PNC-27 Peptide: Potential In Cancer Research

As suggested in animal research studies, PNC-27 is an engineered peptide with potential anti-cancer properties, suggested to eliminate cancer cells inside the organism. Attached to malignant cells, the PNC-27 peptide has been hypothesized to trigger cell necrosis, ultimately leading to the cells’ demise. Animal studies have suggested that this peptide may eliminate cancer cells by causing them to undergo membrane lysis due to the presence of an HDM-2 binding domain.

Scientists are beginning to more deeply examine PNC-27 in research related to various cancers, including leukemia, breast cancer, melanoma, and pancreatic cancer.

PNC-27 Peptide: Mechanism of Action

The cancer peptide PNC-27 has been theorized to promote cell death in cancer cells with little  perceived effect on healthy cells. Researchers suggest this may be through establishing connections with cancer cell membranes and puncturing them to cause rapid cell death, as suggested in experiments.

In 2000, Drs. Joseph Mich and Matthew Pincus of New York’s SUNY Downstate Medical Center were the first to develop PNC proteins. Curiously, the original intent behind the peptides’ synthesis was related to HIV research. However, PNC appeared far more effective in killing cancer cells while purportedly avoiding healthy cells. Several PNC-27 experimental studies have since purported its potential in the context of cancer.

Experimental investigations have purported the impacts and mechanism of action of PNC-27 in killing cancer cells; one such study was conducted by Dr. Ehsan Sarafraz-Yazdi. The authors of this research suggest that the creation of oligomeric holes in the plasma membrane of cancer cells may be the mechanism of action for PNC-27. The researchers speculated that these results may indicate the specific placement of MDM2 mutations in malignant cells.

PNC-27 Peptide and Cancer Cells

In 2006, researchers hypothesized that PNC-28, structurally and functionally related to PNC-27, might specifically suppress the development of pancreatic cancer cells in living organisms. The chemical-inducing necrosis in several tumor cell lines, whereas normal cells were unaffected, prompted the team to test if the cancer peptide might completely halt the progression of the disease.

Following two weeks of peptide exposure and two weeks of follow-up, researchers suggested that the peptide appeared to have blocked tumor development in animal models. Furthermore, the researchers exposed the animal models to the cancer peptide PNC-27 after tumor formation,  with results suggesting that peptide exposure seemingly decreased both tumor size and the rate of tumor growth.

According to a 2014 research, PNC-27 presentation appeared to have caused tumor cell necrosis in a leukemia cell line that depends on plasma membrane HDM2 expression. As a result, scientists were able to build on previous work suggesting that PNC-27 might reduce tumor cells in solid tissues by binding to hdm-2 proteins.

Scientists experimented to see whether non-solid tumor cells could express hdm-2 in their membranes like solid tissue cells. To their surprise, scientists speculated that the peptide might trigger necrosis in these non-solid tumor cells as HDM2 binding does in solid tissue cells and that their cell membranes produced HDM2.

PNC-27 Peptide Research

Researchers hypothesized that the peptide’s p53 residues might superimpose on the structure for the identical hdm2 residues in a 2009 experimental study of PNC-27. Therefore, PNC-27 was determined to cross the membranes of hdm-2 cancer cells. Due to the large quantities of HDM in cancer cells’ membranes, PNC-27 has been theorized to target cancer cells while selectively avoiding injury to organs.

In a subsequent study, researchers reported that hdm2 might render normally insensitive untransformed cells responsive to PNC-27. The researchers now have the necessary data to speculate that the PNC-27 peptide might specifically target HDM-2 in cancer cell membranes and destroy them by membrane lysis.

At the same time, separate 2010 research reported that PNC-27 appeared to have killed cancer cells in their entirety, not in pieces. Researchers were curious whether the cancer cell membrane holes were caused by partial or complete peptide cleavage. This investigation determined it to be the latter. The experiment purported that the whole peptide may have impacted malignant cell membranes but did not seem to affect the surrounding cells.

PNC-27 Peptide Overview

Animal studies have suggested that PNC-27 peptide may have various practical impacts, including reduced pain levels within a week of exposure. As a result of their immune systems responding to the elimination of cancer cells, results in animal research models indicated the development of flu-like symptoms within three weeks. Increases in bilirubin and lactate dehydrogenase were speculated at the six-week point.

