gnetin-c and Leukemia--Myeloid--Acute

Acute myelogenous leukemia (AML) is a clinically heterogeneous disease that is frequently associated with relapse and a poor prognosis. Among the various subtypes, AML with the monosomal karyotype (AML-MK) has an extremely unfavorable prognosis. We performed screening to identify antitumor compounds that are capable of inducing apoptosis in primary leukemia cells harboring the AML-MK karyotype and identified a naturally occurring stilbene, Gnetin-C, with potent anti-tumor activities against AML cells from patients with various cytogenetic abnormalities, including patients with the AML-MK karyotype. Gnetin-C simultaneously inhibits the ERK1/2 and the AKT/mTOR pathways, two signals that are essential for the survival of leukemia cells. A combination of Gnetin-C with low doses of chemotherapeutic drugs led to synergistic anti-tumor effects against AML cells. In an immunodeficient mouse model of human leukemia, Gnetin-C attenuated the formation of leukemia, depleted leukemia cells and improved survival. These findings suggest that Gnetin-C has antitumor activities in AML and supports the therapeutic potential of blocking two different pathways in AML.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzofurans; Cell Cycle; Dose-Response Relationship, Drug; Drug Synergism; Extracellular Signal-Regulated MAP Kinases; HL-60 Cells; Humans; Karyotype; Leukemia, Myeloid, Acute; Mice, Inbred NOD; Mice, Knockout; Primary Cell Culture; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Stilbenes; Time Factors; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; U937 Cells; Xenograft Model Antitumor Assays