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

ContextResistance 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.ObjectiveThis work investigated the effects of stachydrine in CML.Materials and methodsCML 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.ResultsStachydrine 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 conclusionsOur 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.