• 생명과학회지
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• 제16권5호
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• pp.759-766
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• 2006

급성 전골수성 백혈병은 염색체 전위의 결과로 생긴 PML/RAR$({\alpha})$ 융합 단백의 과발현으로 영향을 받은 전골 수세포의 분화 정지로 발생하는 골수성 백혈병의 일종이다. 삼산화 비소는 세포고사를 유발하여 급성전골수성 백혈병의 관해를 유도한다는 것이 밝혀졌으나 이 약제에 대한 감수성이 다양하여 고형암에 적용하기에는 제한점이 있다. All-trans-retinoic acid (ATRA)에 감수성인 NB4 세포주와 내성인 UF-1 세포주 모두에 삼산화 비소가 세포고사를 유도하였다. 백혈병 세포주를 삼산화 비소로 처리하여, 세포내 GSH 농도가 낮아지고 세포고사의 감수성이 높아지는 상관관계를 찾았으며 전골수성 암세포를 수지상 세포 표면 표식자를 가진 세포로 분화시켰다. ATRA에 대한 감수성인 세포주와 내성인 세포주의 삼산화 비소에 대한 반응의 차이를 이해하고, 전골수 세포가 수지상 세포로 분화하는 과정을 규명한다면, 삼산화 비소에 의한 전골수성 백혈병의 완전관해의 기전을 밝힐 수 있고 또한 임상적용을 확대할 수 있을 것이다.

• Radiation Oncology Journal
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• 제23권4호
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• pp.211-216
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• 2005

목적: all-trans retinoic acid (ATRA)는 뇌종양 세포의 증식억제효과가 있으며, ATRA와 방사선의 병용은 악성 뇌종양의 치료 효과를 증진시키는 방법이 될 수 있다. 그러나 ATRA에 의해 항산화효소가 증가되며 이로 인해 방사선에 의해 생성된 reactive oxygen species (ROS)가 제거된다면 방사선의 효과는 낮아질 수 있다. 본 연구에서는 ATRA에 의해 유도되는 카탈라제(catalase)에 의한 방사선감수성의 변화를 보고자하였다. 대상 및 방법: 백서 교종세포(36B10)을 대상으로 ATRA 및 ATRA의 화학적 억제제인 3-amino-1, 2, 4-triazole (ATZ) 와 병용하여 카탈라제 활성도, 방사선감수성 및 ROS의 변화를 측정하였다. 카탈라제 활성도는 $H_2O_2$의 소멸을 자외선 분광광도계로 측정하는 방법을 이용해 정량하였으며, 방사선감수성은 단일집락군형성능력으로, ROS 는 2, 7-dichlorofluorescein diacetate 를 분광광도계로 측정하였다. 결과: 카탈라제 활성도는 ATRA의 농도(10, 25, $50{\mu}M$)에 따라 증가하였다. ATRA ($10{\mu}M$)와 방사선(4 Gy)의 병용에 의해 생존분획은 상승적(supra-auditive)으로 감소하였으며, 이 감소된 생존분획은 ATZ 동시 투여에 의해 증가하였다. ATRA $10{\mu}M$ 또는 $25{\mu}M$을 48시간 처리 후 ROS는 대조군에 비해 각각 1.5배, 2배 증가하였고, 4 Gy와 ATRA의 병용군에서는 2.5배 증가하였다. ATRA와 방사선의 병용에 의해 증가된 ROS는 ATZ에 의해 감소되었다. 결론: ATRA에 의해 유도되는 카탈라제는 방사선감수성을 감소시키지 않으며, 오히려 ROS의 증가에 의해 방사선감수성을 상승시켰다. 따라서 ATRA와 방사선의 병용은 뇌종양의 치료에 유용한 방법이 될 수 있을 것으로 보인다.

