 may be caused by the peptide-inducing transmembrane pore development in cancer cells.){kind=link}
Studies suggest membrane-active peptide PNC-27 may interact with the HDM-2 protein in solid tissue tumor cell membranes. Research suggests that tumor cell necrosis (cell death) may be caused by the peptide-inducing transmembrane pore development in cancer cells but not in normal ones.
Several cancer lines, including pancreatic, breast, leukemia, and melanoma cancers, have suggested remarkable responses to PNC-27’s possible selective targeting capabilities.
PNC-27 Peptide: What is it?
Researchers have examined immuno-supporting substances in the context of cancer for decades. According to recent studies, immunotherapy is far less dangerous than radiation and chemotherapy.
This is because immunotherapy triggers the immune system to attack the disease rather than introducing toxic substances into the bloodstream. Pain perception may accompany PNC-27 and PNC-28, two types of peptides that do not seem to pose the risk of chemical toxicity.
These peptides were generated in 2000 by a supercomputer at New York’s SUNY Center. The MDM2-P53 tumor suppressor complex is a partner of PNC-27 and PNC-28. As suggested by Sarafraz-Yazdi E, Bowne WB, et al. (2010), it may help eliminate cancer cells by increasing the half-life of P53 in the cell and acting as a competitive inhibitor for binding.
Additionally, these substances have been theorized to lyse cells by binding to their membranes. Findings imply that both PNC-27 and PNC-28 may have had positive clinical studies. Data from studies suggests that this approach may effectively prevent recurrence in the context of cancer.
PNC-27 Peptide: Mechanism of Action
The cell membranes of cancer cells contain HDM-2. Investigations purport that an early target of PNC-27 presentation may be the HDM-2 found in cancer cell membranes. The cell membrane is speculated to be killed when it binds to these proteins, which may cause holes in the membrane. As a result, the cancer cell is destroyed. Since the intact peptide has been suggested to stimulate tumor cell lysis, PNC-27 has been hypothesized to be an anti-cancer peptide.
Studies suggest the peptide called PNC-27 is designed to possibly target cancer cells and kill them while not affecting normal cells. It seems to attach an HDM-2-binding domain from p53 to a membrane-penetrating peptide at its carboxyl-terminal end. The cancer cell membrane might develop transmembrane holes as a result. This study aims to identify if cancer cells can produce pores in response to the whole peptide or to specific portions of it.
PNC-27 Peptide Research
To test whether combined yellow fluorescence happens in the cancer cells’ membranes during cancer cell killing, researchers presented MCF-7 breast cancer cells and untransformed MCF-10-2A breast epithelial cells with PNC-27, a peptide that they had prepared with a green fluorescent label on its amino terminus and a red fluorescent label on its carboxyl terminus.
The findings implied that as cancer cells lysed, there seemed to be an increase in the combined punctate yellow fluorescence in their cell membranes at 30 minutes. This indicates that the peptide may remain intact. The homogeneous mixed yellow membrane fluorescence that MCF-10-2A cells displayed appeared to initially diminish after 30 minutes. Unlike the cancer cells, they (the untransformed cells) seemed still alive and well.
The whole peptide, rather than its fragments, PNC-27, has been theorized to promote membrane lysis in cancer cells. Research suggests the interaction between PNC-27 and intramembrane targets of MCF-7 cells may cause the punctate yellow fluorescence. These targets are not present in the membrane of the untransformed cell line. Because of this interaction, PNC-27 may have a longer half-life. The membranes of the untransformed MCF-10-2A cells lack these targets, which was hinted to cause the double-labeled peptide to undergo degradation after first fluorescing uniformly.
PNC-27 Peptide and HDM-2
Researchers have hinted that the peptide PNC-27 may induce membrane lysis to kill cancer cells (but not normal cells). This is believed to be owing to its HDM-2-binding domain, which corresponds to residues 12-26 of p53, and its transmembrane-penetrating domain. Researchers indicated that the 3D structure of the p53 residues of PNC-27, which they had previously identified, may be directly superimposed on the structure of the same residues linked to HDM-2. This indicates that the peptide could target HDM-2 in the cancer cell membranes.
