# Poptosis or Peptide-Induced Transmembrane Pore Formation: A Novel Way to Kill Cancer Cells without Affecting Normal Cells

## TL;DR

A new cancer treatment using peptides causes tumor cell death without harming normal cells by forming pores in cancer cell membranes.

## Contribution

Peptide-induced poptosis is introduced as a novel, general cancer treatment with high specificity and effectiveness.

## Key findings

- Peptides like PNC-27 and PNC-28 induce transmembrane pore formation and tumor cell necrosis without affecting normal cells.
- The peptides successfully treat metastatic pancreatic tumors and chemotherapy-resistant cancers in mice.
- PNC-27 forms 1:1 complexes with HDM-2, leading to dimerization and pore formation in cancer cell membranes.

## Abstract

Recent advances in cancer treatment like personalized chemotherapy and immunotherapy are aimed at tumors that meet certain specifications. In this review, we describe a new approach to general cancer treatment, termed peptide-induced poptosis, in which specific peptides, e.g., PNC-27 and its shorter analogue, PNC-28, that contain the segment of the p53 transactivating 12–26 domain that bind to HDM-2 in its 1–109 domain, bind to HDM-2 in the membranes of cancer cells, resulting in transmembrane pore formation and the rapid extrusion of cancer cell contents, i.e., tumor cell necrosis. These peptides cause tumor cell necrosis of a wide variety of solid tissue and hematopoietic tumors but have no effect on the viability and growth of normal cells since they express at most low levels of membrane-bound HDM-2. They have been found to successfully treat a highly metastatic pancreatic tumor as well as stem-cell-enriched human acute myelogenous leukemias in nude mice, with no evidence of off-target effects. These peptides also are cytotoxic to chemotherapy-resistant cancers and to primary tumors. We performed high-resolution scanning immuno-electron microscopy and visualized the pores in cancer cells induced by PNC-27. This peptide forms 1:1 complexes with HDM-2 in a temperature-independent step, followed by dimerization of these complexes to form transmembrane channels in a highly temperature-dependent step parallel to the mode of action of other membranolytic but less specific agents like streptolysin. These peptides therefore may be effective as general anti-cancer agents.