Combination of AG490, a Jak2 inhibitor, and methylsulfonylmethane synergistically suppresses bladder tumor growth via the Jak2/STAT3 pathway

Int J Oncol. 2014 Mar;44(3):883-95. doi: 10.3892/ijo.2014.2250. Epub 2014 Jan 8.


Human urinary bladder cancer is the fifth most common cancer, with a worldwide estimate of about two million patients. Recurrence after complete transurethral prostatic resection is the most important problem in therapy. Combination therapy is a new approach in the treatment of cancers that do not respond to current therapies. These therapies have many advantages over conventional therapies, such as fewer side-effects and greater efficiency. Research efforts using natural compounds for the elimination or growth suppression of the cancer arise from studies on methylsulfonylmethane (MSM). MSM is a natural sulfur compound with no side-effects. AG490 is a tyrosine kinase inhibitor that has been extensively used for inhibiting Jak2 in vitro and in vivo. In our study, the combinatorial effect of these two agents on human bladder cancer cell lines and xenografts was analyzed. We observed that the combination of AG490 and MSM inhibited cancer cell viability and cell migration in vitro. This combination inhibited VEGF mRNA expression in bladder cancer cell lines. In vivo experiments showed that oral administration of AG490 and MSM combination significantly inhibited the growth of tumor xenografts in mice. Our study clearly demonstrates that the predominant effect of this combination is the reduction of signaling molecules including STAT3, STAT5b, IGF-1R, VEGF and VEGF-R2 which are involved in the growth, progression and metastasis of human bladder cancer. The anti-metastatic ability of this drug combination is confirmed using metastatic animal models. Therefore, this combination could have the effect of genesistasis and powerful anticancer effects against bladder cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement / drug effects*
  • Cell Survival / drug effects
  • Dimethyl Sulfoxide / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors
  • Janus Kinase 2 / biosynthesis*
  • Mice
  • RNA, Messenger / biosynthesis
  • Receptor, IGF Type 1 / biosynthesis
  • STAT3 Transcription Factor / biosynthesis*
  • STAT3 Transcription Factor / genetics
  • STAT5 Transcription Factor / biosynthesis
  • STAT5 Transcription Factor / genetics
  • Signal Transduction / drug effects
  • Sulfones / pharmacology
  • Tyrphostins / pharmacology
  • Urinary Bladder Neoplasms / drug therapy
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology
  • Vascular Endothelial Growth Factor A / biosynthesis
  • Vascular Endothelial Growth Factor Receptor-2 / biosynthesis
  • Xenograft Model Antitumor Assays


  • RNA, Messenger
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • STAT5 Transcription Factor
  • STAT5B protein, human
  • Sulfones
  • Tyrphostins
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • dimethyl sulfone
  • KDR protein, human
  • Receptor, IGF Type 1
  • Vascular Endothelial Growth Factor Receptor-2
  • JAK2 protein, human
  • Janus Kinase 2
  • Dimethyl Sulfoxide