PUBLICATION
A novel FTY720 analogue targets SET-PP2A interaction and inhibits growth of acute myeloid leukemia cells without inducing cardiac toxicity
- Authors
- Vicente, C., Arriazu, E., Martínez-Balsalobre, E., Peris, I., Marcotegui, N., García-Ramírez, P., Pippa, R., Rabal, O., Oyarzábal, J., Guruceaga, E., Prósper, F., Mateos, M.C., Cayuela, M.L., Odero, M.D.
- ID
- ZDB-PUB-191011-11
- Date
- 2019
- Source
- Cancer letters 468: 1-13 (Journal)
- Registered Authors
- Keywords
- Acute myeloid leukemia, FTY720, PP2A, SET, cardiac toxicity
- MeSH Terms
-
- Adult
- Aged
- Aged, 80 and over
- Animals
- Apoptosis/drug effects
- Cardiotoxicity/etiology
- Cardiotoxicity/prevention & control*
- Cell Line, Tumor
- Cell Proliferation/drug effects
- DNA-Binding Proteins/metabolism*
- Female
- Fingolimod Hydrochloride/administration & dosage*
- Fingolimod Hydrochloride/analogs & derivatives
- Fingolimod Hydrochloride/toxicity
- Heart Rate/drug effects
- Histone Chaperones/metabolism*
- Humans
- Leukemia, Myeloid, Acute/drug therapy*
- Leukemia, Myeloid, Acute/pathology
- Male
- Middle Aged
- Protein Binding/drug effects
- Protein Phosphatase 2/metabolism*
- Toxicity Tests, Acute
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 31593801 Full text @ Cancer Lett.
Citation
Vicente, C., Arriazu, E., Martínez-Balsalobre, E., Peris, I., Marcotegui, N., García-Ramírez, P., Pippa, R., Rabal, O., Oyarzábal, J., Guruceaga, E., Prósper, F., Mateos, M.C., Cayuela, M.L., Odero, M.D. (2019) A novel FTY720 analogue targets SET-PP2A interaction and inhibits growth of acute myeloid leukemia cells without inducing cardiac toxicity. Cancer letters. 468:1-13.
Abstract
Acute myeloid leukemia (AML) is an aggressive disease associated with very poor prognosis. Most patients are older than 60 years, and in this group only 5-15% of cases survive over 5 years. Therefore, it is urgent to develop more effective targeted therapies. Inactivation of protein phosphatase 2A (PP2A) is a recurrent event in AML, and overexpression of its endogenous inhibitor SET is detected in ∼30% of patients. The PP2A activating drug FTY720 has potent anti-leukemic effects; nevertheless, FTY720 induces cardiotoxicity at the anti-neoplastic dose. Here, we have developed a series of non-phosphorylable FTY720 analogues as a new therapeutic strategy for AML. Our results show that the lead compound CM-1231 re-activates PP2A by targeting SET-PP2A interaction, inhibiting cell proliferation and promoting apoptosis in AML cell lines and primary patient samples. Notably, CM-1231 did not induce cardiac toxicity, unlike FTY720, in zebrafish models, and reduced the invasion and aggressiveness of AML cells more than FTY720 in zebrafish xenograft models. In conclusion, CM-1231 is safer and more effective than FTY720; therefore, this compound could represent a novel and promising approach for treating AML patients with SET overexpression.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping