title: Combination of AG490, a Jak2 inhibitor, and methylsulfonylmethane synergistically suppresses bladder tumor growth via the Jak2/STAT3 pathway.
abstract: 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.
authors.affiliation: Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Youn Hee
authors.initials: YH
authors.lastname: Joung
authors.affiliation: Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Yoon Mi
authors.initials: YM
authors.lastname: Na
authors.affiliation: Department of Surgery, School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Young Bum
authors.initials: YB
authors.lastname: Yoo
authors.affiliation: Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Pramod
authors.initials: P
authors.lastname: Darvin
authors.affiliation: Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Nipin
authors.initials: N
authors.lastname: Sp
authors.affiliation: Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Dong Young
authors.initials: DY
authors.lastname: Kang
authors.affiliation: Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Urology, School of Medicine, Konkuk University Glocal Campus, Chungju 380-704, Republic of Korea.
authors.forename: Hong Sup
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, University College London, London, UK.
authors.forename: Yoon Hee
authors.initials: YH
authors.lastname: Choi
authors.affiliation: Genomic Informatics Center, Hankyong National University, Anseong 456-749, Republic of Korea.
authors.forename: Hak Kyo
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Genomic Informatics Center, Hankyong National University, Anseong 456-749, Republic of Korea.
authors.forename: Kyung Do
authors.initials: KD
authors.lastname: Park
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Byung Wook
authors.initials: BW
authors.lastname: Cho
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Heui Soo
authors.initials: HS
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Jong Hwan
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Young Mok
authors.initials: YM
authors.lastname: Yang
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D013450:Sulfones; D020032:Tyrphostins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C025910:dimethyl sulfone; C000588866:KDR protein, human; D017526:Receptor, IGF Type 1; D040301:Vascular Endothelial Growth Factor Receptor-2; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D004121:Dimethyl Sulfoxide