechanisms underlying their antibacterial effects were investigated through a mouse model of bacterial skin infection, utilizing proteomic analysis as a technological approach.

Dataset Information

Topical application of temperature-sensitive caerin 1.1 and 1.9 gel inhibits TC-1 tumor growth in mice.

Publications

Topical application of temperature-sensitive caerin 1.1 and 1.9 gel inhibits TC-1 tumor growth in mice.

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