Oncolytic virotherapy synergism with signaling inhibitors: Rapamycin increases myxoma virus tropism for human tumor cells

Marianne M. Stanford, John W. Barrett, Steven H. Nazarian, Steven Werden, Douglas McFadden

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Myxoma virus is a rabbit-specific poxvirus pathogen that also exhibits a unique tropism for human tumor cells and is dramatically oncolytic for human cancer xenografts. Most tumor cell lines tested are permissive for myxoma infection in a fashion intimately tied to the activation state of Akt kinase. A host range factor of myxoma virus, M-T5, directly interacts with Akt and mediates myxoma virus tumor cell tropism. mTOR is a regulator of cell growth and metabolism downstream of Akt and is specifically inhibited by rapamycin. We report that treatment of nonpermissive human tumor cell lines, which normally restrict myxoma virus replication, with rapamycin dramatically increased virus tropism and spread in vitro. This increased myxoma replication is concomitant with global elects on mTOR signaling, specifically, an increase in Akt kinase. In contrast to the effects on human cancer cells, rapamycin does not increase myxoma virus replication in rabbit cell lines or permissive human tumor cell lines with constitutively active Akt. This indicates that rapamycin increases the oncolytic capacity of myxoma virus for human cancer cells by reconfiguring the internal cell signaling environment to one that is optimal for productive virus replication and suggests the possibility of a potentially therapeutic synergism between kinase signaling inhibitors and oncolytic poxviruses for cancer treatment.

Original languageEnglish (US)
Pages (from-to)1251-1260
Number of pages10
JournalJournal of Virology
Volume81
Issue number3
DOIs
StatePublished - Feb 1 2007
Externally publishedYes

Fingerprint

Myxoma virus
Oncolytic Virotherapy
tropisms
Tropism
synergism
Sirolimus
Virus Replication
Tumor Cell Line
Poxviridae
virus replication
cell lines
Neoplasms
Myxoma
Phosphotransferases
phosphotransferases (kinases)
Rabbits
rabbits
Host Specificity
neoplasms
Heterografts

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Oncolytic virotherapy synergism with signaling inhibitors : Rapamycin increases myxoma virus tropism for human tumor cells. / Stanford, Marianne M.; Barrett, John W.; Nazarian, Steven H.; Werden, Steven; McFadden, Douglas.

In: Journal of Virology, Vol. 81, No. 3, 01.02.2007, p. 1251-1260.

Research output: Contribution to journalArticle

Stanford, Marianne M. ; Barrett, John W. ; Nazarian, Steven H. ; Werden, Steven ; McFadden, Douglas. / Oncolytic virotherapy synergism with signaling inhibitors : Rapamycin increases myxoma virus tropism for human tumor cells. In: Journal of Virology. 2007 ; Vol. 81, No. 3. pp. 1251-1260.
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