Anti-cancer effect of HIV-1 viral protein R on doxorubicin resistant neuroblastoma.
Several unique biological features of HIV-1 Vpr make it a potentially powerful agent for anti-cancer therapy. First, Vpr inhibits cell proliferation by induction of cell cycle G2 arrest. Second, it induces apoptosis through multiple mechanisms, which could be significant as it may be able to overcome apoptotic resistance exhibited by many cancerous cells, and, finally, Vpr selectively kills fast growing cells in a p53-independent manner. To demonstrate the potential utility of Vpr as an anti-cancer agent, we carried out proof-of-concept studies in vitro and in vivo. Results of our preliminary studies demonstrated that Vpr induces cell cycle G2 arrest and apoptosis in a variety of cancer types. Moreover, the same Vpr effects could also be detected in some cancer cells that are resistant to anti-cancer drugs such as doxorubicin (DOX). To further illustrate the potential value of Vpr in tumor growth inhibition, we adopted a DOX-resistant neuroblastoma model by injecting SK-N-SH cells into C57BL/6N and C57BL/6J-scid/scid mice. We hypothesized that Vpr is able to block cell proliferation and induce apoptosis regardless of the drug resistance status of the tumors. Indeed, production of Vpr via adenoviral delivery to neuroblastoma cells caused G2 arrest and apoptosis in both drug naïve and DOX-resistant cells. In addition, pre-infection or intratumoral injection of vpr-expressing adenoviral particles into neuroblastoma tumors in SCID mice markedly inhibited tumor growth. Therefore, Vpr could possibly be used as a supplemental viral therapeutic agent for selective inhibition of tumor growth in anti-cancer therapy especially when other therapies stop working.
Zhao
Richard Y
RY
Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America. rzhao@som.umaryland.edu
Liang
Dong
D
Li
Ge
G
Larrimore
Christopher W
CW
Mirkin
Bernard L
BL
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D004317:Doxorubicin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009447:Neuroblastoma / Q000188:drug therapy* / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000502:physiology*
D054325:vpr Gene Products, Human Immunodeficiency Virus; D004317:Doxorubicin