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Article ; Online: CYP1-Activation and Anticancer Properties of Synthetic Methoxylated Resveratrol Analogues.

Ruparelia, Ketan C / Zeka, Keti / Beresford, Kenneth J M / Wilsher, Nicola E / Potter, Gerry A / Androutsopoulos, Vasilis P / Brucoli, Federico / Arroo, Randolph R J

Molecules (Basel, Switzerland)

2024 Volume 29, Issue 2

Abstract: Naturally occurring stilbenoids, such as the ( ...

Abstract	Naturally occurring stilbenoids, such as the (
MeSH term(s)	Humans ; Resveratrol/pharmacology ; Catalysis ; Cell Line, Tumor ; Cytochrome P-450 CYP1A1 ; Cytochrome P450 Family 1
Chemical Substances	Resveratrol (Q369O8926L) ; Cytochrome P-450 CYP1A1 (EC 1.14.14.1) ; Cytochrome P450 Family 1 (EC 1.14.14.1)
Language	English
Publishing date	2024-01-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules29020423
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Zs.MO 81: Show issues

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Article ; Online: Anticancer pyridines induce G2/M arrest and apoptosis via p53 and JNK upregulation in liver and breast cancer cells.

Androutsopoulos, Vasilis P / Spandidos, Demetrios A

Oncology reports

2017 Volume 39, Issue 2, Page(s) 519–524

Abstract: In the present study, the synthesis and biological evaluation of one novel pyridine and one novel pyridone anticancer compound is reported. The compounds 6‑(2,4‑dimethoxyphenyl)‑4‑(3,4‑methylenedioxyphenyl)‑1H‑pyridin‑2‑one (1) and 2‑(2,4‑dimethoxyphenyl) ...

Abstract	In the present study, the synthesis and biological evaluation of one novel pyridine and one novel pyridone anticancer compound is reported. The compounds 6‑(2,4‑dimethoxyphenyl)‑4‑(3,4‑methylenedioxyphenyl)‑1H‑pyridin‑2‑one (1) and 2‑(2,4‑dimethoxyphenyl)‑4‑(3,4‑methylenedioxyphenyl)pyridine (2) were synthesized from a chalchone precursor. 1 was more active than 2 in inhibiting the proliferation of MCF‑7 and HepG2 cells, whereas HepG2 cells were more sensitive to the antiproliferative activity of these compounds compared with MCF‑7 cells. The lowest IC50 value was noted for compound 1 in HepG2 cells (IC50=4.5±0.3 µM). The mechanism of action involved induction of G2/M arrest and apoptosis. Both 1 and 2 further induced downregulation of the cell cycle‑associated protein cyclin D1 and upregulation of the cell cycle inhibitors p53 and p21 and the apoptosis‑associated protein JNK in HepG2 cells. Compound 1 was further shown to induce phosphorylation of JNK in HepG2 cells. These results demonstrate promising cytostatic effects for the two novel anticancer compounds in human cancer cells.
MeSH term(s)	Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chalcone/chemistry ; Drug Screening Assays, Antitumor ; Female ; G2 Phase Cell Cycle Checkpoints/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Hep G2 Cells ; Humans ; Liver Neoplasms/drug therapy ; Liver Neoplasms/metabolism ; MAP Kinase Kinase 4/metabolism ; MCF-7 Cells ; Male ; Pyridines/chemical synthesis ; Pyridines/chemistry ; Pyridines/pharmacology ; Tumor Suppressor Protein p53/metabolism ; Up-Regulation
Chemical Substances	Pyridines ; TP53 protein, human ; Tumor Suppressor Protein p53 ; Chalcone (5S5A2Q39HX) ; MAP Kinase Kinase 4 (EC 2.7.12.2)
Language	English
Publishing date	2017-11-28
Publishing country	Greece
Document type	Journal Article
ZDB-ID	1222484-4
ISSN	1791-2431 ; 1021-335X
ISSN (online)	1791-2431
ISSN	1021-335X
DOI	10.3892/or.2017.6116
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Zs.A 4213: Show issues

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Article ; Online: Antiproliferative effects of TSA, PXD‑101 and MS‑275 in A2780 and MCF7 cells: Acetylated histone H4 and acetylated tubulin as markers for HDACi potency and selectivity.

