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1. Chemotherapeutic drugs sensitize human renal cell carcinoma cells to ABT-737 by a mechanism involving the Noxa-dependent inactivation of Mcl-1 or A1

Author

Zantl Niko, Besch Robert, Weber Arnim, Zall Henry, and Häcker Georg

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Human renal cell carcinoma (RCC) is very resistant to chemotherapy. ABT-737 is a novel inhibitor of anti-apoptotic proteins of the Bcl-2 family that has shown promise in various preclinical tumour models. Results We here report a strong over-additive pro-apoptotic effect of ABT-737 and etoposide, vinblastine or paclitaxel but not 5-fluorouracil in cell lines from human RCC. ABT-737 showed very little activity as a single agent but killed RCC cells potently when anti-apoptotic Mcl-1 or, unexpectedly, A1 was targeted by RNAi. This potent augmentation required endogenous Noxa protein since RNAi directed against Noxa but not against Bim or Puma reduced apoptosis induction by the combination of ABT-737 and etoposide or vinblastine. At the level of mitochondria, etoposide-treatment had a similar sensitizing activity and allowed for ABT-737-induced release of cytochrome c. Conclusions Chemotherapeutic drugs can overcome protection afforded by Mcl-1 and A1 through endogenous Noxa protein in RCC cells, and the combination of such drugs with ABT-737 may be a promising strategy in RCC. Strikingly, A1 emerged in RCC cell lines as a protein of similar importance as the well-established Mcl-1 in protection against apoptosis in these cells.

Published
2010
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2. Wiederherstellung der Apoptose-Sensibilität im humanen Nierenzellkarzinom durch Inhibtion der B-Zell Lymphoma-2 Proteine

Author

Zall, Henry, Groll, Michael (Prof. Dr.), and Häcker, Georg Alexander (Prof. Dr.)

Subjects
ddc:540, Chemie
Abstract

The apoptosis resistance of tumor cells is a universal feature of tumor development and of treatment resistance to chemotherapeutic drugs. The reasons for the treatment resistance are uncertain in many tumors, but altered expression of apoptosis-regulating Bcl-2 proteins could be involved. Here, the apoptotic signaling pathway was analyzed in cell lines of human renal cell carcinoma (RCC). Inhibition of anti-apoptotic Bcl-2 proteins demonstrated a strong sensitization of resistant cell lines to chemotherapeutic drugs. The induction of pro-apoptotic Noxa during treatment with drugs was required for the inactivation of anti-apoptotic proteins Mcl-1 and A1. Thus, a molecular aspect of apoptosis resistance in RCC was described and a therapeutic approach by inhibiton of Bcl-2 proteins could be shown. Die Apoptoseresistenz in Tumorzellen ist ein universelles Merkmal der Tumorentwicklung und der Behandlungsresistenz gegen chemotherapeutische Agenzien. Die Gründe für die hohe Widerstandsfähigkeit sind in vielen Tumoren unbekannt, aber eine veränderte Expression der Apoptose-regulierenden Bcl-2 Proteine könnte beteiligt sein. Hier wurde in Zelllinien des humanen Nierenzellkarzinoms (NZK) der Apoptose-Signalweg biochemisch analysiert und nach Apoptose-induzierenden Mechanismen gesucht. Dabei konnten resistente Zelllinien durch pharmakologische Hemmung der anti-apoptotischen Bcl-2 Proteine auf Chemotherapeutika sensibilisiert werden. Der beobachtete Synergismus konnte zudem auf eine Noxa-vermittelte Inaktivierung der anti-apoptotischen Proteine Mcl-1 und A1 zurückgeführt werden. Somit wurde im NZK ein molekularer Aspekt der Apoptoseresistenz beschrieben und ein therapeutischer Zugang durch Inhibition der Bcl-2 Proteine aufgezeigt.

Published
2010

3. Restoration of apoptosis sensitivity in human renal cell carcinoma by inhibition of B-cell lymphoma-2 proteins

Author

Häcker, Georg Alexander (Prof. Dr.), Groll, Michael (Prof. Dr.), Zall, Henry, Häcker, Georg Alexander (Prof. Dr.), Groll, Michael (Prof. Dr.), and Zall, Henry

