• 생명과학회지
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• 제34권2호
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• pp.94-104
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• 2024

β-lapachone은 다양한 유형의 질병을 치료하기 위해 남미 및 중미 지역의 전통 의학에서 널리 사용되어 온 Tabebuia vellanedae의 껍질에서 분리된 천연 퀴논 화합물의 일종이다. β-lapachone은 여러 유형의 암세포에서 강력한 항암 활성을 갖는 것으로 보고되었지만, 간세포암종 세포의 증식에 대한 효과는 아직 불분명하다. 따라서 본 연구에서는 β-lapachone 인간 간세포암종 Hep3B 세포의 증식에 미치는 영향을 조사하였으며, 본 연구의 결과에 의하면, β-lapachone 처리에 의한 Hep3B 세포의 세포생존율 감소는 세포사멸 유도와 밀접한 관련이 있었다. 또한, β-lapachone이 처리된 Hep3B 세포에서는 항세포사멸 인자인 Bcl-2의 발현이 감소한 반면, 세포사멸 유도 인자인 Bax의 발현은 증가하였으며, 이는 caspase cascade의 활성 증가와 연관성이 있었다. 그러나 pan-caspase 억제제가 존재하는 경우 β-lapachone에 의해 유발된 세포사멸은 약화되었으며, 이는 β-lapachone에 의한 세포사멸 유도가 caspase 의존적인 현상임을 의미한다. 아울러, β-lapachone의 처리는 ERK 경로를 활성화시키면서 PI3K/Akt 경로의 활성을 억제하였으며, β-lapachone 유도 세포사멸에 ERK 억제제의 효과는 미미했지만, PI3K 억제제는 β-lapachone에 의해 유도된 세포사멸을 유의하게 증가시켰다. 비록 생체 내 동물 모델에서의 확인이 필요하지만, 본 연구의 결과는 간세포암종 세포에서 β-lapa-chone의 항암 활성을 이해하는 데 유용한 자료로 활용될 것이다.

• 한국독성학회:학술대회논문집
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• 한국독성학회 2001년도 International Symposium on Dietary and Medicinal Antimutgens and Anticarcinogens
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• pp.150-150
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• 2001

$\beta$ -lapachone, the product of a tree (Tabebuia avellanedae) from South America, is known to exhibit various pharmacologic properties, the mechanisms of which are poorly understood. The aim of the present study was to further elucidate the possible mechanisms by which $\beta$-lapachone exerts its anti-proliferative action in cultured human prostate cancer cells.(omitted)

• Tuberculosis and Respiratory Diseases
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• 제79권4호
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• pp.257-266
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• 2016

Background: Idiopathic pulmonary fibrosis is a common interstitial lung disease; it is a chronic, progressive, and fatal lung disease of unknown etiology. Over the last two decades, knowledge about the underlying mechanisms of pulmonary fibrosis has improved markedly and facilitated the identification of potential targets for novel therapies. However, despite the large number of antifibrotic drugs being described in experimental pre-clinical studies, the translation of these findings into clinical practices has not been accomplished yet. NADH:quinone oxidoreductase 1 (NQO1) is a homodimeric enzyme that catalyzes the oxidation of NADH to $NAD^+$ by various quinones and thereby elevates the intracellular $NAD^+$ levels. In this study, we examined the effect of increase in cellular $NAD^+$ levels on bleomycin-induced lung fibrosis in mice. Methods: C57BL/6 mice were treated with intratracheal instillation of bleomycin. The mice were orally administered with ${\beta}$-lapachone from 3 days before exposure to bleomycin to 1-3 weeks after exposure to bleomycin. Bronchoalveolar lavage fluid (BALF) was collected for analyzing the infiltration of immune cells. In vitro, A549 cells were treated with transforming growth factor ${\beta}1$ (TGF-${\beta}1$) and ${\beta}$-lapachone to analyze the extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT). Results: ${\beta}$-Lapachone strongly attenuated bleomycin-induced lung inflammation and fibrosis, characterized by histological staining, infiltrated immune cells in BALF, inflammatory cytokines, fibrotic score, and TGF-${\beta}1$, ${\alpha}$-smooth muscle actin accumulation. In addition, ${\beta}$-lapachone showed a protective role in TGF-${\beta}1$-induced ECM expression and EMT in A549 cells. Conclusion: Our results suggest that ${\beta}$-lapachone can protect against bleomycin-induced lung inflammation and fibrosis in mice and TGF-${\beta}1$-induced EMT in vitro, by elevating the $NAD^+$/NADH ratio through NQO1 activation.

