Proteasome inhibition enhances the killing effect of BikDD gene therapy.

Abstract:

:BikDD, a phosphorylation-mimic mutant of pro-apoptotic protein Bik, elicits strong apoptosis in cancer cells when introduced via an expression platform termed VP16-GAL4-WPRE integrated systemic amplifier (VISA) under the control of a cancer-specific promoter both in vitro and in vivo. C-VISA-BikDD expression plasmid encapsulated in liposomes is currently in the process to initiate a phase I clinical trial for pancreatic cancer. In this study, we report a potential combination approach of BikDD with proteasome inhibitors on the basis of our findings that exogenously expressed BikDD protein undergoes proteasome-mediated degradation via both ubiquitin-dependent and -independent pathways. Inhibition of proteasome increases the protein stability of BikDD, enhancing the apoptotic effect of BikDD. Hence, high proteasome activity may be a mechanism by which intrinsic and acquired resistance occurs in BikDD gene therapy, and a combination therapy with current clinically approved proteasome inhibitor may overcome resistance.

journal_name

Am J Transl Res

authors

Sun Y,Ponz-Sarvise M,Chang SS,Chang WC,Chen CH,Hsu JL,Hung MC

subject

Has Abstract

pub_date

2015-02-15 00:00:00

pages

319-27

issue

2

issn

1943-8141

journal_volume

7

pub_type

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