Biomol Ther.
2022 Nov;30(6):553-561. 10.4062/biomolther.2022.023.
Growth Inhibitory and Pro-Apoptotic Effects of Hirsuteine in Chronic Myeloid Leukemia Cells through Targeting Sphingosine Kinase 1
- Affiliations
-
- 1Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
- 2School and Hospital of Stomatology, Tianjin Medical University, Tianjin 300070, China
- 3State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
- 4Department of Clinical Laboratory, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin 300060, China
- KMID: 2534705
- DOI: http://doi.org/10.4062/biomolther.2022.023
Abstract
- Chronic myeloid leukemia (CML) is a slowly progressing hematopoietic cell disorder. Sphingosine kinase 1 (SPHK1) plays established roles in tumor initiation, progression, and chemotherapy resistance in a wide range of cancers, including leukemia. However, small-molecule inhibitors targeting SPHK1 in CML still need to be developed. This study revealed the role of SPHK1 in CML and investigated the potential anti-leukemic activity of hirsuteine (HST), an indole alkaloid obtained from the oriental plant Uncaria rhynchophylla, in CML cells. These results suggest that SPHK1 is highly expressed in CML cells and that overexpression of SPHK1 represents poor clinical outcomes in CML patients. HST exposure led to G2/M phase arrest, cellular apoptosis, and downregulation of Cyclin B1 and CDC2 and cleavage of Caspase 3 and PARP in CML cells. HST shifted sphingolipid rheostat from sphingosine 1-phosphate (S1P) towards the ceramide coupled with a marked inhibition of SPHK1. Mechanistically, HST significantly blocked SPHK1/S1P/S1PR1 and BCR-ABL/PI3K/Akt pathways. In addition, HST can be docked with residues of SPHK1 and shifts the SPHK1 melting curve, indicating the potential protein-ligand interactions between SPHK1 and HST in both CML cells. SPHK1 overexpression impaired apoptosis and proliferation of CML cells induced by HST alone. These results suggest that HST, which may serve as a novel and specific SPHK1 inhibitor, exerts anti-leukemic activity by inhibiting the SPHK1/S1P/ S1PR1 and BCR-ABL/PI3K/Akt pathways in CML cells, thus conferring HST as a promising anti-leukemic drug for CML therapy in the future.
- Full Text Links
-
- Actions
-
Cited
- CITED
-
- Close
- Share
-
- Similar articles
-
- Protective Effects of K6PC-5, A Sphingosine Kinase Activator, Against 1-methyl-4-phenylpyridinium-induced Dopaminergic Neuronal Cell Death
- Sphingosine 1-Phosphate Triggers Apoptotic Signal for B16 Melanoma Cells via ERK and Caspase Activation
- Treatment-free remission after discontinuation of imatinib, dasatinib, and nilotinib in patients with chronic myeloid leukemia
- Targeting the CXCL12/CXCR4 axis in acute myeloid leukemia: from bench to bedside
- Assessment of the Cytotoxic and Apoptotic Effects of Chaetominine in a Human Leukemia Cell Line
