Abstract
BackgroundCombined treatment of oncolytic adenoviruses with chemotherapeutic agents is foreseen as a therapeutic option for cancer. Here we have investigated the potential to use gemcitabine in combination with the oncolytic adenovirus AduPARE1A to treat pancreatic cancer and evaluate the underlying mechanism.MethodsWe treated pancreatic cancer cell lines BxPC-3 and PANC-1 with AduPARE1A and gemcitabine individually or in combination and analyzed cell viability, combination index, apoptosis and viral production. We also investigated the effects of the combination on tumor growth and mice survival in two xenograft models. Furthermore, we analyzed uPAR promoter activity from different uPAR-controlled adenovirus and studied NF-κB mediated effects.ResultsSynergistic cell killing from the combination AduPARE1A/Gemcitabine was observed in BxPC-3 and PANC-1 cells. Moreover, the combination treatment produced therapeutic benefits over either individual modality in two mouse models bearing orthotopic tumors, showing reduced tumor progression and significant prolonged mouse survival. Mechanistic studies showed that the synergistic cell death was not due to an increase in viral replication but occurred through an enhancement of apoptotic cell death. Gemcitabine stimulation increased the transcription of uPAR-controlled transgenes through the induction of NF-κB acting on the uPAR promoter. Interestingly, NF-κB gemcitabine-mediated induction of AduPAR adenoviruses interfered with the activation of NF-κB regulated genes, probably as a result of an intracellular competition for NF-κB DNA binding. Consequently, AduPARE1A infection sensitized cells to gemcitabine-induced apoptosis in the combined treatment.ConclusionsThese data highlights the potential of the combination as a treatment modality for pancreatic cancer patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0413-2) contains supplementary material, which is available to authorized users.
Highlights
Combined treatment of oncolytic adenoviruses with chemotherapeutic agents is foreseen as a therapeutic option for cancer
Combination therapy of gemcitabine and AduPARE1A show synergistic effects To investigate the potential interest of gemcitabine and AduPARE1A combination therapy for pancreatic cancer, we first examined the cytotoxic effects of individual treatments and their combination in BxPC-3 and PANC-1 cell lines
Cells were infected with different viral doses of AduPARE1A and exposed to several gemcitabine concentrations, alone or in combination, and cell viability of the culture was measured 3 days later
Summary
Combined treatment of oncolytic adenoviruses with chemotherapeutic agents is foreseen as a therapeutic option for cancer. We have investigated the potential to use gemcitabine in combination with the oncolytic adenovirus AduPARE1A to treat pancreatic cancer and evaluate the underlying mechanism. Oncolytic mutants are being evaluated in the clinic and emerge as a novel approach to treat cancer. Clinical trials in pancreatic cancer patients with ONYX015, a p53 binding defective oncolytic adenovirus, proved that the administration was safe, clinical efficacy was not observed when administered alone and only minor responses and stable disease were observed in combination with gemcitabine [2]. We previously developed an oncolytic adenovirus that drives the E1A gene under the control of the urokinasetype plasminogen activator receptor (uPAR) promoter, designated AduPARE1A, and showed its selective replication and its strong antitumor activity in pancreatic cancer models [3, 4]. Despite its anticancer activity demonstrated in the preclinical studies as a monotherapy, multimodal strategies to enhance antitumor efficacy are essential for successful clinical outcome
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