Effects and Mechanisms of Acylated Flavonoid on Cancer Chemopreventive Activity

Sakao, Kozue; Hou, De‐Xing

doi:10.1007/s40495-020-00233-6

Cited by 5 publications

(4 citation statements)

References 60 publications

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“…Acylated polyphenols from natural plant sources are often modified in glycosidic sugar chains and have been reported to stabilize pigment and structure [22,23] and to enhance cytoprotective, antioxidant, and anti-inflammatory effects [24][25][26]. In contrast, there are few reports of acylation of aglycones in nature and few information on O-acylated flavonoids [10,12]. Thus, we synthesized 4Ac-Q via acetylation of its hydroxyl group.…”

Section: Discussionmentioning

confidence: 99%

“…Those properties limit the potential application of quercetin. Recent studies have attempted to improve its bioavailability and bioactivity by modifying quercetin structure with various chemical methods [10][11][12]. Acylation is one such modification, especially the O-acylation of quercetin, which has been reported to improve various biological activities, such as anticancer, antivirus, antiplatelet, and cytoprotection effects [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

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Hydroxyl Group Acetylation of Quercetin Enhances Intracellular Absorption and Persistence to Upregulate Anticancer Activity in HepG2 Cells

Sakao,

Saruwatari,

Minami

et al. 2023

IJMS

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Quercetin, a flavonoid compound widely distributed in many plants, is known to have potent antitumor effects on several cancer cells. Our previous study revealed that the acetylation of quercetin enhanced its antitumor effect. However, the mechanisms remain unknown. This study aimed to elucidate the bioavailability of acylated quercetin in the HepG2 cell model based on its antitumor effect. The positions of quercetin 3,7,3′,4′-OH were acetylated as 3,7,3′,4′-O-tetraacetylquercetin (4Ac-Q). The inhibitory effect of 4Ac-Q on HepG2 cell proliferation was assessed by measuring cell viability. The apoptosis was characterized by apoptotic proteins and mitochondrial membrane potential shifts, as well as mitochondrial reactive oxygen species (ROS) levels. The bioavailability of 4Ac-Q was analyzed by measuring the uptake and metabolites in HepG2 cells with high performance liquid chromatography (HPLC)—photodiode array detector (PDA) and—ultraviolet/visible detector (UV/Vis). The results revealed that 4Ac-Q enhanced the inhibitory effect on HepG2 cell proliferation and induced its apoptosis significantly higher than quercetin. Protein array analysis of apoptosis-related protein indicated that 4Ac-Q increased the activation or expression of pro-apoptotic proteins, including caspase-3, -9, as well as second mitochondria-derived activator of caspases (SMAC), and suppressed the expression of apoptosis inhibiting proteins such as cellular inhibitor of apoptosis (cIAP)-1, -2, Livin, Survivin, and X-linked inhibitor of apoptosis (XIAP). Furthermore, 4Ac-Q stimulated mitochondrial cytochrome c release into the cytosol by enhancing ROS level and depolarizing the mitochondrial membrane. Finally, the analysis of uptake and metabolites of 4Ac-Q in HpG2 cells with HPLC-PDA and -UV/Vis revealed that 4Ac-Q was metabolized to quercetin and several different acetylated quercetins which caused 2.5-fold higher quercetin present in HepG2 cells than parent quercetin. These data demonstrated that acetylation of the quercetin hydroxyl group significantly increased its intracellular absorption. Taken together, our findings provide the first evidence that acetyl modification of quercetin not only substantially augments the intracellular absorption of quercetin but also bolsters its metabolic stability to elongate its intracellular persistence. Therefore, acetylation could serve as a strategic approach to enhance the ability of quercetin and analogous flavonoids to suppress cancer cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hydroxyl Group Acetylation of Quercetin Enhances Intracellular Absorption and Persistence to Upregulate Anticancer Activity in HepG2 Cells

Sakao,

Saruwatari,

Minami

et al. 2023

IJMS

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“…In a previous study [36], it was found that the addition of acetate groups at C-5 and C-7 of the flavone framework played a crucial role in the antidiabetic action of glucose absorption processes [36]. The results of the work by Sakao & Hou [37] indicated that, when compared to the parent compound, the modified flavonoid by acylation displayed higher antioxidant activity, anti-inflammatory activity, cytoprotective impact, and the potential to trigger apoptosis in cancer cells [37]. In our previous investigation [25], successful modification of artocarpin using acetic anhydride was achieved.…”

