Abstract
Plant phenolic compounds have shown the ability to cooperate with one another at low doses in producing enhanced anticancer effects. This may overcome the limitations (e.g., poor bioavailability and high-dose toxicity) in developing these agents as cancer medicines. We have previously reported that the hydroxycinnamic acid derivative (HCAD) methyl-4-hydroxycinnamate and the phenolic diterpene carnosic acid (CA) can synergistically induce massive calcium-dependent apoptosis in acute myeloid leukemia (AML) at non-cytotoxic concentrations of each agent. Here, we explored the chemical nature of the synergy between HCADs and either CA, in inducing cytotoxicity, or the active metabolite of vitamin D (calcitriol), in enhancing the differentiation of AML cells. This was done by determining the structure–activity relationship of a series of hydroxycinnamic acids and their derivatives (methyl hydroxycinnamates and hydroxybenzylideneacetones) in combination with CA or calcitriol. The HCAD/CA synergy required the following critical structural elements of an HCAD molecule: (a) the para-hydroxyl on the phenolic ring, (b) the carbon C7–C8 double bond, and (c) the methyl-esterified carboxyl. Thus, the only HCADs capable of synergizing with CA were found to be methyl-4-hydroxycinnamate and methyl ferulate, which also most potently enhanced calcitriol-induced cell differentiation. Notably, the C7–C8 double bond was the major requirement for this HCAD/calcitriol cooperation. Our findings may contribute to the rational design of novel synergistically acting AML drugs based on prototype combinations of HCADs with other agents studied here.
Highlights
The utilization of small-molecule drugs of plant origin in the chemotherapy of solid malignancies and lymphoid leukemias illustrates the importance of phytochemicals for clinical oncology [1]
The results demonstrated that the para position of the hydroxyl group on the phenolic ring, the C7–C8 double bond and the methyl-esterified carboxyl group, as in MHC, are critical for the capacity of an hydroxycinnamic acid derivative (HCAD) molecule to synergize with carnosic acid (CA)
In order to determine the structural requirements of HCADs for the cooperation with CA, we synthesized two series of coumaric and ferulic acid derivatives: methyl hydroxycinnamates and hydroxybenzylideneacetones
Summary
The utilization of small-molecule drugs of plant origin (e.g., paclitaxel, vinblastine, topotecan, etoposide, etc.) in the chemotherapy of solid malignancies and lymphoid leukemias illustrates the importance of phytochemicals for clinical oncology [1]. Plantderived polyphenols, such as curcumin (CUR), epigallocatechin gallate or resveratrol, have been widely investigated for the anti-cancer activity in both laboratory and clinical studies (see [2,3,4,5,6] for recent reviews). Biomedicines 2021, 9, 1517 at doses incompatible with human use [7,15]. One approach to lower the pharmacologically effective concentrations of polyphenols and to reduce their possible side effects is to take advantage of the ability of these compounds to cooperate with other antitumor agents and with one another in producing enhanced anticancer effects, as demonstrated in a number of studies conducted using various in-vitro and in-vivo models (e.g., [16,17,18,19,20,21])
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