Androutsopoulos, Vasilis P / Spandidos, Demetrios A

Oncology reports

2017 Volume 38, Issue 6, Page(s) 3412–3418

Abstract: Inhibition of histone deacetylase enzymes (HDACs) has been well documented as an attractive target for the development of chemotherapeutic drugs. The present study investigated the effects of two prototype hydroxamic acid HDAC inhibitors, namely ... ...

Abstract	Inhibition of histone deacetylase enzymes (HDACs) has been well documented as an attractive target for the development of chemotherapeutic drugs. The present study investigated the effects of two prototype hydroxamic acid HDAC inhibitors, namely Trichostatin A (TSA) and Belinostat (PXD‑101) and the benzamide Entinostat (MS‑275) in A2780 ovarian carcinoma and MCF7 breast adenocarcinoma cells. The three HDACi inhibited the proliferation of A2780 and MCF7 cells at comparable levels, below the µM range. Enzyme inhibition assays in a cell‑free system showed that TSA was the most potent inhibitor of total HDAC enzyme activity followed by PXD‑101 and MS‑275. Incubation of A2780 and MCF7 cells with the hydroxamates TSA and PXD‑101 for 24 h resulted in a dramatic increase of acetylated tubulin induction (up to 30‑fold for TSA). In contrast to acetylated tubulin, western blot analysis and flow cytometry indicated that the induction of acetylated histone H4 was considerably smaller. The benzamide MS‑275 exhibited nearly a 2‑fold induction of acetylated histone H4 and an even smaller induction of acetylated tubulin in A2780 and MCF7 cells. Taken together, these data suggest that although the three HDACi were equipotent in inhibiting proliferation of MCF7 and A2780 cells, only the benzamide MS‑275 did not induce acetylated tubulin expression, a marker of class IIb HDACs.
MeSH term(s)	Acetylation/drug effects ; Benzamides/administration & dosage ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Cell Proliferation/drug effects ; Cell-Free System ; Female ; Histone Deacetylase Inhibitors/administration & dosage ; Histone Deacetylases/genetics ; Humans ; Hydroxamic Acids/administration & dosage ; MCF-7 Cells ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Protein Processing, Post-Translational/drug effects ; Sulfonamides/administration & dosage ; Tubulin/genetics
Chemical Substances	Benzamides ; Histone Deacetylase Inhibitors ; Hydroxamic Acids ; Sulfonamides ; Tubulin ; trichostatin A (3X2S926L3Z) ; benzamide (6X80438640) ; Histone Deacetylases (EC 3.5.1.98) ; belinostat (F4H96P17NZ)
Language	English
Publishing date	2017-12
Publishing country	Greece
Document type	Journal Article
ZDB-ID	1222484-4
ISSN	1791-2431 ; 1021-335X
ISSN (online)	1791-2431
ISSN	1021-335X
DOI	10.3892/or.2017.6015
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Article ; Online: Benzo[a]pyrene sensitizes MCF7 breast cancer cells to induction of G1 arrest by the natural flavonoid eupatorin-5-methyl ether, via activation of cell signaling proteins and CYP1-mediated metabolism.

Androutsopoulos, Vasilis P / Tsatsakis, Aristeidis M

Toxicology letters

2014 Volume 230, Issue 2, Page(s) 304–313

Abstract: ... E5M further induced a dose dependent increase in the cell signaling proteins p21, JNK and p-JNK ... antiproliferative activity via enhanced induction of p21, JNK and p-JNK that in turn results by cytochrome P450 CYP1 ...

