Structure-Activity Relationship of Hydroxycinnamic Acid Derivatives for Cooperating with Carnosic Acid and Calcitriol in Acute Myeloid Leukemia Cells

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...

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Autores principales:	Aviram Trachtenberg, Katarzyna Sidoryk, Somaya Alreate, Suchismita Muduli, Andrzej Leś, Marcin Cybulski, Michael Danilenko
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	structure-activity relationship hydroxycinnamates carnosic acid vitamin D acute myeloid leukemia Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/fc0aea6bca7c4151b478a93281c8f298
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spelling	oai:doaj.org-article:fc0aea6bca7c4151b478a93281c8f2982021-11-25T16:48:27ZStructure-Activity Relationship of Hydroxycinnamic Acid Derivatives for Cooperating with Carnosic Acid and Calcitriol in Acute Myeloid Leukemia Cells10.3390/biomedicines91115172227-9059https://doaj.org/article/fc0aea6bca7c4151b478a93281c8f2982021-10-01T00:00:00Zhttps://www.mdpi.com/2227-9059/9/11/1517https://doaj.org/toc/2227-9059Plant 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.Aviram TrachtenbergKatarzyna SidorykSomaya AlreateSuchismita MuduliAndrzej LeśMarcin CybulskiMichael DanilenkoMDPI AGarticlestructure-activity relationshiphydroxycinnamatescarnosic acidvitamin Dacute myeloid leukemiaBiology (General)QH301-705.5ENBiomedicines, Vol 9, Iss 1517, p 1517 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	structure-activity relationship hydroxycinnamates carnosic acid vitamin D acute myeloid leukemia Biology (General) QH301-705.5
spellingShingle	structure-activity relationship hydroxycinnamates carnosic acid vitamin D acute myeloid leukemia Biology (General) QH301-705.5 Aviram Trachtenberg Katarzyna Sidoryk Somaya Alreate Suchismita Muduli Andrzej Leś Marcin Cybulski Michael Danilenko Structure-Activity Relationship of Hydroxycinnamic Acid Derivatives for Cooperating with Carnosic Acid and Calcitriol in Acute Myeloid Leukemia Cells
description	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.
format	article
author	Aviram Trachtenberg Katarzyna Sidoryk Somaya Alreate Suchismita Muduli Andrzej Leś Marcin Cybulski Michael Danilenko
author_facet	Aviram Trachtenberg Katarzyna Sidoryk Somaya Alreate Suchismita Muduli Andrzej Leś Marcin Cybulski Michael Danilenko
author_sort	Aviram Trachtenberg
title	Structure-Activity Relationship of Hydroxycinnamic Acid Derivatives for Cooperating with Carnosic Acid and Calcitriol in Acute Myeloid Leukemia Cells
title_short	Structure-Activity Relationship of Hydroxycinnamic Acid Derivatives for Cooperating with Carnosic Acid and Calcitriol in Acute Myeloid Leukemia Cells
title_full	Structure-Activity Relationship of Hydroxycinnamic Acid Derivatives for Cooperating with Carnosic Acid and Calcitriol in Acute Myeloid Leukemia Cells
title_fullStr	Structure-Activity Relationship of Hydroxycinnamic Acid Derivatives for Cooperating with Carnosic Acid and Calcitriol in Acute Myeloid Leukemia Cells
title_full_unstemmed	Structure-Activity Relationship of Hydroxycinnamic Acid Derivatives for Cooperating with Carnosic Acid and Calcitriol in Acute Myeloid Leukemia Cells
title_sort	structure-activity relationship of hydroxycinnamic acid derivatives for cooperating with carnosic acid and calcitriol in acute myeloid leukemia cells
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/fc0aea6bca7c4151b478a93281c8f298
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Structure-Activity Relationship of Hydroxycinnamic Acid Derivatives for Cooperating with Carnosic Acid and Calcitriol in Acute Myeloid Leukemia Cells

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