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confidence: 94%

Anticancer Activity Study of Modified Artocarpin Compound from Pudau Plant (Artocarpus kemando Miq.)

et al. 2023

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This research is a continuation of the successful isolation of artocarpin from the root of Artocarpus kemando Miq reported in our previous study. In the previous study, the artocarpin was characterized with UV-Vis and FTIR techniques. In this follow-up investigation, the artocarpin was subjected to a transesterification reaction using acetic anhydride and pyridine as catalysts, and the product of the reaction was specified as compound 1. The compound 1 was further characterized with different techniques to gain more complete data and then tested for anticancer activity test against P-388 murine leukemia cells. Characterizations of the compound 1 using 1H-NMR and 13C-NMR techniques suggest that the modification reaction resulted in the conversion of the -OH groups at C2' and 4' at the artocarpin molecule to -OOCH3, and based on the MS analysis, the compound was proposed to have the molecular formula of C30H32O8. Another important feature of compound 1 that should be noted is the significant improvement in stability compared to the unmodified artocarpin. Anticancer activity tests against P-388 murine leukemia cells revealed that compound 1 has an IC50of 2.35 g/mL, confirming that the compound is categorized as an active anticancer agent and suggesting that the compound has promising potential that deserves further investigations. Doi: 10.28991/ESJ-2023-07-03-05 Full Text: PDF

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“…On the other hand, there are few reports on acylated derivatives of naturally occur ring flavonoids, with most of them being compounds in which the sugar of the glycoside is acylated and modified [17]. Instead, the synthesis of acylated flavonoid derivatives has been actively studied due to the advantages of high yield and adequate evaluation of bio activity.…”

Section: Introductionmentioning

confidence: 99%

Anticancer Activity and Molecular Mechanisms of Acetylated and Methylated Quercetin in Human Breast Cancer Cells

Sakao,

Hamamoto,

Urakawa

et al. 2024

Molecules

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Quercetin, a flavonoid polyphenol found in many plants, has garnered significant attention due to its potential cancer chemoprevention. Our previous studies have shown that acetyl modification of the hydroxyl group of quercetin altered its antitumor effects in HepG2 cells. However, the antitumor effect in other cancer cells with different gene mutants remains unknown. In this study, we investigated the antitumor effect of quercetin and its methylated derivative 3,3′,4′,7-O-tetramethylquercetin (4Me-Q) and acetylated derivative 3,3′,4′,7-O-tetraacetylquercetin (4Ac-Q) on two human breast cancer cells, MCF-7 (wt-p53, caspase-3-ve) and MDA-MB-231 (mt-p53, caspase-3+ve). The results demonstrated that 4Ac-Q exhibited significant cell proliferation inhibition and apoptosis induction in both MCF-7 and MDA-MB-231 cells. Conversely, methylation of quercetin was found to lose the activity. The human apoptosis antibody array revealed that 4Ac-Q might induce apoptosis in MCF-7 cells via a p53-dependent pathway, while in MDA-MB-231 cells, it was induced via a caspase-3-dependent pathway. Furthermore, an evaluation using a superoxide inhibitor, MnTBAP, revealed 4Ac-Q-induced apoptosis in MCF-7 cells in a superoxide-independent manner. These findings provide valuable insights into the potential of acetylated quercetin as a new approach in cancer chemoprevention and offer new avenues for health product development.

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Effects and Mechanisms of Acylated Flavonoid on Cancer Chemopreventive Activity

Cited by 5 publications

References 60 publications

Hydroxyl Group Acetylation of Quercetin Enhances Intracellular Absorption and Persistence to Upregulate Anticancer Activity in HepG2 Cells

Hydroxyl Group Acetylation of Quercetin Enhances Intracellular Absorption and Persistence to Upregulate Anticancer Activity in HepG2 Cells

Anticancer Activity Study of Modified Artocarpin Compound from Pudau Plant (Artocarpus kemando Miq.)

Anticancer Activity and Molecular Mechanisms of Acetylated and Methylated Quercetin in Human Breast Cancer Cells

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