Abstract
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.
Highlights
Prostate cancer (PC) represents the second most common cancer in men with more than 1.2 million new cases and more than 350,000 deaths estimated worldwide [1]
The immunotoxin hD7-1(VL-VH)-PE40 was generated by cloning the anti-prostate specific membrane antigen (PSMA) scFv hD7-1 via NcoI/NotI restriction sites into the plasmid pHOG21
The immunotoxin was expressed in E.coli XL-1 blue bacteria and successfully obtained in high purity of about 82% after immobilized metal affinity chromatography (IMAC) (Figure 1b)
Summary
Prostate cancer (PC) represents the second most common cancer in men with more than 1.2 million new cases and more than 350,000 deaths estimated worldwide [1]. The reason is that PC is driven by alterations in several signaling pathways promoting tumor progression and resistance followed by treatment failure [2] One of these signaling pathways is the intrinsic apoptotic pathway. The pro-apoptotic activators BID, BIM, and PUMA and the sensitizers BAD and NOXA are upregulated and bind via their so-called BH3 (B-cell lymphoma-2 (Bcl-2) homology domain 3) domain to the anti-apoptotic proteins. Upregulation of anti-apoptotic Bcl-2 proteins in advanced prostate cancer leads to therapeutic resistance by prevention of cell death. 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. Combination therapy led to a significantly prolonged survival of mice bearing prostate cancer xenografts based on an inhibition of tumor growth
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