Abstract	Eupatorin-5-methyl ether (E5M) is a flavone containing 4 methoxy groups that is present in plants with medicinal activity, whereas luteolin (L) is a polyhydroxylated flavone commonly encountered in dietary products. In the present study we investigated the interaction of the two flavonoids with cytochrome P450 CYP1 enzymes in breast cancer MCF7 cells. Both compounds induced a dose dependent increase in CYP1A1 and CYP1B1 mRNA levels, as well as in EROD activity, a marker of CYP1 enzyme activity. Induction of cytochrome P450 CYP1 expression by E5M was accompanied by translocation of the ligand-activated transcription factor AhR to the nucleus, as demonstrated by confocal immunofluoresence. More importantly, although E5M was less active than L in inhibiting proliferation of MCF7 cells, when the cells were pretreated with the CYP1 inducer Benzo[a]pyrene (BaP) the potency of E5M was augmented. HPLC and LC-MS analysis revealed that E5M was metabolized to a major conversion product assigned E5M1 resulting from one step demethylation reaction in MCF7 cells whereas L metabolism by recombinant CYP1A1 did not reveal any metabolites. E5M1 production in BaP-induced MCF7 cells was attenuated in the presence of the CYP1A1 inhibitor α-napthoflavone. E5M further induced a dose dependent increase in the cell signaling proteins p21, JNK and p-JNK in MCF7 cells. This effect was enhanced in BaP pretreated cells and was associated with G1 arrest and a small percentage of apoptosis (3.5%). E5M antiproliferative effect in BaP pretreated cells was attenuated in the presence of the CYP1A1 inhibitor α-napthoflavone, as demonstrated by Western blotting and FACS analysis. Taken together the results demonstrate that BaP sensitizes MCF7 cells to E5M antiproliferative activity via enhanced induction of p21, JNK and p-JNK that in turn results by cytochrome P450 CYP1-mediated conversion to the metabolite E5M1.
MeSH term(s)	Benzo(a)pyrene/toxicity ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Cytochrome P-450 CYP1A1/physiology ; Cytochrome P-450 CYP1B1/physiology ; Dose-Response Relationship, Drug ; Enzyme Activation ; Female ; Flavones/pharmacology ; G1 Phase Cell Cycle Checkpoints/drug effects ; Humans ; MAP Kinase Kinase 4/metabolism ; MCF-7 Cells
Chemical Substances	CDKN1A protein, human ; Cyclin-Dependent Kinase Inhibitor p21 ; Flavones ; eupatorin-5-methyl ether ; Benzo(a)pyrene (3417WMA06D) ; CYP1A1 protein, human (EC 1.14.14.1) ; CYP1B1 protein, human (EC 1.14.14.1) ; Cytochrome P-450 CYP1A1 (EC 1.14.14.1) ; Cytochrome P-450 CYP1B1 (EC 1.14.14.1) ; MAP Kinase Kinase 4 (EC 2.7.12.2)
Language	English
Publishing date	2014-10-15
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	433788-8
ISSN	1879-3169 ; 0378-4274
ISSN (online)	1879-3169
ISSN	0378-4274
DOI	10.1016/j.toxlet.2013.08.005
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Zs.A 1367: Show issues

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Article ; Online: Tangeretin inhibits the proliferation of human breast cancer cells via CYP1A1/CYP1B1 enzyme induction and CYP1A1/CYP1B1-mediated metabolism to the product 4' hydroxy tangeretin.

Surichan, Somchaiya / Arroo, Randolph R / Tsatsakis, Aristidis M / Androutsopoulos, Vasilis P

Toxicology in vitro : an international journal published in association with BIBRA

2018 Volume 50, Page(s) 274–284

Abstract: Tangeretin is a polymethoxylated flavone with multifaceted anticancer activity. In the present study, the metabolism of tangeretin was evaluated in the CYP1 expressing human breast cancer cell lines MCF7 and MDA-MB-468 and in the normal breast cell line ... ...

