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Open AccessArticle

An Anti-PSMA Immunotoxin Reduces Mcl-1 and Bcl2A1 and Specifically Induces in Combination with the BAD-Like BH3 Mimetic ABT-737 Apoptosis in Prostate Cancer Cells

1
Department of Urology, Medical Center—University of Freiburg, 79106 Freiburg, Germany
2
Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
3
Institute for Transfusion Medicine and Gene Therapy, Medical Center—University of Freiburg, 79106 Freiburg, Germany
4
Center for Chronic Immunodeficiency, University of Freiburg, 79106 Freiburg, Germany
*
Author to whom correspondence should be addressed.
Department of Urology, Antibody-based Diagnostics and Therapies, Medical Center—University of Freiburg, Breisacher Str. 66, 79106 Freiburg, Germany.
Cancers 2020, 12(6), 1648; https://doi.org/10.3390/cancers12061648
Received: 12 May 2020 / Revised: 29 May 2020 / Accepted: 3 June 2020 / Published: 22 June 2020
(This article belongs to the Special Issue Targeted Cancer Therapy)
Background: Upregulation of anti-apoptotic Bcl-2 proteins in advanced prostate cancer leads to therapeutic resistance by prevention of cell death. New therapeutic approaches aim to target the Bcl-2 proteins for the restoration of apoptosis. Methods: The immunotoxin hD7-1(VL-VH)-PE40 specifically binds to the prostate specific membrane antigen (PSMA) on prostate cancer cells and inhibits protein biosynthesis. It was tested with respect to its effects on the expression of anti-apoptotic Bcl-2 proteins. Combination with the BAD-like mimetic ABT-737 was examined on prostate cancer cells and 3D spheroids and in view of tumor growth and survival in the prostate cancer SCID mouse xenograft model. Results: The immunotoxin led to a specific inhibition of Mcl-1 and Bcl2A1 expression in PSMA expressing target cells. Its combination with ABT-737, which inhibits Bcl-2, Bcl-xl, and Bcl-w, led to an induction of the intrinsic apoptotic pathway and to a synergistic cytotoxicity in prostate cancer cells and 3D spheroids. Furthermore, combination therapy led to a significantly prolonged survival of mice bearing prostate cancer xenografts based on an inhibition of tumor growth. Conclusion: The combination therapy of anti-PSMA immunotoxin plus ABT-737 represents the first tumor-specific therapeutic approach on the level of Bcl-2 proteins for the induction of apoptosis in prostate cancer. View Full-Text
Keywords: prostate cancer; PSMA; targeted therapy; combination therapy; immunotoxin; ABT-737; apoptosis; Bcl-2 proteins prostate cancer; PSMA; targeted therapy; combination therapy; immunotoxin; ABT-737; apoptosis; Bcl-2 proteins
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Masilamani, A.P.; Dettmer-Monaco, V.; Monaco, G.; Cathomen, T.; Kuckuck, I.; Schultze-Seemann, S.; Huber, N.; Wolf, P. An Anti-PSMA Immunotoxin Reduces Mcl-1 and Bcl2A1 and Specifically Induces in Combination with the BAD-Like BH3 Mimetic ABT-737 Apoptosis in Prostate Cancer Cells. Cancers 2020, 12, 1648.

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