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.
Highlights
Hematologic malignancies such as acute lymphoblastic leukemia (ALL) and non-Hodgkin’s lymphoma (NHL) are among the main causes of death in pediatric cancer patients throughout the world [1, 2]. ese neoplasms arise from the transformation of immature cells in the case of leukemias and of immature or mature cells in lymphomas, mainly compromising the B lymphocyte population and in a lesser proportion that of T lymphocytes and NK cells [3]
We have previously reported that bactofection of plasmids encoding a peptide from the BH3 domain of the proapoptotic Bax protein, antagonized the antiapoptotic activity of the B-cell lymphoma 2 (Bcl-2) family proteins, restored apoptosis, and induced chemosensitization of tumor cells [29], and we have recently documented that a cell-permeable Bax BH3 peptide expressed and released into the tumor microenvironment via a live-attenuated bacterial vector promoted apoptosis, induced antitumor activity, and increased survival in a murine xenograft model of human B non-Hodgkin’s lymphoma [30]
We report the ability of the Bak BH3 peptide coupled with the Antennapedia fusogenic peptide to promote apoptosis and induce chemosensitization of acute lymphoblastic leukemia and non-Hodgkin lymphoma cell lines
Summary
Hematologic malignancies such as acute lymphoblastic leukemia (ALL) and non-Hodgkin’s lymphoma (NHL) are among the main causes of death in pediatric cancer patients throughout the world [1, 2]. ese neoplasms arise from the transformation of immature cells in the case of leukemias and of immature or mature cells in lymphomas, mainly compromising the B lymphocyte population and in a lesser proportion that of T lymphocytes and NK cells [3]. Ese neoplasms arise from the transformation of immature cells in the case of leukemias and of immature or mature cells in lymphomas, mainly compromising the B lymphocyte population and in a lesser proportion that of T lymphocytes and NK cells [3] Conventional treatments such as chemotherapy and radiotherapy have increased 5-year survival to 92% in pediatric patients with acute lymphoblastic leukemias and 91% in pediatric patients with non-Hodgkin’s lymphoma [4,5,6]. BH3-only proteins are induced in response to stress signals and promote apoptosis by directly binding to effector proteins or binding to antiapoptotic proteins to release the effector proteins [15] In this balance, overexpression of antiapoptotic proteins in tumor cells promotes survival of the transformed cell and represents a mechanism of resistance to treatment [16]. Overexpression of antiapoptotic proteins such as Bcl-2, Bcl-XL, and Mcl-1 has found to be associated with drug resistance in human tumor cell lines [17,18,19], including leukemia [17] and NHL cells [20,21,22,23]
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