1. Academic Validation
  2. Pharmacological inhibition of JAK3 enhances the antitumor activity of imatinib in human chronic myeloid leukemia

Pharmacological inhibition of JAK3 enhances the antitumor activity of imatinib in human chronic myeloid leukemia

  • Eur J Pharmacol. 2018 Apr 15;825:28-33. doi: 10.1016/j.ejphar.2018.02.022.
Kenta Yagi 1 Akira Shimada 2 Toshiaki Sendo 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan; Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, Okayama, Japan.
  • 2 Department of Pediatric Hematology/Oncology, Okayama University Hospital, Dentistry, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan. Electronic address: pajj236e@okayama-u.ac.jp.
Abstract

Imatinib (IMA) is the standard treatment for CML; however, stopping IMA sometimes results in disease relapse, which suggests that leukemic stem cells (LSCs) remain in such patients, even after complete molecular remission has been achieved. Therefore, new strategies will be required to eradicate LSCs. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is part of the Bcr-Abl signaling network, and it is activated in CML, especially in LSCs. JAK2 is known to be associated with CML survival, but the role of JAK3 in CML remains unknown. The antitumor effects of IMA and a JAK3 Inhibitor, tofacitinib were examined using the MTT assay in K562 and KCL22. To investigate the mechanisms of action of IMA and the JAK inhibitors in CML cells, we examined Apoptosis, the cell cycle, and JAK-STAT signaling using flow cytometry, immunofluorescent microscopy, and Western blotting. The pharmacological inhibition of JAK3 by tofacitinib synergistically enhanced the antitumor effects of IMA in CML cells. Furthermore, the administration of IMA plus a JAK Inhibitor reduced the expression of stem cells markers, such as ABCG2 and ALDH1A1. Co-blocking JAK3 with IMA and a JAK3 Inhibitor might represent a new treatment strategy for eradicating LSCs and preventing CML relapses.

Keywords

BCR-ABL; Chronic myeloid leukemia; Imatinib; JAK inhibitor; Tofacitinib.

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