Abstract	Tangeretin is a polymethoxylated flavone with multifaceted anticancer activity. In the present study, the metabolism of tangeretin was evaluated in the CYP1 expressing human breast cancer cell lines MCF7 and MDA-MB-468 and in the normal breast cell line MCF10A. Tangeretin was converted to 4' OH tangeretin by recombinant CYP1 enzymes and by CYP1 enzymes expressed in MCF7 and MDA-MB-468 cells. This metabolite was absent in MCF10A cells that did not express CYP1 enzymes. Tangeretin exhibited submicromolar IC50 (0.25 ± 0.15 μM) in MDA-MB-468 cells, whereas it was less active in MCF7 cells (39.3 ± 1.5 μM) and completely inactive in MCF10A cells (>100 μM). In MDA-MB-468 cells that were coincubated with the CYP1 inhibitor acacetin, an approximately 70-fold increase was noted in the IC50 (18 ± 1.6 μM) of tangeretin. In the presence of the CYP1 inhibitor acacetin, the conversion of tangeretin to 4' OH tangeretin was significantly reduced in MDA-MB-468 cells (2.55 ± 0.19 μM vs. 6.33 ± 0.12 μM). The mechanism of antiproliferative action involved cell cycle arrest at the G1 phase for MCF7 and MDA-MB-468 cells. Tangeretin was further shown to induce CYP1 enzyme activity and CYP1A1/CYP1B1 protein expression in MCF7 and MDA-MB-468 cells. These results suggest that tangeretin inhibits the proliferation of breast cancer cells via CYP1A1/CYP1B1-mediated metabolism to the product 4' hydroxy tangeretin.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cytochrome P-450 CYP1A1/metabolism ; Cytochrome P-450 CYP1B1/metabolism ; Enzyme Induction ; Female ; Flavones/pharmacology ; G1 Phase Cell Cycle Checkpoints/drug effects ; Humans
Chemical Substances	Antineoplastic Agents ; Flavones ; CYP1A1 protein, human (EC 1.14.14.1) ; CYP1B1 protein, human (EC 1.14.14.1) ; Cytochrome P-450 CYP1A1 (EC 1.14.14.1) ; Cytochrome P-450 CYP1B1 (EC 1.14.14.1) ; tangeretin (I4TLA1DLX6)
Language	English
Publishing date	2018-04-04
Publishing country	England
Document type	Journal Article
ZDB-ID	639064-x
ISSN	1879-3177 ; 0887-2333
ISSN (online)	1879-3177
ISSN	0887-2333
DOI	10.1016/j.tiv.2018.04.001
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Zs.A 2223: Show issues

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Article ; Online: The flavonoids diosmetin and luteolin exert synergistic cytostatic effects in human hepatoma HepG2 cells via CYP1A-catalyzed metabolism, activation of JNK and ERK and P53/P21 up-regulation.

Androutsopoulos, Vasilis P / Spandidos, Demetrios A

The Journal of nutritional biochemistry

2013 Volume 24, Issue 2, Page(s) 496–504

Abstract: ... extracellular-signal-regulated kinase (p-ERK), phospho-c-jun N-terminal kinase, p53 and p21 proteins. More importantly, induction of G2 ... M arrest and p53 and p-ERK up-regulation were reversed by the application of the CYP1 inhibitor α ...

Abstract	Various types of tumors are known to overexpress enzymes belonging to the CYP1 family of cytochromes P450. The present study aimed to characterize the metabolism and further antiproliferative activity of the natural flavonoid diosmetin in the CYP1-expressing human hepatoma cell line HepG2. Diosmetin was converted to luteolin in HepG2 cells after 12 and 30 h of incubation. In the presence of the CYP1A inhibitor α-naphthoflavone, the conversion of diosmetin to luteolin was attenuated. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays revealed luteolin to be more cytotoxic than diosmetin. The antiproliferative effect of diosmetin in HepG2 cells was attributed to blockage at the G2/M phase as determined by flow cytometry. Induction of G2/M arrest was accompanied by up-regulation of phospho-extracellular-signal-regulated kinase (p-ERK), phospho-c-jun N-terminal kinase, p53 and p21 proteins. More importantly, induction of G2/M arrest and p53 and p-ERK up-regulation were reversed by the application of the CYP1 inhibitor α-naphthoflavone. Taken together, the data provide new evidence on the tumor-suppressing role of cytochrome P450 CYP1A enzymes and extend the hypothesis that the anticancer activity of dietary flavonoids is enhanced by P450-activation.
MeSH term(s)	Cell Proliferation/drug effects ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Cytochrome P-450 Enzyme System/metabolism ; Cytostatic Agents/pharmacology ; Drug Synergism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Flavonoids/metabolism ; Flavonoids/pharmacology ; G2 Phase Cell Cycle Checkpoints/drug effects ; Hep G2 Cells/drug effects ; Hep G2 Cells/metabolism ; Humans ; Inhibitory Concentration 50 ; Luteolin/pharmacology ; MAP Kinase Kinase 4/metabolism ; Tumor Suppressor Protein p53/metabolism ; Up-Regulation/drug effects
Chemical Substances	CDKN1A protein, human ; Cyclin-Dependent Kinase Inhibitor p21 ; Cytostatic Agents ; Flavonoids ; Tumor Suppressor Protein p53 ; Cytochrome P-450 Enzyme System (9035-51-2) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; MAP Kinase Kinase 4 (EC 2.7.12.2) ; Luteolin (KUX1ZNC9J2) ; diosmetin (TWZ37241OT)
Language	English
Publishing date	2013-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	1014929-6
ISSN	1873-4847 ; 0955-2863
ISSN (online)	1873-4847
ISSN	0955-2863
DOI	10.1016/j.jnutbio.2012.01.012
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Zs.A 2838: Show issues

