Specific hydroxycinnamic acid derivatives synergize with the polyphenol carnosic acid against acute myeloid leukemia cells

Acute myeloid leukemia (AML) is an aggressive cancer of the blood characterized by unregulated proliferation of leukemic blasts. We previously showed that curcumin (CUR) and carnosic acid (CA) applied in combination synergistically induced massive Ca²⁺-dependent apoptosis in human AML cells in-vitro and in-vivo, without affecting normal hematopoietic cells. Here, we synthesized and screened a series of hydroxycinnamic acid derivatives (HCADs) - methyl hydroxycinnamates and hydroxybenzylideneacetones for the ability to cooperate with CA in producing antileukemic effects. We evaluated the structure-activity relationship of eight HCADs in combination with CA at non-cytotoxic concentrations of each compound and revealed that only methyl 4-hydroxycinnamate (KS-3) and methyl 3-methoxy-4-hydroxycinnamate (KS-6) could synergize with CA in inducing a rapid (4-8 h) apoptotic effect accompanied by the dramatic reduction in cell numbers and viability (72 h). Moreover, we observed an analogy between the antileukemic features of KS-3+CA and CUR+CA in that the apoptotic effect of both combinations was mediated by cytosolic Ca²⁺ accumulation and not via the induction of oxidative stress. Notably, KS-3+CA caused no cytotoxicity to normal peripheral blood mononuclear cells. Collectively, we identified combinations of phenolic compounds that kill AML cells through a CUR+CA-like mechanism. Interestingly, this effect strongly depends on both the position of the hydroxyl group on the aromatic ring and the modification of the carbonyl group in a HCAD. Such synergistically acting combinations may provide a prototype of novel safe and effective therapeutics for AML treatment, particularly, in elderly or unfit patients (Supported by the Israel Science Foundation grant 226/16).