Stachydrine is effective and selective against blast phase chronic myeloid leukaemia through inhibition of multiple receptor tyrosine kinases.

Abstract

CONTEXT:

Resistance to BCR-ABL tyrosine kinase inhibitor (TKI) is the cause of treatment failure in blast phase chronic myeloid leukaemia (BP-CML). Agents that act synergistically with BCR-ABL TKI are required to improve response.

OBJECTIVE:

This work investigated the effects of stachydrine in CML.

MATERIALS AND METHODS:

CML cells were treated with control or stachydrine at 20, 40 and 80 µM. Proliferation and apoptosis were examined after 72 h treatment. Combination studies were performed in four groups: control, TKI, stachydrine and the combination of stachydrine and TKI. Immunoblotting analysis was performed in CML cells after 24 h treatment.

RESULTS:

Stachydrine inhibited K562 (IC50 61 µM), KCL22 (IC50 141 µM), LAMA84 (IC50 86 µM), Ba/F3 T315I (IC50 26 µM), Ba/F3 WT (IC50 22 µM) and KU812 (IC50 35 µM) proliferation, and induced apoptosis in these CML cell lines. Stachydrine significantly induced apoptosis, inhibited colony formation and self-renewal in BP-CML CD34+ cells. The combination index of stachydrine and TKI combination was <1. Compared to TKI alone, the combination of stachydrine and TKI significantly induced more apoptosis and decreased colony formation in BP-CML CD34+ cells. Stachydrine decreased phosphorylation levels of multiple receptor tyrosine kinases in CML cells.

DISCUSSION AND CONCLUSIONS:

Our study is the first to demonstrate (1) the anticancer activity of stachydrine on primary patient cancer cells; (2) the inhibitory effects of stachydrine on cancer stem cells; (3) the synergism between stachydrine and other anticancer drugs.

• Authors: Ruixin Gu, Wei Zhang, Dandan Xu
• Journal: Pharmaceutical biology (Pharm Biol) Vol. 60 Issue 1 Pg. 700-707 (Dec 2022) ISSN: 1744-5116 [Electronic] England
• PMID: 35348419 (Publication Type: Journal Article)

Chemical References

• Tyrosine
• Proline
• stachydrine

Topics

• Blast Crisis (drug therapy)
• Cell Line, Tumor
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, metabolism)
• Proline (analogs & derivatives)
• Tyrosine (therapeutic use)