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

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

International journal of oncology (2014-01-10)
Youn Hee Joung, Yoon Mi Na, Young Bum Yoo, Pramod Darvin, Nipin Sp, Dong Young Kang, Sang Yoon Kim, Hong Sup Kim, Yoon Hee Choi, Hak Kyo Lee, Kyung Do Park, Byung Wook Cho, Heui Soo Kim, Jong Hwan Park, Young Mok Yang
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.

MATERIALS
Product Number
Brand
Product Description

Supelco
Dimethyl sulfone, Standard for quantitative NMR, TraceCERT®, Manufactured by: Sigma-Aldrich Production GmbH, Switzerland
Supelco
Methylsulfonylmethane, Pharmaceutical Secondary Standard; Certified Reference Material
USP
Dehydrated Alcohol, United States Pharmacopeia (USP) Reference Standard
Supelco
Ethanol solution, certified reference material, 2000 μg/mL in methanol
Sigma-Aldrich
Ethanol, anhydrous, denatured
Sigma-Aldrich
Dimethyl sulfone, 98%
Sigma-Aldrich
Streptomycin sulfate salt, powder, BioXtra, suitable for mouse embryo cell culture
Sigma-Aldrich
Streptomycin sulfate salt, powder
Sigma-Aldrich
Streptomycin sulfate salt, powder, BioReagent, suitable for cell culture
Streptomycin sulfate, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Ethanol, absolute, denaturated with 0.5-1.5 Vol.% 2-butanone and approx. 0.001% Bitrex (GC), ≥98% (GC)
Sigma-Aldrich
Ethanol, purum, secunda spirit, denaturated with 2% 2-butanone, S15, ~96% (based on denaturant-free substance)
Sigma-Aldrich
Ethanol, tested according to Ph. Eur.
Sigma-Aldrich
Ethyl alcohol, Pure, 190 proof, ACS spectrophotometric grade, 95.0%
Supelco
Streptomycin solution, ~1 mg/mL in 1 mM EDTA, analytical standard
Supelco
Ethanol, standard for GC
Sigma-Aldrich
Ethanol, for residue analysis
Sigma-Aldrich
Ethyl alcohol, Pure, 190 proof, for molecular biology
Sigma-Aldrich
Streptomycin Ready Made Solution, 100 mg/mL in water
Sigma-Aldrich
Ethanol, ACS reagent, prima fine spirit, without additive, F15 o1
Sigma-Aldrich
Ethanol, purum, absolute ethanol, denaturated with 2% 2-butanone, A15 MEK1, ≥99.8% (based on denaturant-free substance)
Sigma-Aldrich
Ethanol, purum, fine spirit, denaturated with 2% 2-butanone, F25 MEK1, ~96% (based on denaturant-free substance)
Sigma-Aldrich
Ethanol, purum, absolute ethanol, denaturated with 1% cyclohexane, A15 CYCLO1, ≥99.8% (based on denaturant-free substance)
Sigma-Aldrich
Ethanol, purum, fine spirit, denaturated with 4.8% methanol, F25 METHYL1, ~96% (based on denaturant-free substance)
Sigma-Aldrich
Ethanol, purum, absolute ethanol, denaturated with 4.8% isopropanol, A15 IPA1, ≥99.8% (based on denaturant-free substance)
Sigma-Aldrich
Ethyl alcohol, Pure, 200 proof, for molecular biology
Sigma-Aldrich
Ethyl alcohol, Pure, 200 proof, ACS reagent, ≥99.5%