• 약학회지
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• 제54권5호
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• pp.370-376
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• 2010

The aim of this study is to investigate the effect of apigenin on the pharmacokinetics of tamoxifen in rats. Tamoxifen was administered orally (10 mg/kg) or intravenously (2 mg/kg) without or with oral administration of apigenin (0.4, 2.0 or 8.0 mg/kg) to rats. The effect of apigenin on the P-glycoprotein (P-gp) and CYP3A4 activity was also evaluated. Apigenin inhibited CYP3A4 enzyme activity with 50% inhibition concentration ($IC_{50}$) of 1.8 ${\mu}M$. In addition, apigenin significantly enhanced the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-gp. The plasma concentrations of tamoxifen were increased significantly by apigenin compared to control. The areas under the plasma concentration-time curve (AUC) and the peak concentrations ($IC_{max}$) of tamoxifen with apigenin were significantly higher than those of the control group. Consequently, the relative bioavailability (RB%) of tamoxifen with apigenin was 2-3-fold higher than the control, and absolute bioavailability (AB%) of tamoxifen were significantly higher (p<0.05 with co-administration, p<0.01 with pretreatment) than those of the control. The increased bioavailability of tamoxifen in rats with apigenin might be associated with the inhibition of an efflux pump P-glycoprotein and CYP3A4 by apigenin. From these results, dosage regimen of tamoxifen may be need to adjust when concomitantly administered with apigenin.

• Journal of the Korean Wood Science and Technology
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• 제34권2호
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• pp.83-87
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• 2006

The leaves of Paulownia coreana Uyeki were extracted with acetone-$H_2O$ (7:3, v/v), concentrated under reduced pressure and fractionated successively with n-hexane, methylene chloride and ethyl acetate, leaving residual water soluble fraction. A portion of the resulting aqueous soluble powder was chromatographed on a Sephadex LH-20 column using aqueous methanol and ethanol-hexane as washing solvents. Three apigenin derivatives were isolated and identified as apigenin-7-O-${\beta}$-D-glucpyranoside, apigenin-7-O-${\beta}$-D-glucuronopyranoside and apigenin-7-O-[${\beta}$-D-glucuronopyranosyl($1{\rightarrow}2$)-O-${\beta}$-D-glucuronopyranoside] by spectroscopic methods including NMR and FAB-MS.

• 약학회지
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• 제52권6호
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• pp.500-506
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• 2008

Apigenin, a natural flavonoid found in a variety of vegetables and fruits, has been shown to possess many biological functions. In this study we found that apigenin stimulated melanin synthesis in a dose-dependent manner in B16 murine melanoma cells. Since in our previous study $K^+$-$Cl^-$-cotransport (KCC) has been shown to mediate the mechanism of action of apigenin in neuronal cells, we further investigated the role of KCC in the melanogenesis-stimulating effect of apigenin in B16 cells. At nontoxic concentrations apigenin induced $Cl^-$-dependent $K^+$ efflux, a hallmark of KCC activity, which was markedly prevented by a specific KCC inhibitor R-(+)-[(2-n-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]acetic acid (DIOA). These results indicate that KCC is functionally present, and activated by apigenin in the B16 cells. In addition, the apigenin-induced stimulation of melanogenesis was also significantly inhibited by DIOA. NEthylmaleimide (NEM), a known KCC activator, induced $Cl^-$ efflux and stimulated melanogenesis in a concentration-dependent fashion. Both effects of NEM were significantly inhibited by DIOA. Taken together, these results suggest that apigenin can modulate melanogenesis through the activation of a membrane ion transporter, KCC in B16 cells. These results further suggest that apigenin may be a good candidate in the therapeutic strategy for hypopigmentation disorders, such as vitiligo.

• 한국식품영양과학회지
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• 제44권6호
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• pp.816-822
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• 2015

본 연구는 감마선 조사에 의해 유도된 apigenin 화합물(radiolysis products)이 인체유래 다양한 암세포에 처리했을 때의 항암 효과를 알아보기 위하여 실험을 진행하였다. Apigenin을 50 kGy로 조사할 경우 유도 화합물이 생성됨을 확인할 수 있었으며, radiolysis 화합물을 분획하여 인체유래 섬유육종세포(HS68)에 대한 독성을 평가한 결과 독성이 없는 것으로 나타났다. 다양한 암세포에 항암 활성을 평가한 결과 폐암(H1975)세포주의 경우 다른 암세포에 비해 효과가 높은 것으로 나타났다. Annexin V/PI 염색을 통해 감마선 조사된 apigenin 처리구에서 apoptosis의 발현을 확인할 수 있었으며, ROS(reactive oxygen species) 평가 결과에서도 농도 의존적으로 발현을 확인할 수 있었다. 본 연구는 방사선 구조 변환 연구를 통해 방사선을 이용한 새로운 신약 개발 가능성을 제시하는 기초자료로 활용될 수 있을 것으로 판단하였다.

