PNC-27 Research

PNC-27 peptide is a synthetic compound created solely to destroy cancer cells. It is a peptide from the PNC family of investigational proteins designed to target cancerous cells, induce cell necrosis, and leave healthy, normal cells unharmed and intact.

PNC-27 consists of an HDM-2 binding domain similar to p53 residues 12-26 and a transmembrane-penetrating portion. PNC-27 peptide binds to and kills cancerous cells via membrane lysis, or the breakdown of the cell membrane, according to research.

Scientific Studies of the PNC-27 Peptide

Dr. Ehsan Sarafraz-Yazdi and many other researchers revealed how PNC-27 impacts and benefits cancer research in a 2010 research article published by the American Association for Cancer.

According to the study’s authors, the mechanism of action of PNC-27 results from oligomeric pores developing in the plasma membrane of tumor cells. Untransformed or non-tumor cells do not form oligomeric pores. PNC-27 selectivity on cancer cells is caused by MDM2’s mis-localization to cancerous cell plasma membranes.

These hypotheses are believed by scientist to describe the distinct localization of MDM2 variants in cancerous cell plasma membranes. Due to this knowledge, the PNC-27 peptide is believed to be the next anti-cancer drug to enter clinical trials.

How Does the PNC-27 Peptide Work?

PNC-27 was initially developed to treat HIV, but its anti-cancer properties which included killing cancer cells while leaving healthy cells alone emerged thus changing its initial use.

The PNC-27 peptide is not toxic and only harms cancerous cells. PNC-27 binds to individual cancer cell membranes, causing holes to form. Due to the difference in osmotic pressure between the inside and outside of the tumor cells, the holes cause a rapid implosion, resulting in immediate cell death.

HDM-2 is found in the cell membranes of cancer cells. When PNC-27 is administered, the peptide immediately moves to bind to the HDM-2 peptide in the plasma membrane of cancerous cells. PNC-27 causes damage by inducing membrane lysis and, thus, cancer cell death by binding to the HDM-2 peptides.

The Peptide Reviews and Clinical Trials of PNC-27

According to PNC-27 research in animal samples, the peptide reduces pain levels subjectively for about a week after administration. The animal samples develop flu-like symptoms during the third week of administration, indicating that the animal’s immune system reacts to the death of cancerous cells.

Bilirubin and lactate dehydrogenase levels rise during the sixth week of PNC-27 treatment. Around the tenth week, the tumors soften and become more pliable, resulting in significant tumor breakdown.

The tumor’s size may grow more extensive in the tenth week. In any case, it could be due to inflammation due to the immune system’s response. Animals’ energy levels increase, and cancer-related symptoms decrease in the third month.

The results of the PNC-27 clinical trials show that the entire peptide affects the cell membranes of cancerous cells. Furthermore, the noncancerous or non-transformed cells surrounding the cancerous cells were unharmed and healthy. Moreover, research results show that PNC-27 influences specific markers in cancerous cell membranes and that PNC-27 has a longer half-life via this mechanism of action.

The Clinical Benefits of PNC-27 Peptide

How PNC-27 Impacts Cancerous Cells?

According to research, it can inhibit pancreatic cancer cell growth in vivo. In different tumor cell lines, including BMRPA—ras transformed rat acinar pancreatic carcinoma cell line, PNC-27 induces necrosis but not apoptosis. Notably, PNC-27 does not affect noncancerous cells. According to scientific findings, the peptide caused a complete blockade of tumor growth during the second week of administration and the second week after treatment, resulting in weak growth of tumor cells that plateaued at small tumor sizes compared to tumor growth in the absence of the peptide.

PNC-27 administration after the appearance of tumor growth at a distant site resulted in a decrease in tumor size followed by a slow increase in tumor growth.

The Anti-Cancer Effect of PNC-27 Peptide

According to studies, PNC-27 induces tumor cell necrosis in a poorly developed non-solid mammalian leukemia cell line based on HDM-2 expression in the cells’ plasma membrane. PNC-27 peptide kills solid tumor cells by binding to HDM-2 proteins within their cell membranes, bypassing the p53 pathway.

PNC-27 peptide can also induce necrosis via membrane lysis in solid tissue tumor cells by binding to HDM-2, independent of the p53 pathway.

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References

1. 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.
2. 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.
3. 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 human 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.
4. 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.
5. 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.