Tumour growth inhibition by an imidazoquinoline is associated with c-Myc down-regulation in urothelial cell carcinoma.
OBJECTIVE
To detect and characterize the potential role of c-Myc in the inhibition of proliferation and induction of cell death of urothelial cell carcinoma by imidazoquinolines, Toll-like receptor-7 (TLR7) agonists, that are thought to exert their immunogenic effects through the MyD88/NF-kappaB pathway.


METHODS
Human (T24) and murine (MBT-2) bladder cancer cell lines were cultured in normal culture medium or medium supplemented with imidazoquinoline. The effects of imidazoquinoline on gene expression, transcription and tumorigenesis were then evaluated. Effects of imidazoquinoline on in vivo bladder tumour growth and gene expression were investigated using a mouse model of orthotopic bladder cancer.


RESULTS
There was a dose-dependent decrease in c-Myc expression in bladder cancer cells treated with imidazoquinoline; the transcriptional activity of c-Myc was also significantly reduced. Furthermore, the in vitro proliferation and tumorigenesis of MBT-2 cells were suppressed in a dose-dependent manner. For in vivo experiments, a third of mice with bladder cancer treated with intravesical imidazoquinoline showed evidence of residual bladder tumour, vs all the placebo-treated mice. In vivo expression of c-Myc, cyclin D2 and proliferating cell nuclear antigen in the bladder tumour tissue were also down-regulated.


CONCLUSIONS
Imidazoquinolines can inhibit c-Myc expression and directly affect cell growth and tumorigenesis of bladder cancer cells, independent of an immune response. These direct effects might be synergistic with previously described immunogenic actions of imidazoquinolines. Our findings could broaden the potential application of imidazoquinoline therapy beyond dermatological malignancies, and further clinical studies are warranted.
Liu
Huixian
H
Department of Urology, The New York-Presbyterian Hospital, Weill Medical College of Cornell University, New York, NY 10021, USA.
Schwartz
Michael J
MJ
Hwang
David H
DH
Scherr
Douglas S
DS
D000818:Animals; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015870:Gene Expression; D006801:Humans; D007093:Imidazoles / Q000819:agonists / Q000627:therapeutic use; D007150:Immunohistochemistry; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000187:drug effects / Q000378:metabolism*; D011804:Quinolines / Q000819:agonists / Q000627:therapeutic use; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D007093:Imidazoles; D016271:Proto-Oncogene Proteins c-myc; D011804:Quinolines; D051199:Toll-Like Receptor 7