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Article ; Online: Human exposure to endocrine disrupting chemicals: effects on the male and female reproductive systems.

Sifakis, Stavros / Androutsopoulos, Vasilis P / Tsatsakis, Aristeidis M / Spandidos, Demetrios A

Environmental toxicology and pharmacology

2017 Volume 51, Page(s) 56–70

Abstract: Endocrine disrupting chemicals (EDCs) comprise a group of chemical compounds that have been examined extensively due to the potential harmful effects in the health of human populations. During the past decades, particular focus has been given to the ... ...

Abstract	Endocrine disrupting chemicals (EDCs) comprise a group of chemical compounds that have been examined extensively due to the potential harmful effects in the health of human populations. During the past decades, particular focus has been given to the harmful effects of EDCs to the reproductive system. The estimation of human exposure to EDCs can be broadly categorized into occupational and environmental exposure, and has been a major challenge due to the structural diversity of the chemicals that are derived by many different sources at doses below the limit of detection used by conventional methodologies. Animal and in vitro studies have supported the conclusion that endocrine disrupting chemicals affect the hormone dependent pathways responsible for male and female gonadal development, either through direct interaction with hormone receptors or via epigenetic and cell-cycle regulatory modes of action. In human populations, the majority of the studies point towards an association between exposure to EDCs and male and/or female reproduction system disorders, such as infertility, endometriosis, breast cancer, testicular cancer, poor sperm quality and/or function. Despite promising discoveries, a causal relationship between the reproductive disorders and exposure to specific toxicants is yet to be established, due to the complexity of the clinical protocols used, the degree of occupational or environmental exposure, the determination of the variables measured and the sample size of the subjects examined. Future studies should focus on a uniform system of examining human populations with regard to the exposure to specific EDCs and the direct effect on the reproductive system.
MeSH term(s)	Benzhydryl Compounds/chemistry ; Benzhydryl Compounds/pharmacokinetics ; Benzhydryl Compounds/toxicity ; Endocrine Disruptors/chemistry ; Endocrine Disruptors/pharmacokinetics ; Endocrine Disruptors/toxicity ; Environmental Exposure/adverse effects ; Environmental Exposure/analysis ; Female ; Humans ; Male ; Molecular Structure ; Pesticides/chemistry ; Pesticides/pharmacokinetics ; Pesticides/toxicity ; Phenols/chemistry ; Phenols/pharmacokinetics ; Phenols/toxicity ; Reproduction/drug effects
Chemical Substances	Benzhydryl Compounds ; Endocrine Disruptors ; Pesticides ; Phenols ; bisphenol A (MLT3645I99)
Language	English
Publishing date	2017-04
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2015938-9
ISSN	1872-7077 ; 1382-6689
ISSN (online)	1872-7077
ISSN	1382-6689
DOI	10.1016/j.etap.2017.02.024
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Article ; Online: Nobiletin bioactivation in MDA-MB-468 breast cancer cells by cytochrome P450 CYP1 enzymes.

