• Radiation Oncology Journal
• /
• 제28권4호
• /
• pp.211-218
• /
• 2010

목적: 레티노인산(All-trans retinoic acid, ATRA)은 뇌종양 세포의 증식을 억제한다. 최근 ATRA에 의한 카타라제의 유도가 보고된 바 있다. 이에 저자들은 ATRA의한 카타라제의 유도가 ATRA의 세포증식 억제 효과와 관련이 있는지 알아보고자 하였다. 대상 및 방법: 36B10세포를 0~50${\mu}M$ ATRA로 24, 48시간 처리한 후 카타라제의 mRNA, 단백질 및 활성도를 측정하였다. 반응성산소종(reactive oxygen species, ROS)은 2',7'-dichlorofluorescin diacetate를 사용하여 측정하였고, 세포사는 clonogenic assay로 측정하였다. 결과: 카타라제의 mRNA, 단백질 및 활성도는 ATRA의 농도 및 처리 시간에 따라 증가하였다. ATRA에 의해 증가한 카타라제의 활성도는 3-amino-1,2,4-triazole (ATZ)에 의해 감소하였다. ATRA에 의해 증가한 ROS는 ATZ에 의해 감소하였다. ATRA에 의해 감소한 세포 생존분획은 ATZ에 의해 부분적으로 증가하였다. 결론: ATRA에 의해 유도된 카타라제는 ROS의 과생산과 관련 있으며 이는 36B10세포의 증식 억제를 가져온다.

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

• 대한의생명과학회지
• /
• 제26권4호
• /
• pp.256-266
• /
• 2020

Carboxypeptidase D (CPD) is a zinc-dependent protease, which is highly expressed in macrophages, and is thought to participate in inflammatory processes. In the present study, we investigated the possible regulatory effect of all-trans retinoic acid (ATRA), which is an active form of vitamin A and plays a critical regulatory role in both the innate and adaptive immunity, on CPD expression and secretion in human monocytic THP-1 cells. CPD mRNA expression first increased, from a concentration as low as 10 nM ATRA to a maximum level of expression, at 1 μM. ATRA enhanced intracellular CPD expression in a time- and concentration-dependent manner but did not affect cell surface CPD expression. Interestingly, 9-cis-RA did not affect CPD expression. Additionally, an experiment with RAR/RXR selective agonist or antagonists demonstrated that ATRA-induced enhancement of CPD expression was RAR/RXR dependent. ATRA also enhanced CPD secretion from THP-1 cells; however, this enhancement was RAR/RXR-independent. The anti-inflammatory agent dexamethasone reversed ATRA-induced enhancement of CPD expression and secretion. Our results suggest ATRA exerts regulatory effects on expression and secretion of CPD in human monocytes, and ATRA-induced CPD secretion may be associated with inflammatory response.

• Macromolecular Research
• /
• 제16권8호
• /
• pp.682-685
• /
• 2008

The aim of this work was to develop and evaluate solid lipid nanoparticles (SLN) containing all-trans-retinoic acid (ATRA) for topical delivery. SLN composed of coconut oil and curdlan improved the suspension instability of ATRA in aqueous solution. The photodegradation of ATRA by light was reduced by incorporation in SLN. The loading efficiency of ATRA in SLN was higher than 95% (w/w). The amounts of ATRA released from SLN at $4^{\circ}C$ and at $37^{\circ}C$ were less than 15% and more than 60% (w/w) for 96 h, respectively. The ATRA-loaded SLN can be used as a potential carrier for topical delivery.

• Journal of Pharmaceutical Investigation
• /
• 제31권3호
• /
• pp.167-172
• /
• 2001

All-trans retinoic acid (ATRA), vitamin A acid, has been shown to exert anticancer activity in a number of types of cancers, particularly in acute promyelocytic leukaemia (APL). Due to its highly variable bioavailability and induction of its own metabolism after oral treatment, development of parenteral dosage forms are required. However, its poor aqueous solubility and chemical unstability give major drawbacks in parenteral administration. This study was undertaken to investigate a possibility to develop a parenteral formulation of ATRA by employing solid lipid nanoparticle (SLN) as a carrier. By optimizing the production parameters and the composition of SLNs, SLNs with desired mean particle size (<100 nm) as a parenteral dosage form could be produced from trimyristin (as solid lipid), Egg phosphatidylcholine and Tween 80 (as SLN stabilizer). The mean particle size of SLN formulation of ATRA was not changed during storage, suggesting its physical stability. Thermal analysis confirmed that the inner lipid core of SLNs exist at solid state. The mean particle size of ATRA-loaded SLNs was not significantly changed by the lyophilization process. ATRA could be efficiently loaded in SLNs, while maintaining its anticancer activity against HL-60, a well-known APL cell line. Furthermore, by lyophilization, ATRA loaded in SLN could be retained chemically stable during storage. Taken together, our present study demonstrates that physically and chemically stable ATRA formulation adequate for parenteral administration could be obtained by employing SLN technology.

