Pyrimethamine as a Potent and Selective Inhibitor of Acute Myeloid Leukemia Identified by High-throughput Drug Screening.
Hematopoietic stem and progenitor cell differentiation are blocked in acute myeloid leukemia (AML) resulting in cytopenias and a high risk of death. Most patients with AML become resistant to treatment due to lack of effective cytotoxic and differentiation promoting compounds. High MN1 expression confers poor prognosis to AML patients and induces resistance to cytarabine and alltrans-retinoic acid (ATRA) induced differentiation. Using a high-throughput drug screening, we identified the dihydrofolate reductase (DHFR) antagonist pyrimethamine to be a potent inducer of apoptosis and differentiation in several murine and human leukemia cell lines. Oral pyrimethamine treatment was effective in two xenograft mouse models and specifically targeted leukemic cells in human AML cell lines and primary patient cells, while CD34+ cells from healthy donors were unaffected. The antileukemic effects of PMT could be partially rescued by excess folic acid, suggesting an oncogenic function of folate metabolism in AML. Thus, our study identifies pyrimethamine as a candidate drug that should be further evaluated in AML treatment.
Amit
A
Sharma
Nidhi
N
Jyotsana
Courteney K
CK
Lai
Anuhar
A
Chaturvedi
Razif
R
Gabdoulline
Kerstin
K
Görlich
Cecilia
C
Murphy
Jan E
JE
Blanchard
Arnold
A
Ganser
Eric
E
Brown
John A
JA
Hassell
R Keith
RK
Humphries
Michael
M
Morgan
Department of Hematology, Hemostasis, Oncology and Stem cell Transplantation, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. heuser.michael@mh-hannover.de.
Michael
M
Heuser
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D005493:Folic Acid Antagonists / Q000494:pharmacology; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D011739:Pyrimethamine / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D011739:Pyrimethamine