Surichan, Somchaiya / Arroo, Randolph R / Ruparelia, Ketan / Tsatsakis, Aristidis M / Androutsopoulos, Vasilis P

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association

2018 Volume 113, Page(s) 228–235

Abstract: Nobiletin is a fully methoxylated flavone that has demonstrated anticancer activity via multiple modes of action. In the present study, the metabolism and further antiproliferative activity of nobiletin was evaluated in the CYP1 expressing human breast ... ...

Abstract	Nobiletin is a fully methoxylated flavone that has demonstrated anticancer activity via multiple modes of action. In the present study, the metabolism and further antiproliferative activity of nobiletin was evaluated in the CYP1 expressing human breast cancer cell line MDA-MB-468 and the normal breast cell line MCF10A. Nobiletin was metabolized in MDA-MB-468 cells to a single-demethylated derivative assigned NP1. This metabolite was absent in MCF10A cells that did not express CYP1 enzymes. Nobiletin exhibited submicromolar IC50 (0.1 ± 0.04 μM) in MDA-MB-468 cells, whereas it was considerably less active in MCF10A cells (40 μM). In MDA-MB-468 cells that were coincubated with the CYP1 inhibitor acacetin, an approximately 300-fold increase was noted in the IC50 (30 ± 2.4 μM) of nobiletin. In the presence of the CYP1 inhibitor acacetin, the conversion of nobiletin to NP1 was significantly reduced in MDA-MB-468 cells. Furthermore, a significant increase was noted in the population of the cells at the G1 phase, following treatment with nobiletin (10 μM) for 24 h compared with the control cells treated with DMSO (0.1%) alone (55.9 ± 0.14 vs. 45.6 ± 1.96), whereas the cell cycle of MCF10A cells was not significantly altered under the same treatment conditions. Taken collectively, the results suggest that nobiletin is selectively bioactivated in MDA-MB-468 breast cancer cells via metabolism by the cytochrome P450 CYP1 family of enzymes.
MeSH term(s)	Activation, Metabolic ; Antineoplastic Agents/metabolism ; Antineoplastic Agents/pharmacology ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cytochrome P-450 CYP1A1/metabolism ; Female ; Flavones/metabolism ; Flavones/pharmacology ; Humans ; Inhibitory Concentration 50
Chemical Substances	Antineoplastic Agents ; Flavones ; nobiletin (D65ILJ7WLY) ; Cytochrome P-450 CYP1A1 (EC 1.14.14.1)
Language	English
Publishing date	2018-01-31
Publishing country	England
Document type	Journal Article
ZDB-ID	782617-5
ISSN	1873-6351 ; 0278-6915
ISSN (online)	1873-6351
ISSN	0278-6915
DOI	10.1016/j.fct.2018.01.047
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Zs.A 529: Show issues

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Article ; Online: The resveratrol analogue, 3,4,5,4'‑trans-tetramethoxystilbene, inhibits the growth of A375 melanoma cells through multiple anticancer modes of action.

Androutsopoulos, Vasilis P / Fragiadaki, Irene / Spandidos, Demetrios A / Tosca, Androniki

International journal of oncology

2016 Volume 49, Issue 4, Page(s) 1305–1314

Abstract: Resveratrol is a natural dietary product that has demonstrated multifaceted anticancer activity. Several analogues of resveratrol have been synthesized in an effort to enhance the pharmacological potency and improve the pharmacokinetic properties of the ... ...

