INNO-406 inhibits the growth of chronic myeloid leukemia and promotes its apoptosis via targeting PTEN
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RESEARCH ARTICLE
INNO‑406 inhibits the growth of chronic myeloid leukemia and promotes its apoptosis via targeting PTEN Jiandong Sun1 · Yilin Wang1 · Lirong Sun1 Received: 11 May 2020 / Accepted: 7 August 2020 © Japan Human Cell Society 2020
Abstract Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm. INNO-406 is a novel tyrosine kinase inhibitor (TKI) that possess specific Lyn kinase inhibitory activity with no or limited activity against other sarcoma (Src) family member kinases. The present study aimed to confirm the anti-tumor effect of INNO-406 on CML cells, and elucidate the underlying molecular mechanism. CML cells were treated by INNO-406 at the concentration of 5, 25, 50, 100 μM at the indicated time. Cell proliferation was measured by MTT. Cell apoptosis were detected by Western blot and flow cytometry, respectively. As suggested by the findings, INNO-406 significantly inhibited the proliferation and induced apoptosis of CML cells. In addition, INNO-406 promoted the expression level of PTEN. Rescue experiment revealed that PTEN knockdown reversed the effect of INNO-406 which indicated the correlation between INNO-406 and PTEN. Further study determined that PTEN inhibited the phosphorylation of AKT and 4EBP1 and subsequently altered the expression of apoptotic proteins including bax, cytoplasmic cytochrome c (cyto-c), cleaved caspase3 and bcl-2. In vivo study further confirmed that INNO-406 inhibited the growth of CML cells by targeting PTEN. Based on the above findings, this work extended our understanding of INNO-406 in the therapy of CML and its molecular mechanism. Keywords INNO-406 · Chronic myeloid leukemia · Proliferation · Apoptosis · PTEN Abbreviations CML Chronic myeloid leukemia ABL Abelson murine leukemia BCR Breakpoint cluster region TKIs Tyrosine kinase inhibitors BCA Bicinchoninic acid assay SDS-PAGE Sodium dodecyl sulfate–polyacrylamide gel electrophoresis ECL Enhanced chemiluminescence OD Optical densities
This article has been posted as a preprint on Research Square Preprint Platform. (https://www.researchsquare.com/article/rs16330/v1). * Lirong Sun [email protected] 1
Department of Pediatric Hematology, Affiliated Hospital of Qingdao University, Huangdao District, 1677 Wutaishan Road, Qingdao 266555, Shandong, China
Introduction Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the formation of the fusion gene consist of Abelson murine leukemia (ABL) gene and breakpoint cluster region (BCR) which encodes a constitutively active Bcr-Abl tyrosine kinase [1–3]. Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 tyrosine kinase have made great development in the treatment of CML over the decades which improved 10 year overall survival from approximately 20% to 80–90% [4, 5]. However, about 25% of the children and half of the adults are still insensitive to chemotherapy or will relapse. Moreover, side effects, such as skin toxicity and allergic reaction are still clinical challenges which limited application of TKI [6,
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