Abstract
Notch signaling pathway plays an important role in tumorigenesis by maintaining the activity of self-renewal of cancer stem cells, and therefore, it is hypothesized that interference of Notch signaling may inhibit tumor formation and progression. H101 is a recombinant oncolytic adenovirus that is cytolytic in cells lacking intact p53, but it is unable to eradicate caner stem cells. In this study, we tested a new strategy of tumor gene therapy by combining a Notch1-siRNA with H101 oncolytic adenovirus. In HeLa-S3 tumor cells, the combined therapy blocked the Notch pathway and induced apoptosis in tumors that are p53-inactive. In nude mice bearing xenograft tumors derived from HeLa-S3 cells, the combination of H101/Notch1-siRNA therapies inhibited tumor growth. Moreover, Notch1-siRNA increased Hexon gene expression at both the transcriptional and the translational levels, and promoted H101 replication in tumors, thereby enhancing the oncolytic activity of H101. These data demonstrate the feasibility to combine H101 p53-targted oncolysis and anti-Notch siRNA activities as a novel anti-cancer therapy.
Highlights
Most forms of cancer chemotherapy are unable to eradicate all malignant cells, and they often are highly toxic because of their lack of selectivity to cancer cells
The Notch signaling pathway plays an important role in the regulation of cell growth and differentiation, tissue renewal, and cell homeostasis, and the pathway may be disregulated in several carcinomas [17,18]
Notch1 antisense RNA treatment may lead to growth inhibition and even cell death if stably transfected in cervical cancer cells [19]
Summary
Most forms of cancer chemotherapy are unable to eradicate all malignant cells, and they often are highly toxic because of their lack of selectivity to cancer cells. New efforts have focused on developing interventions that include tumor-specific replicating viruses and siRNA. A virus-based strategy takes advantage of the fact that the intracellular replication and production of adenoviral progeny requires the cell cycle gatekeeper p53 to be in an inactive status, and in many tumors, p53 is either mutated or epigenetically silenced. The viral early gene E1B, which encodes a 55-kDa protein (E1B 55K), is essential to viral replication. E1B interacts with cellular p53 and inactivates it to allow viral replication. ONYX-015, a modified adenovirus lacking the E1B 55K gene, can only replicate and lyse tumor cells that have inactivated p53, sparing the normal cells that retain wild-type p53 function [1]. Clinical trials in patients with recurrent head and neck cancer, metastatic colorectal cancer, or pancreatic cancer have shown that ONYX-015, when used alone or in combination with chemotherapy, is safe and has significant antitumor activity in a subset of patients [2,3,4]
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