• 한국환경성돌연변이발암원학회:학술대회논문집
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• 한국환경성돌연변이발암원학회 2002년도 Current Trends in Toxicological Sciences
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• pp.95-95
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• 2002

• Biomolecules & Therapeutics
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• 제27권2호
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• pp.178-184
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• 2019

Parkinson's disease is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons within the substantia nigra pars compacta. In the present study, we investigated whether ${\beta}-Lapachone$ (${\beta}-LAP$), a natural naphthoquinone compound isolated from the lapacho tree (Tabebuia avellanedae), elicits neuroprotective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mouse model. ${\beta}-LAP$ reduced the tyrosine hydroxylase (TH)-immunoreactive fiber loss induced by MPTP in the dorsolateral striatum, and alleviated motor dysfunction as determined by the rotarod test. In addition, ${\beta}-LAP$ protected against MPTP-induced loss of TH positive neurons, and upregulated B-cell lymphoma 2 protein (Bcl-2) expression in the substantia nigra. Based on previous reports on the neuroprotective role of nuclear factor-E2-related factor-2 (Nrf2) in neurodegenerative diseases, we investigated whether ${\beta}-LAP$ induces upregulation of the Nrf2-hemeoxygenae-1 (HO-1) signaling pathway molecules in MPTP-injected mouse brains. Western blot and immunohistochemical analyses indicated that ${\beta}-LAP$ increased HO-1 expression in glial fibrillary acidic protein-positive astrocytes. Moreover, ${\beta}-LAP$ increased the nuclear translocation and DNA binding activity of Nrf2, and the phosphorylation of upstream adenosine monophosphate-activated protein kinase (AMPK). ${\beta}-LAP$ also increased the localization of p-AMPK and Nrf2 in astrocytes. Collectively, our data suggest that ${\beta}-LAP$ exerts neuroprotective effect in MPTP-injected mice by upregulating the p-AMPK/Nrf2/HO-1 signaling pathways in astrocytes.

• The Korean Journal of Physiology and Pharmacology
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• 제17권1호
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• pp.9-13
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• 2013

The aim of the present study was to examine the effect of micellar systems on the absorption of beta-lapachone (b-lap) through different intestinal segments using a single-pass rat intestinal perfusion technique. B-lap was solubilized in mixed micelles composed of phosphatidylcholine and sodium deoxycholate, and in sodium lauryl sulfate (SLS)-based conventional micelles. Both mixed micelles and SLS micelles improved the in situ permeability of b-lap in all intestinal segments tested although the mixed micellar formulation was more effective in increasing the intestinal absorption of b-lap. The permeability of b-lap was greatest in the large intestinal segments. Compared with SLS micelles, the effective permeability coefficient values measured with mixed micelles were 5- to 23-fold higher depending on the intestinal segment. Our data suggest that b-lap should be delivered to the large intestine using a mixed micellar system for improved absorption.

• Radiation Oncology Journal
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• 제31권2호
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• pp.57-65
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• 2013

