Amphipathic Tail-Anchoring Peptide is a Promising Therapeutic Agent for Cancer Treatment

Abstract

The amphipathic tail-anchoring peptide (ATAP) derived from the human anti-apoptotic protein Bfl-1 is a potent inducer of apoptosis by targeting mitochondria permeability transition. By linking ATAP to an internalizing RGD peptide (iRGD), selective targeting for ATAP to tumor cells could be achieved. Targeting of ATAP-iRGD peptide to tumorigenic cells resulted in mitochondrion-dependent cell death through release of cytochrome c. Confocal fluorescence microscopy showed that Dylight488-labeled ATAP-iRGD could effectively penetrate into cells and distribute along the mitochondria network. Flow cytometry results showed that expression level of integrinαV or integrinαVβ3 receptors is higher in ATAP-iRGD sensitive (DU145, KYSE-150 and PC3) cells, when compared with ATAP-iRGD insensitive (K562 human leukemia cell) cell line. These results indicate that integrins act as a receptor to mediate uptake of ATAP-iRGD into the cancer cells. Studies with xenograft model showed that intravenous injection of ATAP-iRGD could suppress the growth of several human carcinoma cells implemented into the nude mice. Toxicological studies revealed that repetitive intravenous delivery of ATAP-iRGD did not produce significant toxicity in different organs of the SV129 mice. Our data suggest that ATAP-iRGD is a promising agent with high efficacy and limited toxicity for cancer therapy.