Abstract

The apoptosis resistance of tumor cells is a universal feature of tumor development and of treatment resistance to chemotherapeutic drugs. The reasons for the treatment resistance are uncertain in many tumors, but altered expression of apoptosis-regulating Bcl-2 proteins could be involved. Here, the apoptotic signaling pathway was analyzed in cell lines of human renal cell carcinoma (RCC). Inhibition of anti-apoptotic Bcl-2 proteins demonstrated a strong sensitization of resistant cell lines to chemotherapeutic drugs. The induction of pro-apoptotic Noxa during treatment with drugs was required for the inactivation of anti-apoptotic proteins Mcl-1 and A1. Thus, a molecular aspect of apoptosis resistance in RCC was described and a therapeutic approach by inhibiton of Bcl-2 proteins could be shown., Die Apoptoseresistenz in Tumorzellen ist ein universelles Merkmal der Tumorentwicklung und der Behandlungsresistenz gegen chemotherapeutische Agenzien. Die Gründe für die hohe Widerstandsfähigkeit sind in vielen Tumoren unbekannt, aber eine veränderte Expression der Apoptose-regulierenden Bcl-2 Proteine könnte beteiligt sein. Hier wurde in Zelllinien des humanen Nierenzellkarzinoms (NZK) der Apoptose-Signalweg biochemisch analysiert und nach Apoptose-induzierenden Mechanismen gesucht. Dabei konnten resistente Zelllinien durch pharmakologische Hemmung der anti-apoptotischen Bcl-2 Proteine auf Chemotherapeutika sensibilisiert werden. Der beobachtete Synergismus konnte zudem auf eine Noxa-vermittelte Inaktivierung der anti-apoptotischen Proteine Mcl-1 und A1 zurückgeführt werden. Somit wurde im NZK ein molekularer Aspekt der Apoptoseresistenz beschrieben und ein therapeutischer Zugang durch Inhibition der Bcl-2 Proteine aufgezeigt.

Published
2010

4. Restoration of apoptosis sensitivity in human renal cell carcinoma by inhibition of B-cell lymphoma-2 proteins

Author

Groll, Michael (Prof. Dr.), Häcker, Georg Alexander (Prof. Dr.), Zall, Henry, Groll, Michael (Prof. Dr.), Häcker, Georg Alexander (Prof. Dr.), and Zall, Henry

Abstract

The apoptosis resistance of tumor cells is a universal feature of tumor development and of treatment resistance to chemotherapeutic drugs. The reasons for the treatment resistance are uncertain in many tumors, but altered expression of apoptosis-regulating Bcl-2 proteins could be involved. Here, the apoptotic signaling pathway was analyzed in cell lines of human renal cell carcinoma (RCC). Inhibition of anti-apoptotic Bcl-2 proteins demonstrated a strong sensitization of resistant cell lines to chemotherapeutic drugs. The induction of pro-apoptotic Noxa during treatment with drugs was required for the inactivation of anti-apoptotic proteins Mcl-1 and A1. Thus, a molecular aspect of apoptosis resistance in RCC was described and a therapeutic approach by inhibiton of Bcl-2 proteins could be shown., Die Apoptoseresistenz in Tumorzellen ist ein universelles Merkmal der Tumorentwicklung und der Behandlungsresistenz gegen chemotherapeutische Agenzien. Die Gründe für die hohe Widerstandsfähigkeit sind in vielen Tumoren unbekannt, aber eine veränderte Expression der Apoptose-regulierenden Bcl-2 Proteine könnte beteiligt sein. Hier wurde in Zelllinien des humanen Nierenzellkarzinoms (NZK) der Apoptose-Signalweg biochemisch analysiert und nach Apoptose-induzierenden Mechanismen gesucht. Dabei konnten resistente Zelllinien durch pharmakologische Hemmung der anti-apoptotischen Bcl-2 Proteine auf Chemotherapeutika sensibilisiert werden. Der beobachtete Synergismus konnte zudem auf eine Noxa-vermittelte Inaktivierung der anti-apoptotischen Proteine Mcl-1 und A1 zurückgeführt werden. Somit wurde im NZK ein molekularer Aspekt der Apoptoseresistenz beschrieben und ein therapeutischer Zugang durch Inhibition der Bcl-2 Proteine aufgezeigt.

Published
2010

6. Chemotherapeutic drugs sensitize human renalcell carcinoma cells to ABT-737 by a mechanisminvolving the Noxa-dependent inactivation ofMcl-1 or A1.

Author

Zall, Henry, Weber, Arnim, Besch, Robert, Zantl, Niko, and Häcker, Georg

Subjects
*RENAL cell carcinoma, *DRUG therapy, *VINBLASTINE, *ETOPOSIDE, *PODOPHYLLOTOXIN
Abstract

Background: Human renal cell carcinoma (RCC) is very resistant to chemotherapy. ABT-737 is a novel inhibitor of antiapoptotic proteins of the Bcl-2 family that has shown promise in various preclinical tumour models. Results: We here report a strong over-additive pro-apoptotic effect of ABT-737 and etoposide, vinblastine or paclitaxel but not 5-fluorouracil in cell lines from human RCC. ABT-737 showed very little activity as a single agent but killed RCC cells potently when anti-apoptotic Mcl-1 or, unexpectedly, A1 was targeted by RNAi. This potent augmentation required endogenous Noxa protein since RNAi directed against Noxa but not against Bim or Puma reduced apoptosis induction by the combination of ABT-737 and etoposide or vinblastine. At the level of mitochondria, etoposidetreatment had a similar sensitizing activity and allowed for ABT-737-induced release of cytochrome c. Conclusions: Chemotherapeutic drugs can overcome protection afforded by Mcl-1 and A1 through endogenous Noxa protein in RCC cells, and the combination of such drugs with ABT-737 may be a promising strategy in RCC. Strikingly, A1 emerged in RCC cell lines as a protein of similar importance as the well-established Mcl-1 in protection against apoptosis in these cells. [ABSTRACT FROM AUTHOR]

Published
2010
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