• Asian Pacific Journal of Cancer Prevention
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• 제13권5호
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• pp.1809-1817
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• 2012

Background: Gastric cancer is frequently lethal despite aggressive multimodal therapies, and new treatment approaches are therefore needed. Retinoids are potential candidate drugs: they prevent cell differentiation, proliferation and malignant transformation in gastric cancer cell lines. They interact with nuclear retinoid receptors (the retinoic acid receptors [RARs] and retinoid X receptors [RXRs]), which function as transcription factors, each with three subclasses, ${\alpha}$, ${\beta}$ and ${\gamma}$. At present, little is known about retinoid expression and influence on prognosis in gastric cancers. Patients and Methods: We retrospectively analyzed the expression of the subtypes RARa, $RAR{\beta}$, $RAR{\gamma}$, RXRa, $RXR{\beta}$, $RXR{\gamma}$ by immunohistochemistry in 147 gastric cancers and 51 normal gastric epithelium tissues for whom clinical follow-up data were available and correlated the results with clinical characteristics. In addition, we quantified the expression of retinoid receptor mRNA using real-time PCR (RT-PCR) in another 6 gastric adenocarcinoma and 3 normal gastric tissues. From 2008 to 2010, 80 patients with gastric cancers were enrolled onto therapy with all-trans-retinoic acid (ATRA). Results: RARa, $RAR{\beta}$, $RAR{\gamma}$ and $RXR{\gamma}$ positively correlated with each other (p < 0.001) and demonstrated significantly lower levels in the carcinoma tissue sections (p < 0.01), with lower $RAR{\beta}$, $RAR{\gamma}$ and RXRa expression significantly related to advanced stages (p < =0.01). Tumors with poor histopathologic grade had lower levels of RARa and $RAR{\beta}$ in different histological types of gastric carcinoma (p < 0.01). Patients whose tumors exhibited low levels of RARa expression had significantly lower overall survival compared with patients who had higher expression levels of this receptor (p < 0.001, HR=0.42, 95.0% CI 0.24-0.73), and patients undergoing ATRA treatment had significantly longer median survival times (p = 0.007, HR=0.41, 95.0% CI 0.21-0.80). Conclusions: Retinoic acid receptors are frequently expressed in epithelial gastric cancer with a decreased tendency of expression and RARa may be an indicator of a positive prognosis. This study provides a molecular basis for the therapeutic use of retinoids against gastric cancer.

• The Korean Journal of Physiology and Pharmacology
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• 제19권2호
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• pp.105-109
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• 2015

NgR1, a Nogo receptor, is involved in inhibition of neurite outgrowth and axonal regeneration and regulation of synaptic plasticity. P19 embryonal carcinoma cells were induced to differentiate into neuron-like cells using all trans-retinoic acid and the presence and/or function of cellular molecules, such as NgR1, NMDA receptors and STAT3, were examined. Neuronally differentiated P19 cells expressed the mRNA and protein of NgR1, which could stimulate the phosphorylation of STAT3 when activated by Nogo-P4 peptide, an active segment of Nogo-66. During the whole period of differentiation, mRNAs of all of the NMDA receptor subtypes tested (NR1, NR2A-2D) were consistently expressed, which meant that neuronally differentiated P19 cells maintained some characteristics of neurons, especially central nervous system neurons. Our results suggests that neuronally differentiated P19 cells expressing NgR1 may be an efficient and convenient in vitro model for studying the molecular mechanism of cellular events that involve NgR1 and its binding partners, and for screening compounds that activate or inhibit NgR1.

• Tuberculosis and Respiratory Diseases
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• 제44권1호
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• pp.162-174
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• 1997

