Eupatorin-Induced Cell Death in Human Leukemia Cells Is Dependent on Caspases and Activates the Mitogen-Activated Protein Kinase Pathway

Estévez, Sara; Marrero, María Teresa; Quintana, José; Estévez, Francisco

doi:10.1371/journal.pone.0112536

Cited by 32 publications

(16 citation statements)

References 29 publications

(31 reference statements)

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“…Fluorescent microscopy and flow cytometric analysis of propidium iodide-stained cells were performed as described 42 . Briefly, cells were harvested and fixed in 3% paraformaldehyde and incubated at room temperature for 10 min.…”

Section: Methodsmentioning

confidence: 99%

Design, synthesis, in vitro antiproliferative activity and apoptosis-inducing studies of 1-(3′,4′,5′-trimethoxyphenyl)-3-(2′-alkoxycarbonylindolyl)-2-propen-1-one derivatives obtained by a molecular hybridisation approach

Preti

Romagnoli

Rondanin

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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Inhibition of microtubule function using tubulin targeting agents has received growing attention in the last several decades. The indole scaffold has been recognized as an important scaffold in the design of novel compounds acting as antimitotic agents. Indole-based chalcones, in which one of the aryl rings was replaced by an indole, have been explored in the last few years for their anticancer potential in different cancer cell lines. Eighteen novel (3′,4′,5′-trimethoxyphenyl)-indolyl-propenone derivatives with general structure 9 were synthesized and evaluated for their antiproliferative activity against a panel of four different human cancer cell lines. The highest IC50 values were obtained against the human promyelocytic leukemia HL-60 cell line. This series of chalcone derivatives was characterized by the presence of a 2-alkoxycarbonyl indole ring as the second aryl system attached at the carbonyl of the 3-position of the 1-(3′,4′,5′-trimethoxyphenyl)-2-propen-1-one framework. The structure–activity relationship (SAR) of the indole-based chalcone derivatives was investigated by varying the position of the methoxy group, by the introduction of different substituents (hydrogen, methyl, ethyl or benzyl) at the N-1 position and by the activity differences between methoxycarbonyl and ethoxycarbonyl moieties at the 2-position of the indole nucleus. The antiproliferative activity data of the novel synthesized compounds revealed that generally N-substituted indole analogues exhibited considerably reduced potency as compared with their parent N-unsubstituted counterparts, demonstrating that the presence of a hydrogen on the indole nitrogen plays a decisive role in increasing antiproliferative activity. The results also revealed that the position of the methoxy group on the indole ring is a critical determinant of biological activity. Among the synthesized derivatives, compound 9e, containing the 2-methoxycarbonyl-6-methoxy-N-1H-indole moiety exhibited the highest antiproliferative activity, with IC50 values of 0.37, 0.16 and 0.17 μM against HeLa, HT29 and MCF-7 cancer cell lines, respectively, and with considerably lower activity against HL-60 cells (IC50: 18 μM). This derivative also displayed cytotoxic properties (IC50 values ∼1 μM) in the human myeloid leukemia U-937 cell line overexpressing human Bcl-2 (U-937/Bcl-2) via cell cycle progression arrest at the G2-M phase and induction of apoptosis. The results obtained also demonstrated that the antiproliferative activity of this molecule is related to inhibition of tubulin polymerisation. The presence of a methoxy group at the C5- or C6-position of the indole nucleus, as well as the absence of substituents at the N-1-indole position, contributed to the optimal activity of the indole-propenone-3′,4′,5′-trimethoxyphenyl scaffold.

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Section: Methodsmentioning

confidence: 99%

Design, synthesis, in vitro antiproliferative activity and apoptosis-inducing studies of 1-(3′,4′,5′-trimethoxyphenyl)-3-(2′-alkoxycarbonylindolyl)-2-propen-1-one derivatives obtained by a molecular hybridisation approach

Preti

Romagnoli

Rondanin

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…It is an irreversible event and occurs before changes in plasma membrane permeability. DNA isolation and gel electrophoresis were performed as described previously 37 . Briefly, cells (1 × 10 5 ) were collected by centrifugation, washed with PBS and incubated in 30 μL of lysis buffer [50 mM Tris-HCl (pH 8.0), 10 mM EDTA, 0.5% sodium dodecyl sulphate], containing 1 μg μL −1 RNase A at 37 °C for 1 h. Then, 3 μL of proteinase K (10 μg μL −1 ) was added and the mixture was incubated at 50 °C for an additional 2 h. DNA was extracted with 100 μL of phenol-chloroform-isoamyl alcohol (24:24:1) and mixed with 5 μL of loading solution [10 mM EDTA, 1% (w/v) low melting-point agarose, 0.25% bromophenol blue and 40% sucrose, pH 8.0].…”