• 생명과학회지
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• 제17권1호
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• pp.110-115
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• 2007

Tumor suppressor 유전자로알려진 early growth response gene 1 (EGR-1)에 있어 항산화 천연물인 apigenin과 그대사물인 isovitexin에 의한 장관 상피성 종양세포에 대하여 항종양 역할을 규명하였다. Apigenin 과 isovitexin은 대장암세포에서의 EGR-1 단백질의 발현을 9-12시간의 노출에 의해 농도 의존적으로 증가하였다. 또한 신호전달측면에서 이런 apigenin에 의한 EGR-1 유전자의 유도가 U0126 화합물에 의해 완벽하게 저해 받는 것으로 보아 ERK1/2 MAP kinase pathway의 이 신호전달계에서의 관여를 보여주었다. 본 연구에서 apigenin에 의해 농도 의존적으로 대장암세포의 세포활성의 저해를 MTT assay를 통해 보였고, 또한 EGR-1 siRNA를 transfectien한 세포의 경우 이런 apigenin에 의한 세포활성의 저해효과를 완화하였다. 따라서 apigenin에 의한 항종암세포 세포활성 억제에 있어 EGR-1의 중요성을 보여 준다. 이런 EGR-1에 의해 유도되는 유전자중 대표적으로 NAG-1 유전자의 경우 apigenin과 isovitexin에 의해 24-48시간에 발현이 증가하였다. 결론적으로 암세포 증식억제활성이 있고 apoptosis 유도효과가 있는 NAG-1의 유도에 의해 대장암 세포의 세포활성이 억제된 것으로 의미되고 향후 apigenin 유도의 NAG-1유전자에 의한 암세포증식의 억제기전에 대한 명확한 연구가 요구된다.

• 약학회지
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• 제55권6호
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• pp.485-491
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• 2011

Previously, we have reported that apigenin, a natural flavonoid found in a variety of vegetables and fruits, stimulated melanogenesis through the activation of $K^+-Cl^-$-cotransport (KCC) in B16 melanoma cells. In this study we investigated the possible involvement of reactive oxygen species (ROS) in the mechanism of apigenin-induced melanogenesis in B16 cells. Apigenin elevated intracellular ROS level in a dose-dependent manner. Treatment with various inhibitors of NADPH oxidase, diphenylene iodonium (DPI), apocynin (Apo) and neopterine (NP) significantly inhibited both the generation of ROS and melanogenesis induced by apigenin. In addition these inhibitors profoundly inhibited apigenin-induced $Cl^-$-dependent $K^+$ efflux, a hallmark of KCC activity. However, the apigenin-induced ROS generation was not significantly affected by treatment with a specific KCC inhibitor R-(+)-[(2-n-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]acetic acid (DIOA). These results indicate that the ROS production may be a upstream regulator of the apigenin-induced KCC stimulation, and in turn, melanogenesis in the B16 cells. Taken together, these results suggest that the NADPH oxidase-mediated ROS production may play an important role in the apigenin-induced melanogenesis in B16 cells. These results further suggest that NADPH oxidase may be a good target for the management of hyperpigmentation disorders.

• Biomolecules & Therapeutics
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• 제20권1호
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• pp.62-67
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• 2012

TNF-related apoptosis-inducing ligand (TRAIL) is a promising agent for management of cancer because of its selective cytotoxicity to cancer cells. However, some cancer cells have resistance to TRAIL. Accordingly, novel treatment strategies are required to overcome TRAIL resistance. Here, we examined the synergistic apoptotic effect of apigenin in combination with TRAIL in Huh-7 cells. We found that combined treatment of TRAIL and apigenin markedly inhibited Huh-7 cell growth compared to either agent alone by inducing apoptosis. Combined treatment with apigenin and TRAIL induced chromatin condensation and the cleavage of poly (ADP-ribose) polymerase (PARP). In addition, enhanced apoptosis by TRAIL/apigenin combination was quantified by annexin V/PI flow cytometry analysis. Western blot analysis suggested that apigenin sensitizes cells to TRAIL-induced apoptosis by activating both intrinsic and extrinsic apoptotic pathway-related caspases. The augmented apoptotic effect by TRAIL/apigenin combination was accompanied by triggering mitochondria-dependent signaling pathway, as indicated by Bax/Bcl-2 ratio up-regulation. Our results demonstrate that combination of TRAIL and apigenin facilitates apoptosis in Huh-7 cells.

