Figure 1. The researchers utilized Western blot and lentiviral transduction methods to analyze CREB expression in Ba/F3 cells, demonstrating its role in inhibiting leukemia progression and improving survival. (Cheng JC, et al., 2008)
Stachydrine inhibits receptor tyrosine kinases-mediated signalling in CML cells.
Stachydrine is effective and selective against blast phase chronic myeloid leukaemia through inhibition of multiple receptor tyrosine kinases
Paper
2022
Pharmaceutical Biology |
DOI
Background
This study investigated stachydrine, a bioactive compound from Leonurus japonicus, against chronic myeloid leukaemia (CML). Stachydrine inhibited proliferation and induced apoptosis in imatinib-sensitive and -resistant CML cell lines, including Ba/F3 T315I, and reduced colony formation and self-renewal in blast phase CML CD34+ stem/progenitor cells. It showed selectivity for leukaemic over normal cord blood cells. Stachydrine synergized with BCR-ABL tyrosine kinase inhibitors and decreased phosphorylation of multiple receptor tyrosine kinases, including BCR-ABL, Src, c-Kit and Stat3.
Key Findings
Stachydrine inhibited proliferation of K562, KCL22, LAMA84, KU812, Ba/F3 WT and Ba/F3 T315I cells with IC50 values 22–141 µM and induced apoptosis, without cross-resistance in imatinib-resistant T315I cells. It significantly suppressed colony formation and serial replating of primary BP-CML CD34+ cells and induced apoptosis more in BP-CML than normal cord blood CD34+ cells. Combination with imatinib, dasatinib or ponatinib yielded synergy (CI<1) in CML cell lines and enhanced apoptosis, reduced colony formation and self-renewal in BP-CML CD34+ cells, including T315I, compared with TKI alone, while not further affecting normal CB CD34+ cells. Mechanistically, stachydrine decreased phosphorylation of BCR-ABL, Crkl, Src, c-Kit and Stat3 but not total protein levels, indicating inhibition of multiple receptor tyrosine kinase pathways. NF-κB inhibition occurred only at higher concentrations and was not responsible for anti-CML activity. These results support stachydrine as a selective anti-leukaemia agent and TKI-synergizing candidate for BP-CML.
Contribution
Creative Biogene Biotechnology provided the murine CML cell lines Ba/F3-BCR-ABL (Ba/F3 WT) and Ba/F3-BCR-ABL-T315I (Ba/F3 T315I). These reagents enabled the authors to test stachydrine efficacy against wild-type and imatinib-resistant BCR-ABL T315I CML cells, supporting key mechanistic and synergy experiments.
This study investigated stachydrine, a bioactive compound from Leonurus japonicus, against chronic myeloid leukaemia (CML). Stachydrine inhibited proliferation and induced apoptosis in imatinib-sensitive and -resistant CML cell lines, including Ba/F3 T315I, and reduced colony formation and self-renewal in blast phase CML CD34+ stem/progenitor cells. It showed selectivity for leukaemic over normal cord blood cells. Stachydrine synergized with BCR-ABL tyrosine kinase inhibitors and decreased phosphorylation of multiple receptor tyrosine kinases, including BCR-ABL, Src, c-Kit and Stat3.
Key Findings
Stachydrine inhibited proliferation of K562, KCL22, LAMA84, KU812, Ba/F3 WT and Ba/F3 T315I cells with IC50 values 22–141 µM and induced apoptosis, without cross-resistance in imatinib-resistant T315I cells. It significantly suppressed colony formation and serial replating of primary BP-CML CD34+ cells and induced apoptosis more in BP-CML than normal cord blood CD34+ cells. Combination with imatinib, dasatinib or ponatinib yielded synergy (CI<1) in CML cell lines and enhanced apoptosis, reduced colony formation and self-renewal in BP-CML CD34+ cells, including T315I, compared with TKI alone, while not further affecting normal CB CD34+ cells. Mechanistically, stachydrine decreased phosphorylation of BCR-ABL, Crkl, Src, c-Kit and Stat3 but not total protein levels, indicating inhibition of multiple receptor tyrosine kinase pathways. NF-κB inhibition occurred only at higher concentrations and was not responsible for anti-CML activity. These results support stachydrine as a selective anti-leukaemia agent and TKI-synergizing candidate for BP-CML.
Contribution
Creative Biogene Biotechnology provided the murine CML cell lines Ba/F3-BCR-ABL (Ba/F3 WT) and Ba/F3-BCR-ABL-T315I (Ba/F3 T315I). These reagents enabled the authors to test stachydrine efficacy against wild-type and imatinib-resistant BCR-ABL T315I CML cells, supporting key mechanistic and synergy experiments.