Cell-Permeable Bak BH3 Peptide Induces Chemosensitization of Hematologic Malignant Cells

Abstract

Hematologic malignancies such as leukemias and lymphomas are among the leading causes of pediatric cancer death worldwide, and although survival rates have improved with conventional treatments, the development of drug-resistant cancer cells may lead to patient relapse and limited possibilities of a cure. Drug-resistant cancer cells in these hematologic neoplasms are induced by overexpression of the antiapoptotic B-cell lymphoma 2 (Bcl-2) protein families, such as Bcl-XL, Bcl-2, and Mcl-1. We have previously shown that peptides from the BH3 domain of the proapoptotic Bax protein that also belongs to the Bcl-2 family may antagonize the antiapoptotic activity of the Bcl-2 family proteins, restore apoptosis, and induce chemosensitization of tumor cells. Furthermore, cell-permeable Bax BH3 peptides also elicit antitumor activity and extend survival in a murine xenograft model of human B non-Hodgkin’s lymphoma. However, the activity of the BH3 peptides of the proapoptotic Bak protein of the Bcl-2 family against these hematologic malignant cells requires further characterization. In this study, we report the ability of the cell-permeable Bak BH3 peptide to restore apoptosis and induce chemosensitization of acute lymphoblastic leukemia and non-Hodgkin’s lymphoma cell lines, and this event is enhanced with the coadministration of cell-permeable Bax BH3 peptide and represents an attractive approach to improve the patient outcomes with relapsed or refractory hematological malignant cells.

Antimicrobial Peptides Mediate Apoptosis by Changing Mitochondrial Membrane Permeability

“…Bcl-2 and Bcl-XL are anti-apoptotic proteins that inhibit the activities of Bak and Bax [ 48 , 49 , 50 ]. PETK, which is a Bax-derived peptide that contains the same BH domain as Bax, can change the permeability of the OMM by the same oligomerization mechanism and subsequently activate the apoptosis program mediated by caspase-3 [ 33 ]. This kind of artificially modified AMPs, such as PETK targeting the OMM, are good candidate drugs for the treatment of tumors and infectious diseases [ 21 ].…”

“…According to the mechanisms of action of PETK, LL-37, 17BIPHE2, and HN [ 27 , 28 , 30 , 33 ], we can conclude that AMPs initiate MOMP through two distinct pathways, leading to apoptosis. One way is the direct participation of AMPs in MOMP to promote cell apoptosis with the same specific framework of apoptotic proteins regulating MOMP.…”

“…One way is the direct participation of AMPs in MOMP to promote cell apoptosis with the same specific framework of apoptotic proteins regulating MOMP. These AMPs are usually artificially modified proapoptotic proteins [ 33 ]. The other way is to regulate the expression of apoptotic proteins, in order to indirectly regulate MOMP and subsequent apoptosis [ 27 , 31 ].…”

“…In the absence of caspases, AMPs can also trigger inflammation with the release of pro-apoptotic factors. Although increased expression of activated caspase-3 in the apoptotic pathway was detected [ 33 , 43 ], it is not clear whether this is caused by the apoptotic chain reaction (the combination of Cyt c with Apaf-1 to trigger apoptosis) induced directly by AMPs or by the AMP-induced expression of caspase genes. Because of the composition and structural characteristics of AMPs and the mechanism of their multi-target action, the simultaneous existence of these two causes is not excluded, but this still needs to be supported by more thorough evidence.…”