Enhanced antitumor efficacy of telomerase-specific oncolytic adenovirus with valproic acid against human cancer cells

Abstract

Replication-selective oncolytic viruses are being developed for human cancer therapy. We previously developed an attenuated adenovirus Telomelysin), in which the human telomerase reverse transcriptase promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site. OBP-301 can replicate in, and causes selective lysis of, human cancer cells. Valproic acid (VPA), which is an effective antiepileptic drug, is known to inhibit the histone deacetylase activities. We determined whether the antitumor effect of OBP-301 could be enhanced by VPA in human lung cancer cells. In an in vitro cell viability assay, OBP-301 infection killed four human lung cancer cell lines, H1299, H1299-R5 (a subline of H1299 with a low level of the coxsackievirus and adenovirus receptor (CAR) expression), H460, and A549, more efficiently in the presence of VPA than in its absence. VPA treatment increased CAR expression in all the four lung cancer cells. Consistent with their CAR upregulation, the infection efficiency of adenoviruses in the presence of VPA was significantly higher than that in its absence. The molecular mechanism of this combined effect could be explained by an increase in adenovirus infectivity via VPA-mediated upregulation of CAR. These results suggest that treatment with OBP-301 in combination with VPA is a promising strategy for human lung cancer.

Role of zoledronic acid in oncolytic virotherapy: Promotion of antitumor effect and prevention of bone destruction

“…Zoledronic acid significantly increased the expression level of CAR in human osteosarcoma cells. Consistent with this effect of ZOL, we previously found that histone deacetylase inhibitor, radiation, and valproic acid also increase the expression level of CAR in human cancer cells. Although the infection efficiency of OBP‐301 was significantly increased in 143B and MNNG/HOS cells at 2 h after infection, ZOL could not enhance the replication of OBP‐301 during 72 h after infection.…”

Strategies to Develop Potent Oncolytic Viruses and Enhance Their Therapeutic Efficacy

“…Strategies to Develop Potent Oncolytic Viruses as well. [57][58][59] Ki67, L-plastin, and cyclooxygenase-2 are other examples of such promoters investigated to control viral replication in various cancers. [60][61][62][63] Dual targeting with promoters from both classes to enhance the therapeutic benefit in heterogeneous tumor cell populations has also been exploited with promising results.…”