연구배경 : HSVtk 유전자를 암세포에 이입하여 GCV에 대해 선택적으로 감수성을 증가시키는 HSVtk/GCV 유전자치료에서 bystander effect는 모든 암세포에 유전자를 이입하지 않고도 치료효과를 얻을 수 있도록 한다. 그러나 현존하는 viral vector는 유전자이입 효율이 낮아 임상적으로 치료효과를 기대하는데는 한계가 있다. 따라서 유전자의 이입효율이 높은 새로운 vector의 개발과 함께 bystander effect의 극대화를 통해 치료효과를 증가시킬 수 있는 방법 등이 요구된다. 최근 gap junction을 통한 세포간의 metablic cooperation이 bystander effect의 주요기전임이 밝혀졌고 retinoids는 gap junction을 통한 세포간의 communication을 증가시킨다고 보고되었다. 저자들은 HSVtk/GCV 유전자치료에서 bystander effect에 미치는 retinoids의 효과를 조사하였다. 방 법 : Adenovus와 retrovirus vector를 이용하여 connexin 43를 발현하는 악성중피종세포와 connexin 43를 발현하지 않는 SKHep-J 세포주에 HSVtk 유전자를 이입한 후 HSVtk 유전자가 이입된 세포와 HSVtk 유전자가 이입되지 않은 세포들을 여러가지 비율로 혼합한 mixing study를 시행하였으며 $10^{-10}M-10^{-6}M$ RA 처리 유무에 따른 bystander effect에 의한 살상효과를 비교하였다. 그리고 gap junction을 통한 세포간의 communication에 대한 retinoids의 영향을 조사하기 위해 retinoids 처리에 따른 세포간 communication을 FACS를 이용하여 double-dye transfer study로 측정하였다. 결 과 : Connexin 43를 발현하지 않는 SKHep-J 세포주에서는 RA 처리유무에 따른 bystander effect에 의한 살상효과의 차이가 없었다. 그러나 connexin 43를 발현하는 악성중피종 세포주에서는 $10^{-8}M-10^{-6}M$ RA처리시 세포간의 communication과 bystander effect가 RA를 처리하지 않은 대조군에 비해 유의하게 증가되었다. 결 론 : RA는 gap junction을 통한 세포간의 communication을 증가시켜 HSVtk/GCV 유전자치료에서 bystander effect에 의한 살상효과를 증가시켰다. 이러한 결과는 HSVtk/GCV 유전자치료의 효과를 증가시킬 수 있는 새로운 방법이 될 수 있을 것으로 생각된다.

• Toxicological Research
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• 제32권3호
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• pp.239-243
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• 2016

Propolis is a multicomponent, active, complex resinous substance collected by honeybees from a variety of plant sources. We have studied the effect of propolis on neurite outgrowth of SH-SY5Y human neuroblastoma cells induced to differentiate by all-trans-retinoic acid (RA). Propolis, at a concentration of $3{\mu}g/mL$, had no significant effect on the viability of differentiating SH-SY5Y cells. However, the neurite outgrowth of the differentiating SH-SY5Y cells treated with propolis ($0.3{\sim}3{\mu}g/mL$) for 48 hr was significantly inhibited in a dose-dependent manner. Treatment of RA-stimulated differentiating SH-SY5Y cells with 0.3 to $3{\mu}g/mL$ propolis resulted in decreased level of transglutaminase and 43-kDa growth-associated protein (GAP-43) in a dose-dependent manner. The results indicate that propolis is able to inhibit neurite outgrowth of differentiating SH-SY5Y cells.

• Toxicological Research
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• 제26권1호
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• pp.61-66
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• 2010

Retinoids have many beneficial effects on dermatological applications. But, retinoids cause skin irritation. In this study, the safety of retinoids was clarified via both primary skin irritation test in rabbits and sensitization study using an integrated model for the differentiation of chemical-induced allergic and irritant skin reaction (IMDS), an alternative method to sensitization test. The effects of retinoids on the change of ultraviolet A (UVA)-induced matrix metalloproteinase-1 (MMP-1) in human skin fibroblasts and the modulation of type-1 pN collagen synthesis in hairless mice were examined to clarify the anti-wrinkle effects. Alltrans retinol (t-ROL) and its derivative, all-trans retinoic acid (t-RA), showed mild skin irritation but did not induce the sensitization. t-ROL and t-RA exerted anti-wrinkle effects by inhibiting the UVA-induced MMP-1 in human skin fibroblasts and increasing the type-1 pN collagen synthesis in hairless mice. These findings suggest that retinoids do not induce the allergy, and show anti-wrinkle effects by decreasing MMP-1 activation and increasing collagen synthesis.

