Combination therapy with AG-490 and interleukin 12 achieves greater antitumor effects than either agent alone.
Constitutive activation of Janus kinases (JAKs) and signal transducers and activators of transcription (STAT) occurs at very high frequency in various hematopoietic malignancies and solid tumors. It has been demonstrated that the tyrosine kinase inhibitor, AG-490, selectively blocks JAK activity and completely eliminates leukemia cells in a severe combined immunodeficient (SCID) mouse model. Because many cytokines, including interleukin (IL)-12, have been shown to signal through JAK/STAT pathways, AG-490 may inhibit cytokine-based cancer therapy. In this study, we evaluated the effects of AG-490 on IL-12 functional signaling and IL-12-mediated antitumor response in vivo. Previous studies have established the critical roles of macrophages and IFN-gamma in mediating IL-12-induced antitumor effects. Our results show that in vivo administration of AG-490 causes tumor cell apoptosis but does not inhibit IL-12-mediated macrophage activation and IFN-gamma production by lymphocytes. Furthermore, our data indicate that combined therapy with AG-490 and IL-12-induces greater antitumor effects than either agent alone in a murine myeloma tumor model. These results suggest that JAK/STAT inhibitors deserve further investigation for use with IL-12 therapy in treating human cancers with elevated JAK/STAT activity.
Burdelya
Lyudmila
L
Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Catlett-Falcone
Robyn
R
Levitzki
Alexander
A
Cheng
Fengdong
F
Mora
Linda B
LB
Sotomayor
Eduardo
E
Coppola
Domenico
D
Sun
JiaZhi
J
Sebti
Said
S
Dalton
William S
WS
Jove
Richard
R
Yu
Hua
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D018664:Interleukin-12; D007371:Interferon-gamma