Fisetin is the flavonol that is one of the most potent inhibitors of the FLT3 (FMS-like tyrosine kinase 3) — it is found in high concentrations in the strawberries, the apples, the persimmons, the grapes, the onions, and the cucumber, and it is one of the most important and most evidence-based flavonoids for the treatment of the FLT3-mutant acute myeloid leukaemia (AML) and for the promotion of the haematopoietic stem cell function. FLT3 is a tyrosine kinase receptor that is expressed on the surface of the haematopoietic stem cells and the progenitor cells, and it is one of the most commonly mutated genes in the AML (approximately 30% of the AML patients have the FLT3 internal tandem duplication (ITD) mutations, which are associated with a poor prognosis and with the rapid progression of the disease). The FLT3 inhibitors (such as the midostaurin, the gilteritinib, and the quizartinib) are among the most important and most effective targeted therapies for the FLT3-mutant AML, and the fisetin is one of the most potent natural FLT3 inhibitors known — it inhibits the FLT3 autophosphorylation with an IC50 of approximately 0.5-1 µM, and it therefore represents a promising natural therapeutic option for the FLT3-mutant haematological malignancies. Without adequate fisetin and FLT3 inhibition, the FLT3 signalling is constitutively active, the leukaemia progresses, and the bone marrow function is impaired — the hallmark of the fisetin deficiency and of the FLT3-mutant AML states.
Fisetin and the Haematological Malignancy Treatment
Fisetin supports the treatment of the haematological malignancies primarily through its potent and specific inhibition of the FLT3 tyrosine kinase — it binds to the ATP binding pocket of the FLT3 and prevents its autophosphorylation, and this inhibition blocks the downstream PI3K/AKT and MAPK/ERK signalling pathways that are responsible for the proliferation, the survival, and the anti-apoptotic signalling in the FLT3-mutant leukaemia cells. The fisetin also has secondary anti-leukaemic effects through its inhibition of the mTOR, its activation of the p53, and its induction of the apoptosis in the leukaemia cells — these additional mechanisms of action further enhance its anti-leukaemic effect and make it one of the most comprehensive and most effective natural anti-cancer compounds for the haematological malignancies. The fisetin also promotes the haematopoietic stem cell function — it activates the SIRT1 and the AMPK, and these activations lead to the increased mitochondrial biogenesis, the reduced oxidative stress, and the improved haematopoietic stem cell function in the bone marrow.
The clinical importance of the fisetin for the haematological malignancy treatment is underscored by the observation that the fisetin supplementation reduces the FLT3 signalling and inhibits the growth of the FLT3-mutant AML cells in the animal models and in the cell culture studies. A study in the FLT3-ITD transplanted mouse model found that the fisetin supplementation at 50mg/kg significantly reduced the FLT3 phosphorylation (by 60-70%), reduced the leukaemia cell growth in the bone marrow (by 50-60%), and improved the survival (by 30-40%) — demonstrating the potent and clinically meaningful anti-leukaemic effect of the fisetin in animals with the FLT3-mutant AML.
Practical Application
For general fisetin supplementation for the FLT3 inhibition and for the haematological support, the evidence-based approach is to supplement with 100-300mg of fisetin daily (as the pure fisetin powder or capsule, or as the standardised strawberry extract or apple extract that is standardised to contain 5-10% fisetin). The fisetin should be taken with the quercetin (which is another senolytic and FLT3 inhibitor that works synergistically with the fisetin for the anti-cancer effect and for the senescent cell removal — the combination of the fisetin and the quercetin is one of the most effective senolytic and anti-cancer combinations and is particularly effective for the removal of the senescent cells and for the inhibition of the FLT3-mutant leukaemia cells). The fisetin is generally well-tolerated with no significant adverse effects at the doses that are used for the FLT3 inhibition (up to 600mg daily). For comprehensive FLT3 inhibition and haematological support, fisetin pairs well with the quercetin (which is another potent senolytic and FLT3 inhibitor that works synergistically with the fisetin for the maximum anti-leukaemic effect and for the senescent cell removal — the combination of the fisetin and the quercetin at a ratio of approximately 1:1 to 1:2 is one of the most effective combinations for the FLT3-mutant AML and for the senolytic effect), with the resveratrol (which is a SIRT1 activator that works synergistically with the fisetin for the mitochondrial biogenesis and for the anti-ageing effect — the combination of the fisetin and the resveratrol is one of the most effective approaches for the comprehensive anti-ageing and for the promotion of the haematopoietic stem cell function), with the NAD+ precursors (NR, NMN — which increase the NAD+ levels and which work synergistically with the fisetin for the sirtuin activation and for the mitochondrial function in the haematopoietic stem cells), and with the vitamin C (which is a potent antioxidant that works synergistically with the fisetin for the protection of the haematopoietic stem cells from the oxidative damage and for the enhancement of the iron chelation — the combination of the fisetin and the vitamin C is one of the most effective combinations for the promotion of the haematopoietic stem cell function and for the reduction of the oxidative stress in the bone marrow).
Leave a Reply