• 대한의생명과학회지
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• 제16권1호
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• pp.1-9
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• 2010

In order to understand the effects of all-trans-RA on palate development, RA was injected into the abdominal cavity of pregnant mice and then the embryos were taken in the following days and analyzed morphologically as well as molecular biologically. When RA was administered at the stage of E11 or E15, the overall craniofacial development was retarded. The length from jaw to eye was shortened, compared to that of normal group. When the E11 embryos were exposed to RA, cleft lip was also found along with the cleft palate. In vitro palate culture experiment also revealed that RA caused cleft palate. When RT-PCR was performed, early stage administration of RA at E11 inhibited the upregulation of Hoxa7 expression at E15 through E17. Whereas in control group, high level of Hoxa7 expression was detected in the palate of E15 to E17. In the case of Bax, the expression was decreased from E16, while remaining constant in control group. When TUNEL analysis was performed following the RA treatment at E15, TUNEL positive cells were detected in the mesenchymal cells as well as epithelial cells of palatal shelves of E16 and in E17 embryos. Whereas in normal control, TUNEL positive cells were observed mostly at the epithelium around the nasal cavity and oral cavity where rugae is made. These results altogether indicate that exposure to RA during palate development causes facial deformity including cleft palate and cleft lip by modulating the expression of homeotic genes such as Hoxa7 as well as an apoptosis-related gene, Bax, and thus malregulating the apoptosis.

• BMB Reports
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• 제39권6호
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• pp.722-729
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• 2006

Recently, we have reported that 3-hydrogenkwadaphnin (3-HK), a diterpene ester isolated from Dendrostellera lessertii (Thymealeaceae), is very effective against leukemia cell lines without any detectable effects on normal cells (Moosavi et al., 2005b). In this study, we report that 3-HK induces $G_1$ cell-cycle arrest, differentiation and apoptosis in APL NB4 cell line. Indeed, the drug between 24 to 96 h induced 7-65% growth inhibition of NB4 cells. Cell viability was also decreased by 2-55% between 24 to 96 h treatments with the drug, respectively. These effects of the drug were also dose-dependent. According to flow cytomtry results, 3-HK (15 nM) induced a significant G1-arrest up to 24 h which was consequently followed with appearance of sub-$G_1$ peak at 72 to 96 h. Hoechst 33258 staining and DNA fragmentation assays confirmed the occurrence of apoptosis among the treated cells. On the other hand, NBT reducing assay, Wright-Giemsa staining, phagocytic activity and expression of cell surface markers (CD11b and CD14) confirmed that the inhibition of proliferation is associated with differentiation especially toward macrophage-like morphology. Interestingly, 3-HK at 5 and 10 nM enhanced the effects of all-trans retinoic acid (ATRA) in NB4 cells. Based on these results, 3-HK might become an ideal candidate for treatment of APL patients pending full exploration of its biological functions.

• 한국생물공학회:학술대회논문집
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• 한국생물공학회 2001년도 추계학술발표대회
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• pp.867-870
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• 2001

아급성 독성 시험으로부터, 미립구내의 레티노익 산을 기준으로 한 투여량이 100mg/kg 일때는 4마리의 치사 개체가 보이는 등의 심각한 독성 효과가 유발되었으며, 25 및 50mg/kg인 경우에 독성 효과가 거의 나타나지 않음을 관찰하였다. 50mg/kg의 투여량의 경우, 일부 동물에서 뼈골절 현상이 나타났지만, 이러한 독성효과는 항염증제를 같이 투여함으로써 극복될 수 있을 것으로 생각되어졌다. 따라서, 앞으로의 실험에서는 항염증제를 이용하여, 가능한 독성을 억제하연서, 보다 빠른 기간 내에 상태가 회복될 수 있도록 하는 연구를 행할 것이다.