These days, specialists know that HDM-2 is present in many cancer cell membranes but is absent from the membranes of several untransformed cell lines. The results imply that PNC-27 may bind to HDM-2 and is attached to cell membranes in colocalization tests. Moreover, they speculate that untransformed MCF-10-2A cells that were not susceptible to PNC-27 may have become responsive when they transfected a plasmid encoding full-length HDM-2 with a signal for membrane localization into these cells. So, it seems that PNC-27 may preferentially trigger cancer cell membrane lysis by targeting HDM-2 in their membranes.
PNC-27 Peptide and Ovarian Cancer
Researchers aim to introduce PNC-27, a new peptide that may selectively target cancer cells by creating trans-membrane holes while avoiding normal cells. They aimed to determine how PNC-27 might affect the ovarian cancer cell line SKOV3-luc-D3 in a lab setting. They then aimed to find the MTD of daily bolus intraperitoneal (IP) presentations in control mice using nu/nu animal models, and they used SKOV3-luc-D3 cells in vitro to find out how toxic PNC-27 may be around the MTD.
They grew, passaged, and maintained SKOV3-luc-D3 cells in the lab. MTT and LDH experiments were performed to compare PNC-27’s cytotoxicity to that of a control peptide. Healthy female nu/nu mice were given daily bolus presentations (ITDs) of PNC-27 for the MTD. Toxicities were evaluated using the sluggishness scale (SS) and bodily condition score (BCS). The MTD of PNC-27 was determined using a 3 + 3 up-and-down design. The last step was to implant female nu/nu mice with SKOV3-luc-D3 cells intraperitoneally. The tumor burden was evaluated using BCS and weight change. After a sufficient tumor burden had been determined, the mice were given PNC-27 at either the MTD (n = 5) or one level below the MTD (n = 5). Histopathologic, BCS and SS sections were used to investigate PNC-27 toxicity.
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References
[i] Sookraj KA, Bowne WB, Adler V, Sarafraz-Yazdi E, Michl J, Pincus MR. The anti-cancer peptide, PNC-27, induces tumor cell lysis as the intact peptide. Cancer Chemother Pharmacol. 2010 Jul;66(2):325-31. doi: 10.1007/s00280-009-1166-7. Epub 2010 Feb 25. PMID: 20182728.
[ii] Sarafraz-Yazdi E, Bowne WB, Adler V, Sookraj KA, Wu V, Shteyler V, Patel H, Oxbury W, Brandt-Rauf P, Zenilman ME, Michl J, Pincus MR. Anticancer peptide PNC-27 adopts an HDM-2-binding conformation and kills cancer cells by binding to HDM-2 in their membranes. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):1918-23. doi: 10.1073/pnas.0909364107. Epub 2010 Jan 11. PMID: 20080680; PMCID: PMC2836618.
[iii] Stevens, E. & Gartman, C. & Sarafraz-Yazdi, E. & Michl, Josef. (2013). Evaluation of PNC-27-mediated toxicity in an intraperitoneal mouse model of human ovarian cancer. Gynecologic Oncology. 131. 266. 10.1016/j.ygyno.2013.07.052.
[iv] Sarafraz-Yazdi E, Gorelick C, Wagreich AR, Salame G, Angert M, Gartman CH, Gupta V, Bowne WB, Lee YC, Abulafia O, Pincus MR, Michl J. Ex vivo Efficacy of Anti-Cancer Drug PNC-27 in the Treatment of Patient-Derived Epithelial Ovarian Cancer. Ann Clin Lab Sci. 2015 Fall;45(6):650-8. PMID: 26663795.
[v] Silberstein, M. (2020). Is PNC-27 and PNC-28 the Best way to cure Cancer?. The Science Journal of the Lander College of Arts and Sciences, 13(2). Retrieved from https://touroscholar.touro.edu/sjlcas/vol13/iss2/7