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Research ArticleExperimental Studies

CJ14939, a Novel JAK Inhibitor, Increases Oxaliplatin-induced Cell Death Through JAK/STAT Pathway in Colorectal Cancer

JUN KI HONG, DO YEON KIM, JAE-SIK SHIN, YEA SEONG RYU, JAI-HEE MOON, DONG-IN KOH, SEUL LEE, JINWOO LEE, WON JUN LEE, EUN YOUNG LEE, SOO-A JUNG, SEUNG CHAN KIM, HA NA YU, MI JIN KIM, SEUNG-WOO HONG, SANG SOO PARK, JOONYEE JUNG, SEUNG MI KIM, EUN HO KIM, HONG-RAE JEONG, JI HEE GONG, JIEUN KIM, TAE WON KIM and DONG-HOON JIN
Anticancer Research April 2022, 42 (4) 1813-1819; DOI: https://doi.org/10.21873/anticanres.15657
JUN KI HONG
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
2Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea;
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DO YEON KIM
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
2Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea;
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JAE-SIK SHIN
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
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YEA SEONG RYU
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
2Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea;
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JAI-HEE MOON
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
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DONG-IN KOH
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
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SEUL LEE
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
2Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea;
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JINWOO LEE
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
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WON JUN LEE
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
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EUN YOUNG LEE
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
2Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea;
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SOO-A JUNG
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
2Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea;
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SEUNG CHAN KIM
3CJ HealthCare R&D Center, Icheon-si, Republic of Korea;
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HA NA YU
3CJ HealthCare R&D Center, Icheon-si, Republic of Korea;
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MI JIN KIM
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
2Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea;
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SEUNG-WOO HONG
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
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SANG SOO PARK
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
2Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea;
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JOONYEE JUNG
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
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SEUNG MI KIM
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
2Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea;
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EUN HO KIM
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
2Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea;
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HONG-RAE JEONG
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
2Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea;
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JI HEE GONG
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
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JIEUN KIM
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
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TAE WON KIM
4Department of Oncology, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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  • For correspondence: twkimmd{at}amc.seoul.kr inno183{at}amc.seoul.kr
DONG-HOON JIN
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea;
2Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea;
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  • For correspondence: twkimmd{at}amc.seoul.kr inno183{at}amc.seoul.kr
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    Figure 1.

    CJ14939 inhibited cell growth and reduced the levels of phospho (p)-Janus kinase-1 (JAK1)/signal transducer and activator of transcription-3 (STAT3) in colon cancer cell lines. A: Different colorectal cancer cell lines were seeded in 96-well plates and treated with 360 nM-100 μM CJ14939 for 72 h. 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assays were then performed to determine the half-maximal inhibitory concentration (IC50) of CJ14939 for each cell line. B: HCT116 and SW620 cells were treated with increasing concentrations of CJ14939, then JAK1, STAT3 and their phosphorylated forms were analyzed by western blotting. CJ14939 inhibited phosphorylation in a concentration-dependent manner. γ-Tubulin was used as a loading control.

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    Figure 2.

    Synergistic effects were induced in HCT116 cells by CJ14939 and oxaliplatin combination. A: Upper panel: HCT116 cells were treated with CJ14939 (5,000 nM) with/without oxaliplatin (500 nM) for 48 h. Cell death was determined by trypan blue exclusion. Lower panel: After treatment, cells were harvested, lysed, and analyzed by western blot using antibodies against Janus kinase-1 (JAK1)/signal transducer and activator of transcription-3 (STAT3), phospho (p)-JAK1, p-STAT3, and cleaved caspase-3. γ-Tubulin was used as a loading control. B: Upper panel: Colony-forming assays were performed following treatment of HCT116 cells with CJ14939 (5,000 nM) with/without oxaliplatin (500 nM). After 14 days, cells were fixed, stained, and photographed. Representative photographs are shown. Lower panel: The graph shows that relative colony numbers were reduced most by the combination treatment. Data are the means±standard deviation of three separate experiments, performed in triplicate. Significantly different from the control at: *p<0.05, **p<0.01, and ***p<0.001.

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    Figure 3.

    CJ14939 and oxaliplatin combination treatment induced death in SW620 cells. A: Upper panel: SW620 cells were treated with CJ14939 (5,000 nM) with/without oxaliplatin (500 nM) for 48 h. Cell death was determined by trypan blue exclusion. Lower panel: After treatment, cells were harvested, lysed, and analyzed by western blot using antibodies against Janus kinase-1 (JAK1)/signal transducer and activator of transcription-3 (STAT3), phospho (p)-JAK1, p-STAT3, and cleaved caspase-3. γ-Tubulin was used as a loading control. B: Upper panel: Colony-forming assays were performed following treatment of SW620 cells with CJ14939 (5,000 nM) with/without oxaliplatin (500 nM). After 14 days, cells were fixed, stained, and photographed. Representative photographs are shown. Lower panel: The graph shows that relative colony numbers were reduced most by the combination treatment. Data are the means±standard deviation of three separate experiments, performed in triplicate. *Significantly different from the control at p<0.05.

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    Figure 4.

    CJ14939 enhanced the anticancer effect of oxaliplatin in a colorectal cancer cell-derived xenograft model. Balb-C nude mice were injected subcutaneously with SW620 cells. When tumor volumes reached 100 mm3, CJ14939 (50 mg/kg) was administered by oral gavage for 18 days, with/without oxaliplatin (6 mg/kg). Tumor volumes and body weights were measured every 3 days. At the end of the experiment, mice were sacrificed, and tumor sizes checked and photographed. A: Mean tumor volumes over the experimental course. B: Relative tumor size. C: Mean relative body weights were unchanged by CJ14939, oxaliplatin, and their combination. *Significantly different from the vehicle-treated control at p<0.05.

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April 2022
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CJ14939, a Novel JAK Inhibitor, Increases Oxaliplatin-induced Cell Death Through JAK/STAT Pathway in Colorectal Cancer
JUN KI HONG, DO YEON KIM, JAE-SIK SHIN, YEA SEONG RYU, JAI-HEE MOON, DONG-IN KOH, SEUL LEE, JINWOO LEE, WON JUN LEE, EUN YOUNG LEE, SOO-A JUNG, SEUNG CHAN KIM, HA NA YU, MI JIN KIM, SEUNG-WOO HONG, SANG SOO PARK, JOONYEE JUNG, SEUNG MI KIM, EUN HO KIM, HONG-RAE JEONG, JI HEE GONG, JIEUN KIM, TAE WON KIM, DONG-HOON JIN
Anticancer Research Apr 2022, 42 (4) 1813-1819; DOI: 10.21873/anticanres.15657

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CJ14939, a Novel JAK Inhibitor, Increases Oxaliplatin-induced Cell Death Through JAK/STAT Pathway in Colorectal Cancer
JUN KI HONG, DO YEON KIM, JAE-SIK SHIN, YEA SEONG RYU, JAI-HEE MOON, DONG-IN KOH, SEUL LEE, JINWOO LEE, WON JUN LEE, EUN YOUNG LEE, SOO-A JUNG, SEUNG CHAN KIM, HA NA YU, MI JIN KIM, SEUNG-WOO HONG, SANG SOO PARK, JOONYEE JUNG, SEUNG MI KIM, EUN HO KIM, HONG-RAE JEONG, JI HEE GONG, JIEUN KIM, TAE WON KIM, DONG-HOON JIN
Anticancer Research Apr 2022, 42 (4) 1813-1819; DOI: 10.21873/anticanres.15657
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Keywords

  • JAK/STAT
  • CJ14939
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  • Colorectal cancer
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