| Autor: |
Xiang W; Department of Haematology, Singapore General Hospital, National Cancer Centre Singapore, Singapore 169608, Singapore., Sng C; Department of Haematology, Singapore General Hospital, National Cancer Centre Singapore, Singapore 169608, Singapore., Lam YH; Department of Haematology, Singapore General Hospital, National Cancer Centre Singapore, Singapore 169608, Singapore., Kok ZH; Department of Haematology, Singapore General Hospital, National Cancer Centre Singapore, Singapore 169608, Singapore., Linn YC; Department of Haematology, Singapore General Hospital, National Cancer Centre Singapore, Singapore 169608, Singapore., Neo SY; Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore 117543, Singapore., Siew YY; Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore 117543, Singapore., Singh D; Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore 117543, Singapore., Koh HL; Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Singapore 117543, Singapore., Chuah C; Department of Haematology, Singapore General Hospital, National Cancer Centre Singapore, Singapore 169608, Singapore.; Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore 169857, Singapore. |
| Abstrakt: |
While BCR::ABL1 tyrosine kinase inhibitors have transformed the treatment paradigm for chronic myeloid leukemia (CML), disease progression and treatment resistance due to BCR::ABL1-dependent and BCR::ABL1-independent mechanisms remain a therapeutic challenge. Natural compounds derived from plants have significantly contributed to cancer pharmacotherapy. This study investigated the efficacy of an active component of Leea indica , a local medicinal plant, in CML. Using high-performance liquid chromatography-electrospray ionization-mass spectrometry, a chemical constituent from L. indica extract was isolated and identified as gallic acid. Commercially obtained gallic acid was used as a chemical standard. Gallic acid from L. indica inhibited proliferation and induced apoptosis in CML cell lines, as did the chemical standard. Furthermore, gallic acid induced apoptosis and decreased the colony formation of primary CML CD34 + cells. The combination of isolated gallic acid or its chemical standard with BCR::ABL1 tyrosine kinase inhibitors resulted in a significantly greater inhibition of colony formation and cell growth compared to a single drug alone. Mechanistically, CML cells treated with gallic acid exhibited the disruption of multiple oncogenic pathways including ERK/MAPK, FLT3 and JAK/STAT, as well as impaired mitochondrial respiration. Rescue studies showed that gallic acid is significantly less effective in inducing apoptosis in mitochondrial respiration-deficient ρ 0 cells compared to wildtype cells, suggesting that the action of gallic acid is largely through the inhibition of mitochondrial respiration. Our findings highlight the therapeutic potential of L. indica in CML and suggest that gallic acid may be a promising lead chemical constituent for further development for CML treatment. |