• The Korean Journal of Physiology and Pharmacology
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• 제24권6호
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• pp.493-502
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• 2020

Apigenin, a naturally occurring flavonoid, is known to exhibit significant anticancer activity. This study was designed to determine the effects of apigenin on two malignant mesothelioma cell lines, MSTO-211H and H2452, and to explore the underlying mechanism(s). Apigenin significantly inhibited cell viability with a concomitant increase in intracellular reactive oxygen species (ROS) and caused the loss of mitochondrial membrane potential (ΔΨm), and ATP depletion, resulting in apoptosis and necroptosis in monolayer cell culture. Apigenin upregulated DNA damage response proteins, including the DNA double strand break marker phospho (p)-histone H2A.X. and caused a transition delay at the G₂/M phase of cell cycle. Western blot analysis showed that apigenin treatment upregulated protein levels of cleaved caspase-3, cleaved PARP, p-MLKL, and p-RIP3 along with an increased Bax/Bcl-2 ratio. ATP supplementation restored cell viability and levels of DNA damage-, apoptosisand necroptosis-related proteins that apigenin caused. In addition, N-acetylcysteine reduced ROS production and improved ΔΨm loss and cell death that were caused by apigenin. In a 3D spheroid culture model, ROS-dependent necroptosis was found to be a mechanism involved in the anti-cancer activity of apigenin against malignant mesothelioma cells. Taken together, our findings suggest that apigenin can induce ROS-dependent necroptotic cell death due to ATP depletion through mitochondrial dysfunction. This study provides us a possible mechanism underlying why apigenin could be used as a therapeutic candidate for treating malignant mesothelioma.

• Biomolecules & Therapeutics
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• 제14권3호
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• pp.137-142
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• 2006

Apigenin, a natural flavonoid found in a variety of vegetables and fruits, has been shown to possess many biological functions. In this study we investigated the role of apigenin in the production of reactive oxygen species (ROS) through the modulation of activity of $K^+-Cl^-$-cotransport (KCC) in IMR-32 human neuroblastoma cells. Apigenin induced $Cl^-$-dependent $K^+$ efflux, a hallmark of KCC activity, which was markedly prevented by different kinds of KCC inhibitors (calyculin-A, genistein and $BaCl_2$). These results indicate that KCC is functionally present, and activated by apigenin in the IMR-32 cells. Treatment with apigenin also induced a sustained increase in the level of intracellular ROS. The KCC inhibitors also significantly inhibited the apigenin-induced ROS generation. Taken together, these results suggest that apigenin can modulate ROS generation through the activation of a membrane ion transporter, KCC. These results further suggest that the alteration of KCC activity may play a role in the mechanism of degenerative diseases and/or carcinogenesis in neuronal tissues through the regulation of ROS production.

• 생명과학회지
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• 제20권10호
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• pp.1519-1524
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• 2010

Apigenin은 과일과 야채에 들어있는 플라보노이드로 다양한 악성 세포에 항증식효과를 보여준다. 세포성장 저해효과를 확인하기 위하여 KB 구강암세포주를 96 well plate에 $6{\times}10^3$ cells/well로 분주하고 24시간 후에 apigenin을 24시간 동안 처치하여 MTT assay를 수행하였다. Apigenin은 배양 후 용량 의존적으로 세포사를 유도하였다. Apigenin 100 ${\mu}M$을 24시간 동안 처치하고 대조군과 세포성장을 비교하였을 때 유의적인 감소를 확인하였다. KB 구강암세포주에서의 apoptosis를 확인하기 위해 DAPI 염색을 수행하였다. Apigenin을 처치한 세포에서 핵의 응축이 존재함을 형광현미경으로 확인하였다. 우리는 누드마우스에 KB 구강암세포주를 이식하여 세포 성장 억제 효과를 알아보았다. Apigenin을 마우스에 25, 50 mg/kg을 0.2 ml의 PBS에 녹여 경구투여 하였다. 종양 사이즈는 대조군과 25, 50 mg/kg apigenin 투여군을 비교하였을 때 유의적으로 감소하였다. Apoptosis 분석을 위해 TUNEL염색을 수행하였다. 25 mg/kg apigenin 투여군과 대조군을 비교하였을 때 apoptosis의 유의적인 증가를 확인하였다. 육안적 소견을 위한 H&E 염색은 이상이 없었다. 본 연구는 apigenin이 구강암세포주 성장 억제를 apoptosis의 유도를 통하여 확인하였다.