Hypoxia enhances the replication of oncolytic herpes simplex virus in p53- breast cancer cells.
Hypoxic cancer cells are refractory to conventional chemotherapy. Herpes simplex virus type-1 (HSV-1)-derived oncolytic viruses are safe for therapy since they lack the neurovirulence gene ICP34.5. Cancer cells containing high MEK activity are permissive to the HSV-1-derived oncolytic virus, R3616. Considering that hypoxia increases MEK activity, we determined whether hypoxic MDA-MB-231 and MCF-7 cells were more permissive to R3616, compared to normoxic cells. We observed nine-fold higher (3.5 x 10e6 pfu/4 x 10e5 pfu/ml) titers in MDA-MB-231 hypoxic cells compared to normoxic; however, hypoxic MCF-7 cells did not yield higher R3616 titers. Markers for early and late viral infection were consistent with this result: (1) virus-induced chaperone-enriched (VICE) domains were observed in MDA-MB-231 cells, and (2) the HSV-1 glycoprotein C (gC), a protein produced late in infection, accumulated in hypoxic MDA-MB-231 cells. Thus, oncolytic R3616 virus may target hypoxic p53(-) breast cancer cells.
Fasullo
Michael
M
Ordway Research Institute, Albany, NY 12208, USA.
Burch
April D
AD
Britton
Alicia
A
D001943:Breast Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004279:DNA, Viral / Q000378:metabolism; D005260:Female; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication
D004279:DNA, Viral; D016159:Tumor Suppressor Protein p53