Abstract 1232: 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. 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. Moreover, A-PACs possess a unique ether bond and have ortho-hydroxyl phenolic groups that have the potential to bind to iron, alter redox status, and other biological effects. We found that pre-treatment with antioxidants or holo-transferrin (iron-saturated transferrin) partially protected AML cells from A-PAC induced cell death (p AML-PDX mice (n = 15), were treated for 2.5 weeks via intraperitoneal injections of A-PACs (25 or 50 mg/kg dose every 3 days) or a vehicle control (PBS every 3 days). Mice were sacrificed and leukemia engraftment was evaluated using anti-human CD45 and CD33. Moreover, primary cells treated with A-PACs were assessed for effects on iron metabolism, oxidative stress, cytokine response, and survival pathways by gene expression analysis or flow cytometry. Administration of A-PACs to AML-PDX tumors reduced tumor burden. Mice that were treated with the vehicle control had engraftment of AML primary cells equivalent to 12.51% (95% CI: 4.9, 20.11; n = 5), whereas the mice treated with the 50 mg/kg and 25 mg/kg A-PACs showed a level of engraftment of 5.2% (95% CI: 1.5, 8.9; n = 5) and 5.4% (95% CI: 2.3, 8.5; n = 5), respectively. These results indicated more than a 50% reduction in engraftment, which was better or equal to the effects we observed in mice treated with high-dose cytarabine, a standard care drug. Moreover, no toxic effects were observed in the mice. It was also found that both cells and mice treated with A-PACs lead to the production of specific subset of cytokines. Global gene expression data showed consistent upregulation of some of these cytokines, and also upregulation of NF-κB and enzymes indicative of oxidative stress. The results indicate that A-PACs not only target primary AML cells in vitro, but are also effective in vivo by a potentially novel mechanism. Further elucidation of this mechanism may uncover new vulnerabilities of this disease. Citation Format: Laura M. Bystrom, Luis Andres Lara-Martinez, Bernardo Gomel, Burak Isal, Hongliang Zong, Sabrina Martinez, Catherine Neto, Stefano Rivella, Monica L. Guzman. A-type proanthocyanidins selectively target acute myeloid leukemia cells in vitro and in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1232.