Section: Methodsmentioning

confidence: 99%

“…Caspase activity was evaluated by measuring proteolytic cleavage of the chromogenic substrates DEVD- p NA (for caspase-3 like protease activity), VEID- p NA (for caspase-6 activity), IETD- p NA (for caspase-8 activity) and LEHD- p NA (for caspase-9 activity) as described previously 37 .…”

Section: Methodsmentioning

confidence: 99%

Synthesis and biological evaluation of alpha-bromoacryloylamido indolyl pyridinyl propenones as potent apoptotic inducers in human leukaemia cells

Romagnoli

Prencipe

Cara³

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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The combination of two pharmacophores into a single molecule represents one of the methods that can be adopted for the synthesis of new anticancer molecules. To investigate the influence of the position of the pyridine nitrogen on biological activity, two different series of α-bromoacryloylamido indolyl pyridinyl propenones 3a–h and 4a–d were designed and synthesized by a pharmacophore hybridization approach and evaluated for their antiproliferative activity against a panel of six human cancer cell lines. These hybrid molecules were prepared to combine the α-bromoacryloyl moiety with two series of indole-inspired chalcone analogues, possessing an indole derivative and a 3- or 4-pyridine ring, respectively, linked on either side of 2-propen-1-one system. The structure-activity relationship was also investigated by the insertion of alkyl or benzyl moieties at the N-1 position of the indole nucleus. We found that most of the newly synthesized displayed high antiproliferative activity against U-937, MOLT-3, K-562, and NALM-6 leukaemia cell lines, with one-digit to double-digit nanomolar IC50 values. The antiproliferative activities of 3-pyridinyl derivatives 3f–h revealed that N-benzyl indole analogues generally exhibited lower activity compared to N-H or N-alkyl derivatives 3a–b and 3c–e, respectively. Moreover, cellular mechanism studies elucidated that compound 4a induced apoptosis along with a decrease of mitochondrial membrane potential and activated caspase-3 in a concentration-dependent manner.

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“…One important characteristic of flavonoids can be related to their O-methylation as methoxyflavonoids generally exhibit stronger cytotoxic activity than non-methoxylated flavonoids [ 227 ]. This feature becomes evident considering the activities of some O-methylated flavonoids bearing different numbers of methoxyl groups in their diphenylpropane (C6-C3-C6) skeleton, such as eupatorin [ 216 ], wogonin [ 193 , 228 ], casticin [ 21 , 109 , 111 , 174 ], or tamarixetin [ 168 ] (Table 2 ).…”

Section: Human Cell Lines Used In Antileukemic Studies Of Flavonoidsmentioning

confidence: 99%

Established Human Cell Lines as Models to Study Anti-leukemic Effects of Flavonoids

Sak

Everaus

2016

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Despite the extensive work on pathological mechanisms and some recent advances in the treatment of different hematological malignancies, leukemia continues to present a significant challenge being frequently considered as incurable disease. Therefore, the development of novel therapeutic agents with high efficacy and low toxicity is urgently needed to improve the overall survival rate of patients. In this comprehensive review article, the current knowledge about the anticancer activities of flavonoids as plant secondary polyphenolic metabolites in the most commonly used human established leukemia cell lines (HL-60, NB4, KG1a, U937, THP-1, K562, Jurkat, CCRF- CEM, MOLT-3, and MOLT-4) is compiled, revealing clear anti-proliferative, pro-apoptotic, cell cycle arresting, and differentiation inducing effects for certain compounds. Considering the low toxicity of these substances in normal blood cells, the presented data show a great potential of flavonoids to be developed into novel anti-leukemia agents applicable also in the malignant cells resistant to the current conventional chemotherapeutic drugs.

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Eupatorin-Induced Cell Death in Human Leukemia Cells Is Dependent on Caspases and Activates the Mitogen-Activated Protein Kinase Pathway

Cited by 32 publications

References 29 publications

Design, synthesis, in vitro antiproliferative activity and apoptosis-inducing studies of 1-(3′,4′,5′-trimethoxyphenyl)-3-(2′-alkoxycarbonylindolyl)-2-propen-1-one derivatives obtained by a molecular hybridisation approach

Design, synthesis, in vitro antiproliferative activity and apoptosis-inducing studies of 1-(3′,4′,5′-trimethoxyphenyl)-3-(2′-alkoxycarbonylindolyl)-2-propen-1-one derivatives obtained by a molecular hybridisation approach

Synthesis and biological evaluation of alpha-bromoacryloylamido indolyl pyridinyl propenones as potent apoptotic inducers in human leukaemia cells

Established Human Cell Lines as Models to Study Anti-leukemic Effects of Flavonoids

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