A-type proanthocyanidins selectively target acute myeloid leukemia cells in vitro and in vivo

Acute myelogenous leukemia (AML) is often a fatal disease where after strong induction therapy most patients relapse and die [1, 2]. A-type proanthocyanidins (A-PACs) are a unique class of compounds found in cranberries (Vaccinium macrocarpon Ait.) that we have found to be effective against several leukemia cell lines and primary AML samples in vitro. An A-PAC fraction, isolated from the cranberry powder CystiCran®40 (Naturex; Avignon, France), was found to selectively ablate leukemia stem and progenitor cells, with minimal effects on normal hematopoetic stem cells. Furthermore, AML engraftment of cells treated ex vivo with 62.5 µg/ml A-PACs was decreased compared to controls (90.6%, n = 3, P < 0.001), whereas normal CD34+ cells retained engraftment capability in immunodeficient mice. Administration of A-PACs to AML-patient derived xenotransplants (PDX) significantly reduced tumor burden in mice. Specifically, mice treated with 50 mg/kg and 25 mg/kg of A-PACs exhibited a 56.8% (n = 5) and 58.4% (n = 5) reduction in tumor burden, respectively, compared to the mice treated with the vehicle control (P < 0.05). These effects were better or equal to those observed in mice treated with high-dose cytarabine, a standard care drug. Moreover, no toxic effects were observed in the mice. These results indicate that A-PACs not only target primary AML cells in vitro, but are also effective in vivo by potentially a novel mechanism that may also target stem cells. Further elucidation of this mechanism may uncover new vulnerabilities of AML.