Williams AB, Li L, Nguyen B, Brown P, Levis M, Small DFluvastatin inhibits FLT3 glycosylation in human and murine cells and prolongs survival of mice with FLT3/ITD leukemia. Blood 120: 3069-3079

Departments of Oncology and.
Blood (Impact Factor: 10.45). 08/2012; 120(15):3069-79. DOI: 10.1182/blood-2012-01-403493
Source: PubMed


FLT3 is frequently mutated in acute myeloid leukemia (AML), but resistance has limited the benefit of tyrosine kinase inhibitors (TKI). We demonstrate that statins can impair FLT3 glycosylation, thus leading to loss of surface expression and induction of cell death, as well as mitigation of TKI resistance. Immunofluorescence microscopy confirms a reduction in surface localization and an increase in intracellular FLT3/internal tandem duplication (ITD) accumulation. This aberrant localization was associated with increased STAT5 activation but inhibition of both MAPK and AKT phosphorylation. Growth inhibition studies indicate that FLT3/ITD-expressing cells were killed with an IC(50) within a range of 0.2-2μM fluvastatin. Several mechanisms of resistance could be circumvented by fluvastatin treatment. An increase in the IC(50) for inhibition of phosphorylated FLT3/ITD by lestaurtinib caused by exogenous FLT3 ligand, resistance to sorafenib caused by the D835Y or FLT3/ITD N676K mutations, and activation of the IL-3 compensatory pathway were all negated by fluvastatin treatment. Finally, fluvastatin treatment in vivo reduced engraftment of BaF3 FLT3/ITD cells in Balb/c mice. These results demonstrate that statins, a class of drugs already approved by the US Food and Drug Administration, might be repurposed for the management of FLT3 mutant acute myeloid leukemia cases either alone or in conjunction with FLT3 TKI.

4 Reads
  • Source
    • "Inhibition of STAT5 and STAT3 was also reported [73]. Fluvastatin was able to impair glycosylation of FLT3, one of the most frequently mutated genes in acute myeloid leukemia (AML), treated with tyrosine kinase inhibitors, thus leading to the loss of its surface expression and induction of cell death in vitro and in vivo [74]. Also a combination of statins and ionizing radiations has been reported successful in the suppression of lung tumors [75]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Statins are well known competitive inhibitors of hydroxymethylglutaryl-CoA reductase enzyme (HMG-CoA reductase), thus traditionally used as cholesterol-lowering agents. In recent years, more and more effects of statins have been revealed. Nowadays alterations of lipid metabolism have been increasingly recognized as a hallmark of cancer cells. Consequently, much attention has been directed towards the potential of statins as therapeutic agents in the oncological field. Accumulated in vitro and in vivo clinical evidence point out the role of statins in a variety of human malignancies, in regulating tumor cell growth and anti-tumor immune response. Herein, we summarize and discuss, in light of the most recent observations, the anti-tumor effects of statins, underpinning the detailed mode of action and looking for their true significance in cancer prevention and treatment, to determine if and in which case statin repositioning could be really justified for neoplastic diseases.
    Pharmacological Research 07/2014; 88. DOI:10.1016/j.phrs.2014.06.013 · 4.41 Impact Factor
  • Source
    • "In addition, mevalonate, and isoprenoid intermediates such as geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate (FPP) in the cholesterol synthesis pathway are also depleted after statin treatment [44]. Another intermediate, dolichol, an essential substrate for protein N-glycosylation, is also blocked by statins [45,46]. Considering that GBMs are highly proliferative taking up large quantities of cholesterol, potentially they may be vulnerable to statin treatment [47,48]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Glioblastoma (GBM) is a therapeutic challenge, associated with high mortality. More effective GBM therapeutic options are urgently needed. Hence, we screened a large multi-class drug panel comprising the NIH clinical collection (NCC) that includes 446 FDA-approved drugs, with the goal of identifying new GBM therapeutics for rapid entry into clinical trials for GBM. Screens using human GBM cell lines revealed 22 drugs with potent anti-GBM activity, including serotonergic blockers, cholesterol-lowering agents (statins), antineoplastics, anti-infective, anti-inflammatories, and hormonal modulators. We tested the 8 most potent drugs using patient-derived GBM cancer stem cell-like lines. Notably, the statins were active in vitro; they inhibited GBM cell proliferation and induced cellular autophagy. Moreover, the statins enhanced, by 40-70 fold, the pro-apoptotic activity of irinotecan, a topoisomerase 1 inhibitor currently used to treat a variety of cancers including GBM. Our data suggest that the mechanism of action of statins was prevention of multi-drug resistance protein MDR-1 glycosylation. This drug combination was synergistic in inhibiting tumor growth in vivo. Compared to animals treated with high dose irinotecan, the drug combination showed significantly less toxicity. Our data identifies a novel combination from among FDA-approved drugs. In addition, this combination is safer and well tolerated compared to single agent irinotecan. Our study newly identifies several FDA-approved compounds that may potentially be useful in GBM treatment. Our findings provide the basis for the rational combination of statins and topoisomerase inhibitors in GBM.
    Journal of Translational Medicine 01/2014; 12(1):13. DOI:10.1186/1479-5876-12-13 · 3.93 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Fms-like tyrosine kinase 3 (FLT3) performs a vital role in the pathogenesis of hematopoietic malignancies. Therefore in recent times, the focus of several studies was on use of FLT3 as a prognostic marker. The present study investigated the molecular characterization and incidence of FLT3 mutations in acute leukemia patients in Pakistan. A total of 55 patients were studied, of which 25 were suffering from acute lymphoblastic leukemia (ALL) and 30 were suffering from acute myeloid leukemia (AML). The polymerase chain reaction demonstrated FLT3/ ITD mutations in 1 (4%) of 25 ALL patients, a male with the L2 subtype. In AML cases the rate was 4 (13.3%) of 30, three males and one female. The AML-M4 subtype was found in three and the AML M2 subtype in the other. In the AML cases, a statistically significant (p=0.009) relationship was found between WBC (109/L) and FLT3/ ITD positivity. However, no significant relationship was found with other clinical parameters (p>0.05). In acute myeloid leukemia (AML) FLT3/ITD+ mutation was more prevalent in elderly patients 31-40 age groups, 21-30 and 51-60 age groups respectively. In acute lymphoblastic leukemia (ALL) statistically no significant relationship was found between clinical features and FLT3/ITD positivity (p>0.05). However, in acute lymphoblastic leukemia (ALL) FLT3/ITD+ mutation was more commonly found in age groups of 21-30.
    Asian Pacific journal of cancer prevention: APJCP 09/2012; 13(9):4581-5. DOI:10.7314/APJCP.2012.13.9.4581 · 2.51 Impact Factor
Show more

Similar Publications


4 Reads
Available from