Abstract

In OVCAR3 cells, IFNAR1/IFNAR2-RNAi (80-90% knock down) or IRF9-RNAi (80% knockdown) completely inhibited the antiproliferative activity of IFN-alpha. On the other hand, the IRF9-RNAi demonstrated no inhibition of the antiproliferative activity of IFN-gamma. These results suggest that IFN-alpha signals through IFNAR1/IFNAR2 and utilize IRF9 to elicit the anti-cancer activity in OVCAR3 cells. Furthermore, TRAIL gene expression (related to apoptosis) was inhibited by IFNAR1-RNAi or IRF9-RNAi, but not by Stat1-RNAi following IFN-alpha treatment, suggesting that induction of the TRAIL gene plays a role in eliciting the antiproliferative activity of IFN-alpha. The combination of human monocytes and IFN and their effect on tumor cells showed that 4 of 8 human tumors could be eradicated by a combination of human monocytes and IFNs, whereas killing of human diploid required much higher concentrations of monocytes. Contact of activated monocytes with tumor cells for 2 days is required for this effect. Enhanced monocyte antitumor activity sometimes occurs with a combination of Type I and II IFNs.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAI001038-02
Application #
7964665
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2009
Total Cost
$554,055
Indirect Cost

  Institution

Name
National Institute of Allergy and Infectious Diseases
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Green, Daniel S; Nunes, Ana T; Annunziata, Christina M et al. (2016) Monocyte and interferon based therapy for the treatment of ovarian cancer. Cytokine Growth Factor Rev 29:109-15
Johnson, Chase L; Green, Daniel S; Zoon, Kathryn C (2015) Human monocytes in the presence of interferons alpha2a and gamma are potent killers of serous ovarian cancer cell lines in combination with paclitaxel and carboplatin. J Interferon Cytokine Res 35:55-62
Bekisz, Joseph; Sato, Yuki; Johnson, Chase et al. (2013) Immunomodulatory effects of interferons in malignancies. J Interferon Cytokine Res 33:154-61
Tsuno, Takaya; Mejido, Josef; Zhao, Tongmao et al. (2012) BID is a critical factor controlling cell viability regulated by IFN-?. J Immunother 35:23-31
Nakashima, Hideyuki; Miyake, Kotaro; Clark, Christopher R et al. (2012) Potent antitumor effects of combination therapy with IFNs and monocytes in mouse models of established human ovarian and melanoma tumors. Cancer Immunol Immunother 61:1081-92
Miyake, Kotaro; Bekisz, Joseph; Zhao, Tongmao et al. (2012) Apoptosis-inducing factor (AIF) is targeted in IFN-?2a-induced Bid-mediated apoptosis through Bak activation in ovarian cancer cells. Biochim Biophys Acta 1823:1378-88
Baron, Samuel; Finbloom, Joel; Horowitz, Julie et al. (2011) Near eradication of clinically relevant concentrations of human tumor cells by interferon-activated monocytes in vitro. J Interferon Cytokine Res 31:569-73
Tsuno, Takaya; Mejido, Josef; Zhao, Tongmao et al. (2009) IRF9 is a key factor for eliciting the antiproliferative activity of IFN-alpha. J Immunother 32:803-16