Oncolytic herpes simplex virus vectors and taxanes synergize to promote killing of prostate cancer cells

Abstract

Genetically engineered oncolytic herpes simplex virus-1 (HSV-1) vectors selectively replicate in tumor cells causing direct killing whereas sparing normal cells. One clinical limitation of using oncolytic HSV vectors is their attenuated growth. We hypothesized that the appropriately chosen chemotherapeutic agent combined with an oncolytic HSV could be an effective means to promote augmented prostate cancer cell killing both in vitro and in vivo. Here we have identified that G47D synergizes with the microtubule-stabilizing taxane agents docetaxel and paclitaxel to enhance the in vitro killing of prostate cancer cells. In vivo efficacy studies show that when combined with docetaxel, G47D could be reduced at least 10-fold. Immunoblot analysis revealed that docetaxel-induced accumulation of the phospho-specific mitotic markers op18/stathmin or histone-H3 was markedly reduced by G47D, which correlated with enhanced apoptosis and required active viral replication. Furthermore, cell-cycle analysis demonstrated that in the presence of G47D, the majority of 4N cells arrested in mitosis were MPM-2-negative, indicative of cells exiting mitosis prematurely. These findings suggest that G47D may act in part, on mitotically blocked cells to enhance cell death, which may account for the enhanced antitumor efficacy observed in vivo.

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer

“…In a study of E1B55 attenuated adenovirus, Ganly et al 56 emphasized that virus-induced apoptosis was distinct from virus-induced cytolysis: apoptosis causes a premature cessation of viral replication, whereas cytolysis results in release of infective progeny. 45 In the present study; it may be hypothesized that lower cell counts in the HF10-treated group have caused the low apoptosis counts. However; we selected similar tumor areas with moderate to high cell number; for both control and HF10-treated groups; and performed the cell counts in six random fields in the same area.…”

“…We believe that HSV 1 has a tendency to reduce apoptosis through several mechanisms, such as the PKR pathway and the US3 arm of the viral genome. 53 Some oncolytic herpes viruses reduce apoptosis; 45,46,54 whereas others enhance apoptosis. 43,44,47 The effect of oncolytic herpes viruses on apoptosis is strain specific and depends on the underlying genetic variation.…”

“…[39][40][41][42] The effects of oncolytic herpes viruses on apoptosis are controversial: apoptosis is elevated upon viral treatment in some studies, 43,44 but reduced in others. 45,46 Some have argued that induction of premature apoptosis is not a desirable feature of oncolytic viral treatment; 47 instead, reducing or delaying apoptosis may enhance viral penetration of the tumor, another determinant of the potency of an oncolytic virus.…”

Synergistic anti-tumor effects between oncolytic vaccinia virus and paclitaxel are mediated by the IFN response and HMGB1

“…For example, paclitaxel treatment has been shown to enhance the ability of an oncolytic adenovirus to replicate, through stabilization of microtubules increasing intracellular movement of the viral particles. 14 Alternatively, the regulation of certain cellular genes by taxane treatment has been shown to enhance oncolytic Herpes Simplex Virus (HSV) replication 15 while cell death induced by the chemotherapy has also been shown to allow the large virus to better penetrate the tumor. 16 Although these observations are important, most oncolytic agents form acute infections, such that viral infection will lead to cell death, and so enhancing the replication cycle or sensitizing only the infected cells to chemotherapy may not be the most effective way to improve the overall therapeutic benefits.…”

Advance in herpes simplex viruses for cancer therapy

“…Combining oncolytic virotherapy with chemotherapy or radiotherapy generally produces synergic action in preclinical models [57][58][59]. The interaction between HSV and conventional therapies has been studied by many groups (summarized in [60]).…”