Research indicates that the tumors don’t seem to start to soften and undergo substantial disintegration until week 10. In some instances, the tumor’s location may grow. However, researchers consider that this may be due to the fact that the immune system’s reaction is inflammatory. Researchers suggested that animals appeared to have fewer cancer-related symptoms after three months and more vitality.

Please note that none of the substances mentioned in this article have been approved for human or animal consumption and should, therefore, not be acquired nor utilized by unlicensed individuals outside of contained research environments such as laboratories.

References

[i] Sarafraz-Yazdi, Ehsan, Ghadir Salame, Constantine Gorelick, Allison Wagreich, Mallorie Angert, Ovadia Abulafia, Matthew R. Pincus, and Josef Michl. “Abstract C44: Ex Vivo Cytotoxicity of PNC-27 on Primary Humice Ovarian and Endometrial Cancers.” Killing the Tumor Cell (September 15, 2011). doi:10.1158/1538-7445.fbcr11-c44.

[ii] Davitt K, Babcock BD, Fenelus M, Poon CK, Sarkar A, Trivigno V, Zolkind PA, Matthew SM, Grin’kina N, Orynbayeva Z, Shaikh MF, Adler V, Michl J, Sarafraz-Yazdi E, Pincus MR, Bowne WB. The anti-cancer peptide, PNC-27, induces tumor cell necrosis of a poorly differentiated non-solid tissue mice leukemia cell line that depends on expression of HDM-2 in the plasma membrane of these cells. Ann Clin Lab Sci. 2014 Summer;44(3):241-8. PMID: 25117093. doi:10.1007/s00280-009-1166-7

[iii] Sarafraz-Yazdi E, Mumin S, Cheung D, Fridman D, Lin B, Wong L, Rosal R, Rudolph R, Frenkel M, Thadi A, Morano WF, Bowne WB, Pincus MR, Michl J. PNC-27, a Chimeric p53-Penetratin Peptide Binds to HDM-2 in a p53 Peptide-like Structure, Induces Selective Membrane-Pore Formation and Leads to Cancer Cell Lysis. Biomedicines. 2022 Apr 20;10(5):945. doi: 10.3390/biomedicines10050945. PMID: 35625682; PMCID: PMC9138867.

[iv] Qian Y, Lv S, Dong X. Detection and Significance of PNC in Breast Cancer Tissues. Clin Lab. 2021 Jul 1;67(7). doi: 10.7754/Clin.Lab.2020.201134. PMID: 34258978.

[v] Gonzalez E, Ahmed AA, McCarthy L, Chastain K, Habeebu S, Zapata-Tarres M, Cardenas-Cardos R, Velasco-Hidalgo L, Corcuera-Delgado C, Rodriguez-Jurado R, García-Rodríguez L, Parrales A, Iwakuma T, Farooqi MS, Lee B, Weir SJ, Flatt TG. Perinucleolar Compartment (PNC) Prevalence as an Independent Prognostic Factor in Pediatric Ewing Sarcoma: A Multi-Institutional Study. Cancers (Basel). 2023 Apr 10;15(8):2230. doi: 10.3390/cancers15082230. PMID: 37190159; PMCID: PMC10136508.

[vi] Michl J, Scharf B, Schmidt A, Huynh C, Hannan R, von Gizycki H, Friedman FK, Brandt-Rauf P, Fine RL, Pincus MR. PNC-28, a p53-derived peptide that is cytotoxic to cancer cells, blocks pancreatic cancer cell growth in vivo. Int J Cancer. 2006 Oct 1;119(7):1577-85. doi: 10.1002/ijc.22029. PMID: 16688716.

[vii] Thadi A, Lewis L, Goldstein E, Aggarwal A, Khalili M, Steele L, Polyak B, Seydafkan S, Bluth MH, Ward KA, Styler M, Campbell PM, Pincus MR, Bowne WB. Targeting Membrane HDM-2 by PNC-27 Induces Necrosis in Leukemia Cells But Not in Normal Hematopoietic Cells. Anticancer Res. 2020 Sep;40(9):4857-4867. doi: 10.21873/anticanres.14488. PMID: 32878773.

[viii] Alagkiozidis I, Gorelick C, Shah T, Chen YA, Gupta V, Stefanov D, Amarnani A, Lee YC, Abulafia O, Sarafraz-Yazdi E, Michl J. Synergy between Paclitaxel and Anti-Cancer Peptide PNC-27 in the Treatment of Ovarian Cancer. Ann Clin Lab Sci. 2017 May;47(3):271-281. PMID: 28667027.