Abstract	Resveratrol is a natural dietary product that has demonstrated multifaceted anticancer activity. Several analogues of resveratrol have been synthesized in an effort to enhance the pharmacological potency and improve the pharmacokinetic properties of the compound. 3,4,5,4'‑trans‑tetramethoxystilbene (3,4,5,4'‑TMS) is a methoxylated analogue of resveratrol that has demonstrated anti-proliferative activity in vitro (in cancer cell lines) and in vivo (in xenograft models). In the present study, the anticancer effects of 3,4,5,4'‑TMS in A375 human melanoma cells were examined. 3,4,5,4'‑TMS markedly inhibited the proliferation of A375 cells (IC50=0.7 µM), via a mechanism involving mitotic arrest at the prometaphase stage of cell division. This effect was accompanied by the upregulation of the expression of the mitogen activated protein kinases, JNK and p38, and the concomitant activation of p38, that was verified by the nuclear translocation of the phoshorylated form of the protein. The pharmacological inhibition of p38 by SB203580 (4 µM) attenuated the effects of 3,4,5,4'‑TMS, as demonstrated by decreased cell cycle progression at the mitotic phase. Furthermore, 3,4,5,4'‑TMS increased the total levels of Aurora A, while it inhibited the localization of the protein to the spindle poles. Finally, 3,4,5,4'‑TMS exhibited anti-metastatic activity, inhibiting A375 cell migration and the attachment of the cells to a collagen type IV-coated surface. Collectively, the data suggest that 3,4,5,4'‑TMS is an effective chemotherapeutic drug for the treatment of human melanoma and that it exerts its effects through multiple anticancer modes of action.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Drug Screening Assays, Antitumor ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; MAP Kinase Signaling System/drug effects ; Melanoma/drug therapy ; Melanoma/metabolism ; Prometaphase/drug effects ; Stilbenes/pharmacology
Chemical Substances	3,4,5,4'-tetramethoxystilbene ; Antineoplastic Agents ; Stilbenes
Language	English
Publishing date	2016-10
Publishing country	Greece
Document type	Journal Article
ZDB-ID	1154403-x
ISSN	1791-2423 ; 1019-6439
ISSN (online)	1791-2423
ISSN	1019-6439
DOI	10.3892/ijo.2016.3635
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Zs.A 3690: Show issues

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Article: Nobiletin bioactivation in MDA-MB-468 breast cancer cells by cytochrome P450 CYP1 enzymes

Surichan, Somchaiya / Androutsopoulos, Vasilis P / Arroo, Randolph R / Ruparelia, Ketan / Tsatsakis, Aristidis M

Elsevier Ltd Food and chemical toxicology. 2018 Mar., v. 113

2018

Abstract	Nobiletin is a fully methoxylated flavone that has demonstrated anticancer activity via multiple modes of action. In the present study, the metabolism and further antiproliferative activity of nobiletin was evaluated in the CYP1 expressing human breast cancer cell line MDA–MB–468 and the normal breast cell line MCF10A. Nobiletin was metabolized in MDA–MB–468 cells to a single-demethylated derivative assigned NP1. This metabolite was absent in MCF10A cells that did not express CYP1 enzymes. Nobiletin exhibited submicromolar IC50 (0.1 ± 0.04 μM) in MDA–MB–468 cells, whereas it was considerably less active in MCF10A cells (40 μM). In MDA–MB–468 cells that were coincubated with the CYP1 inhibitor acacetin, an approximately 300–fold increase was noted in the IC50 (30 ± 2.4 μM) of nobiletin. In the presence of the CYP1 inhibitor acacetin, the conversion of nobiletin to NP1 was significantly reduced in MDA–MB–468 cells. Furthermore, a significant increase was noted in the population of the cells at the G1 phase, following treatment with nobiletin (10 μM) for 24 h compared with the control cells treated with DMSO (0.1%) alone (55.9 ± 0.14 vs. 45.6 ± 1.96), whereas the cell cycle of MCF10A cells was not significantly altered under the same treatment conditions. Taken collectively, the results suggest that nobiletin is selectively bioactivated in MDA–MB–468 breast cancer cells via metabolism by the cytochrome P450 CYP1 family of enzymes.
Keywords	antineoplastic activity ; breast neoplasms ; breasts ; cytochrome P-450 ; dimethyl sulfoxide ; enzymes ; flavones ; human cell lines ; humans ; inhibitory concentration 50 ; interphase ; mechanism of action ; metabolism ; metabolites ; neoplasm cells
Language	English
Dates of publication	2018-03
Size	p. 228-235.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	782617-5
ISSN	1873-6351 ; 0278-6915
ISSN (online)	1873-6351
ISSN	0278-6915
DOI	10.1016/j.fct.2018.01.047
Database	NAL-Catalogue (AGRICOLA)

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