• Biomolecules & Therapeutics
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• v.30 no.6
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• pp.553-561
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• 2022

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.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1994.04a
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• pp.237-237
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• 1994

혈압강하작용은 oxyindole계 분획에서 제일 강력하였으며, 다음이 hetero-yohimbine계 분획이며, 극성 alkaloid계 분획이 제일 약하였다. 특히, oxyindole계 및 hetero-yohimbine계는 epinephrine의 승압작용을 길항하지 아니하였으므로 이들의 혈압강하작용은 혈관의 수축작용을 길항하는 기전과는 무관함을 알 수 있었다. 반면에 화학적으로는 hetero-yohimbine계 분획에서 hirsuteine, corynantheine 및 hirsutine을 분리하였고 극성 alkaloid 분획에서는 3$\alpha$-dihydrocadambine을 분리 동정하였으며 전자 3종의 alkaloid는 열(10$0^{\circ}C$)에 안정하고 후자는 불안정함을 확인하였다.