PNC-27

Also known as: PNC27, p53(12-26)-penetratin, p53(15)Ant

Evidence: Preclinical

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Overview

Synthetic 32-residue peptide joining p53 residues 12-26 to the penetratin cell-penetrating sequence; it lysed cancer cells but spared normal cells in vitro and prolonged survival in leukemic mice.

PNC-27 was designed by the Pincus and Michl group at SUNY Downstate from conformational analysis of the HDM-2 binding domain of p53. It joins p53 residues 12 to 26 to penetratin, a 17-residue sequence from Antennapedia that carries peptides across membranes. The first paper found it killed many human cancer lines, including p53-null ones, but not normal cells or cord-blood stem cells (Kanovsky 2001). Later work found HDM-2 in the outer membrane of cancer cells and proposed that PNC-27 binds it and forms pores, killing by necrosis within hours rather than by apoptosis (Sarafraz-Yazdi 2010). In vivo data are mouse models of acute myeloid leukemia from an independent group (Wang 2020) and of ovarian cancer with paclitaxel. No human trial has been published or registered.

Benefits

Selective killing of cancer cell lines by membrane lysis (in vitro); reduced leukemia burden and longer survival in AML mouse models; added to paclitaxel's effect in a mouse ovarian cancer model. No human data

Dosing reference

Research dose: No published human dose. Mouse studies used 40 to 100 mg/kg intraperitoneally daily
Common vial sizes: 5 mg

No human dose, route or pharmacokinetic study has been published. In AML mouse models PNC-27 was given at 40 mg/kg intraperitoneally daily for 2 to 3 weeks, and at 100 mg/kg daily for 2 weeks in healthy and leukemic mice (Wang et al., 2020). In cell culture it killed cancer cells within hours. Vendors sell 5 mg vials; that is a vial size, not a dose.

Mechanism

Proposed by the developers' group. The p53 12-26 segment of PNC-27 takes the alpha-helical shape it has when bound to HDM-2. HDM-2 was found in the plasma membrane of many cancer cell lines but not of untransformed lines, PNC-27 colocalized with it, and forcing membrane HDM-2 into resistant MCF-10-2A cells made them susceptible (Sarafraz-Yazdi 2010). The intact peptide, not fragments, sat in cancer cell membranes during lysis (Sookraj 2010), and immuno-electron microscopy showed PNC-27 and HDM-2 in about 1:1 ratios lining ring-shaped pores (Sarafraz-Yazdi 2022). Killing does not depend on p53 status. An independent AML study proposed that PNC-27 strengthens the link between membrane HDM2 and E-cadherin, leading to E-cadherin degradation and membrane damage (Wang 2020).

Evidence

Preclinical: animal or in vitro data only

Peptides from p53 residues 12-26 fused to penetratin killed human cancer cell lines, including p53-null lines, but did not affect normal cells or cord-blood stem cells, and did not induce Bax or p21 (Kanovsky et al., 2001)
The same p53(12-26)-penetratin peptide caused rapid necrosis-like death in three breast cancer lines with minimal toxicity to nonmalignant breast epithelial cells (Do et al., 2003)
HDM-2 was found in the membranes of cancer cells but not untransformed lines; PNC-27 colocalized with it, and adding membrane HDM-2 to resistant cells made them susceptible (Sarafraz-Yazdi et al., 2010)
In human and mouse AML models, 40 mg/kg daily intraperitoneally reduced leukemia burden and leukemia stem cells and lengthened median survival (54 vs 41 days with a control peptide) while sparing normal hematopoietic stem cells (Wang et al., 2020)
Added to weekly paclitaxel, PNC-27 reduced tumor growth in a mouse ovarian cancer model, and paclitaxel-surviving cells expressed more membrane MDM-2 (Alagkiozidis et al., 2017)
Human-trial status: none published, and none registered on ClinicalTrials.gov. Nearly all work comes from the developers' group, whose members hold patents on PNC-27; the AML study was independent but used peptide supplied by Oncolyze. The shorter analog PNC-28 blocked pancreatic tumor growth in mice (Michl et al., 2006)

References

Side effects

No human safety data exist, and no formal toxicology study has been published. In mice, 100 mg/kg intraperitoneally daily for 2 weeks did not impair normal hematopoietic stem cell function (Wang et al., 2020). In vitro it spared several untransformed cell lines, but that selectivity depends on membrane HDM-2 levels and has been tested mainly by the developers. As a pore-forming peptide, damage to normal cells that carry membrane HDM-2 is a theoretical risk that has not been studied.

Storage

Storage: Refrigerate 2-8°C (36-46°F)
Lyophilized: 2+ years at room temp, 3+ years refrigerated
Reconstituted: 28-30 days refrigerated

Pharmacology

Half-life: Not measured: no published pharmacokinetic study in any species. In cell culture the intact peptide persisted in cancer cell membranes but was degraded on untransformed cells (Sookraj et al., 2010)
Bioavailability: Not measured. Mouse efficacy studies gave it intraperitoneally (Wang et al., 2020)
Molecular weight: 4031.8 Da
Sequence: PPLSQETFSDLWKLLKKWKMRRNQFWVKVQRG [p53 12-26 + penetratin, free C-terminal acid]