An effective anti-cancer therapy should exclusively target cancer cells and trigger in them a broad spectrum of cell death pathways that will prevent avoidance. Here, we present a new approach in cancer therapy that specifically targets the mitochondria and ER of cancer cells. We developed a peptide derived from the flexible and transmembrane domains of the human protein NAF-1/CISD2. This peptide (NAF-144-67) specifically permeates through the plasma membranes of human epithelial breast cancer cells, abolishes their mitochondria and ER, and triggers cell death with characteristics of apoptosis, ferroptosis and necroptosis. In vivo analysis revealed that the peptide significantly decreases tumor growth in mice carrying xenograft human tumors. Computational simulations of cancer vs. normal cell membranes reveal that the specificity of the peptide to cancer cells is due to its selective recognition of their membrane composition. NAF-144-67 represents a promising anti-cancer lead compound that acts via a unique mechanism.
Bibliographical noteFunding Information:
This research was supported by the MINERVA Center for Bio-hybrid Complex Systems at the Hebrew University and by the support of the BSF grant number 2020094 to R. N, A. F, L. J. W., and R. E. and the NIH, Grant no. GM 59796 (to R. E.) and GM 111364 (to R. E., L. J. W., R. M.); the Welch Foundation, Grant no. F-1896 (to R. E) and F-1722 (to L. J. W.); and Part of the computations were done using HPC resources from the Texas Advanced Computing Center (TACC) at the University of Texas at Austin. We gratefully acknowledge the use of facilities at the Texas Materials Institute at the University of Texas at Austin.
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