Beta-lapachone (${\beta}$-Lap; 3,4-dihydro-2, 2-dimethyl-2H-naphthol[1, 2-b]pyran-5,6-dione) is a novel anti-cancer drug under phase I/II clinical trials. ${\beta}$-Lap has been demonstrated to cause apoptotic and necrotic death in a variety of human cancer cells in vitro and in vivo. The mechanisms underlying the ${\beta}$-Lap toxicity against cancer cells has been controversial. The most recent view is that ${\beta}$-Lap, which is a quinone compound, undergoes two-electron reduction to hydroquinone form utilizing NAD(P)H or NADH as electron source. This two-electron reduction of ${\beta}$-Lap is mediated by NAD(P)H:quinone oxidoreductase (NQO1), which is known to mediate the reduction of many quinone compounds. The hydroquinone forms of ${\beta}$-Lap then spontaneously oxidizes back to the original oxidized ${\beta}$-Lap, creating futile cycling between the oxidized and reduced forms of ${\beta}$-Lap. It is proposed that the futile recycling between oxidized and reduced forms of ${\beta}$-Lap leads to two distinct cell death pathways. First one is that the two-electron reduced ${\beta}$-Lap is converted first to one-electron reduced ${\beta}$-Lap, i.e., semiquinone ${\beta}$-Lap $(SQ)^{{\cdot}-}$ causing production of reactive oxygen species (ROS), which then causes apoptotic cell death. The second mechanism is that severe depletion of NAD(P)H and NADH as a result of futile cycling between the quinone and hydroquinone forms of ${\beta}$-Lap causes severe disturbance in cellular metabolism leading to apoptosis and necrosis. The relative importance of the aforementioned two mechanisms, i.e., generation of ROS or depletion of NAD(P)H/NADH, may vary depending on cell type and environment. Importantly, the NQO1 level in cancer cells has been found to be higher than that in normal cells indicating that ${\beta}$-Lap may be preferentially toxic to cancer cells relative to non-cancer cells. The cellular level of NQO1 has been found to be significantly increased by divergent physical and chemical stresses including ionizing radiation. Recent reports clearly demonstrated that ${\beta}$-Lap and ionizing radiation kill cancer cells in a synergistic manner. Indications are that irradiation of cancer cells causes long-lasting elevation of NQO1, thereby sensitizing the cells to ${\beta}$-Lap. In addition, ${\beta}$-Lap has been shown to inhibit the repair of sublethal radiation damage. Treating experimental tumors growing in the legs of mice with irradiation and intraperitoneal injection of ${\beta}$-Lap suppressed the growth of the tumors in a manner more than additive. Collectively, ${\beta}$-Lap is a potentially useful anti-cancer drug, particularly in combination with radiotherapy.

• 한국독성학회:학술대회논문집
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• 한국독성학회 2002년도 Current Trends in Toxicological Sciences
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• pp.95-95
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• 2002

Cyclooxygenases (COXs) are key enzymes in the conversion of arachidonic acid into prostanoids, which are involved in cell proliferation and inflammation. Two distinct COXS have been identified: COX-l which is constitutively expressed and COX-2 which is induced by different products such as tumor promoters or growth factors.(omitted)

• 한국생명과학회:학술대회논문집
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• 한국생명과학회 2007년도 제48회 학술심포지움 및 추계국제학술대회
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• pp.42.1-42.1
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• 2007

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• 생명과학회지
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• 제24권1호
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• pp.98-103
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• 2014

NQO1은 플라보 단백질 계통의 2 전자 환원 효소이며 NADH 또는 NADPH를 보조인자로 quinone 계통의 화합물을 hydroquinone으로 환원 한다. 암에서 NQO1은 그에 상응하는 정상 조직과 비교하였을 때 비교적 높은 발현을 나타낸다. NQO1의 다양한 기능 중 quinone 물질 대사는 두 가지 형태의 상반되는 기능을 가진다. 이것은 quinone으로부터 전환된 hydroquinone의 상태적 안정성과 불안정성에 기인하며, 불안정한 hydroquinone의 생성은 산화적 손상 야기 및 DNA 손상은 세포의 운명을 바꾸어 놓게 된다. 따라서 암에서 그 발현이 높은 NQO1을 표적으로 작용하는 생체환원 물질은 암 세포 사멸을 강하게 유도하게 되어 암 치료의 가능성을 보여주고 있다. 항암 표적 분자로서 NQO1 특징과 NQO1을 통해 작용하는 생체환원물질 ${\beta}$-lapachone의 항암 효과와 기전에 대하여 살펴보았다.