Abstract
Acute myeloid leukemia (AML) is a malignant hematopoietic disease with poor prognosis for most patients. Conventional chemotherapy has been the standard treatment approach for AML in the past 40 years with limited success. Although, several targeted drugs were recently approved, their long-term impact on survival of patients with AML is yet to be determined. Thus, it is still necessary to develop alternative therapeutic approaches for this disease. We have previously shown a marked synergistic anti-leukemic effect of two polyphenols, curcumin (CUR) and carnosic acid (CA), on AML cells in-vitro and in-vivo. In this study, we identified another phenolic compound, methyl 4-hydroxycinnamate (MHC), which among several tested phytochemicals could uniquely cooperate with CA in killing AML cells, but not normal peripheral blood mononuclear cells. Notably, our data revealed striking phenotypical and mechanistic similarities in the apoptotic effects of MHC+CA and CUR+CA on AML cells. Yet, we show that MHC is a non-fluorescent molecule, which is an important technical advantage over CUR that can interfere in various fluorescence-based assays. Collectively, we demonstrated for the first time the antileukemic activity of MHC in combination with another phenolic compound. This type of synergistically acting combinations may represent prototypes for novel antileukemic therapy.
Highlights
Acute myeloid leukemia (AML) is a devastating hematological malignancy characterized by poor survival, for older patients, and high relapse rate
We first performed pilot experiments in HL60 cells to determine the maximal non-cytotoxic concentrations (MNC) of several phytochemicals (Supplemental Figure S1) for further screening of these compounds for the ability to cooperate with carnosic acid (CA) in inducing AML cell death
Besides CUR, only methyl 4-hydroxycinnamate (MHC) could strongly synergize with CA in reducing viable cell numbers, as determined in KG-1a, HL60, and U937 AML cells (Figure 1A and Supplemental Figures S2A,D)
Summary
Acute myeloid leukemia (AML) is a devastating hematological malignancy characterized by poor survival, for older patients, and high relapse rate. We have previously shown that CUR combined with another polyphenol, carnosic acid (CA), at noncytotoxic concentrations of each agent synergistically and selectively killed AML cells by inducing massive apoptosis both in vitro and in vivo (Pesakhov et al, 2010, 2016). This synergistic effect was not accompanied by cellular stress and was mediated by cytosolic calcium ([Ca2+]cyt) overload (Pesakhov et al, 2010, 2016)
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