Abstract
BackgroundE1B55kD deleted oncolytic adenovirus was designed to achieve cancer-specific cytotoxicity, but showed limitations in clinical study. To find a method to increase its efficacy, we investigated the correlation between oncolytic effect of such oncolytic adenovirus Adel55 and intracellular heat shock transcription factor 1 (HSF1) activity.MethodsIn the present study, human breast cancer cell line Bcap37 was stably transfected with constitutively active HSF1 (cHSF1) or HSF1 specific siRNA (HSF1i) to establish increased or decreased HSF1 expression levels. Cytotoxicity of Adel55 was analyzed in these cell lines in vitro and in vivo. Furthermore, Adel55 incorporated with cHSF1 (Adel55-cHSF1) was used to treat various tumor xenografts.ResultsAdel55 could achieve more efficient oncolysis in cHSF1 transfected Bcap37 cells, both in vitro and in vivo. However, inhibition of HSF1 expression by HSF1i could rescue Bcap37 cell line from oncolysis by Adel55. A time course study of viral replication established a correlation between higher replication of Adel55 and cytolysis or tumor growth inhibition. Then, we constructed Adel55-cHSF1 for tumor gene therapy and demonstrated that it is more potent than Adel55 itself in oncolysis and replication in both Bcap37 and SW620 xenografts.ConclusionscHSF1 enhances the Adel55 cell-killing potential through increasing the viral replication and is a potential therapeutic implication to augment the potential of E1B55kD deleted oncolytic adenovirus by increasing its burst.
Highlights
E1B55kD deleted oncolytic adenovirus was designed to achieve cancer-specific cytotoxicity, but showed limitations in clinical study
Our results showed that this constitutive heat shock transcription factor 1 (HSF1) mutant overexpression could dramatically increase the replication of Adel55 in tumor cells and enhance the antitumor efficacy of Adel55 in vitro and in vivo
The oncolytic effect of Adel55 correlates with the intracellular HSF1 activity The oncolytic adenovirus we used for our study is Adel55, which was made by deleting the E1B55kD gene of the Ad5 and replacing it with polyA site
Summary
E1B55kD deleted oncolytic adenovirus was designed to achieve cancer-specific cytotoxicity, but showed limitations in clinical study. Oncolytic adenoviruses are a class of promising anticancer agents, which are designed to selectively replicate in tumor cells and lead to cancer-specific cytotoxicity. A mutant adenovirus known as ONYX-015 is an elegant example, which was engineered to delete the E1B55kD viral protein and could preferentially replicate in p53-dysfunctional tumor cells but not the normal tissue [1,2]. It shows unambiguous evidence of antitumor activity in a broader range of tumors than initially anticipated [3,4,5,6]. Our results showed the Adel oncolysis correlates with the HSPs transcription level
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