• Journal of Ginseng Research
• /
• 제48권3호
• /
• pp.298-309
• /
• 2024

Background: 20(S)-ginsenoside Rh2(GRh2), an effective natural histone deacetylase inhibitor, can inhibit acute myeloid leukemia (AML) cell proliferation. Lactate regulated histone lactylation, which has different temporal dynamics from acetylation. However, whether the high level of lactylation modification that we first detected in acute promyelocytic leukemia (APL) is associated with all-trans retinoic acid (ATRA) resistance has not been reported. Furthermore, Whether GRh2 can regulate lactylation modification in ATRA-resistant APL remains unknown. Methods: Lactylation and METTL3 expression levels in ATRA-sensitive and ATRA-resistant APL cells were detected by Western blot analysis, qRT-PCR and CO-IP. Flow cytometry (FCM) and APL xenograft mouse models were used to determine the effect of METTL3 and GRh2 on ATRA-resistance. Results: Histone lactylation and METTL3 expression levels were considerably upregulated in ATRA-resistant APL cells. METTL3 was regulated by histone lactylation and direct lactylation modification. Overexpression of METTL3 promoted ATRA-resistance. GRh2 ameliorated ATRA-resistance by downregulated lactylation level and directly inhibiting METTL3. Conclusions: This study suggests that lactylation-modified METTL3 could provide a promising strategy for ameliorating ATRA-resistance in APL, and GRh2 could act as a potential lactylation-modified METTL3 inhibitor to ameliorate ATRA-resistance in APL.

• Biomolecules & Therapeutics
• /
• 제20권3호
• /
• pp.286-292
• /
• 2012

All-trans retinoic acid (ATRA) is currently used in adjuvant differentiation-based treatment of residual or relapsed neuroblastoma (NB). It has been reported that short-term ATRA treatment induces migration and invasion of SH-SY5Y via transglutaminase-2 (Tgase-2). However, the detailed mechanism of Tgase-2's involvement in NB cell invasion remains unclear. Therefore we investigated the role of Tgase-2 in invasion of NB cells using SH-SY5Y cells. ATRA dose-dependently induced the invasion of SH-SY5Y cells. Cystamine (CTM), a well known tgase inhibitor suppressed the ATRA-induced invasion of SH-SY5Y cells in a dose-dependent manner. Matrix metalloproteinase -9 (MMP-9) and MMP-2, well known genes involved in invasion of cancer cells were induced in the ATRA-induced invasion of the SH-SH5Y cells. Treatment of CTM suppressed the MMP-9 and MMP-2 enzyme activities in the ATRA-induced invasion of the SH-SY5Y cells. To confirm the involvement of Tgase-2, gene silencing of Tgase-2 was performed in the ATRA-induced invasion of the SH-SH5Y cells. The siRNA of Tgase-2 suppressed the MMP-9 and MMP-2 activity of the SH-SY5Y cells. MMP-2 and MMP-9 are well known target genes of NF-${\kappa}B$. Therefore the relationship of Tgase-2 and NF-${\kappa}B$ in the ATRA-induced invasion of the SH-SY5Y cells was examined using siRNA and CTM. ATRA induced the activation of NF-${\kappa}B$ in the SH-SY5Y cells and CTM suppressed the activation of NF-${\kappa}B$. Gene silencing of Tgase-2 suppressed the MMP expression by ATRA. These results suggested that Tgase-2 might be a new target for controlling the ATRA-induced invasion of NBs.

• Imaging Science in Dentistry
• /
• 제33권2호
• /
• pp.97-105
• /
• 2003

Purpose : To evaluate the effect of all-trans-retinoic acid (ATRA) on the radiosensitivity of normal human oral keratinocyte (NHOK). Materials and methods: Relative cell survival fraction including SF2 (survival fraction at 2 Gy) was calculated on the basis of colony formation assay. Data were fitted to the linear-quadratic model to establish the survival curve and calculate α and β values. Using flow cytometry at 1, 2, 3, 4, and 5 days after exposure to 2 and 10 Gy irradiation, cell cycle arrest and apoptosis were analysed. To understand the molecular mechanism of the radiosensitization of ATRA on NHOK, proteins related with apoptosis and cell cycle arrest were investigated by Western blot analysis. Results: Treatment with ATRA resulted in a significant decrease of SF2 value for NHOK from 0.63 to 0.27, and increased α and β value, indicating that ATRA increased radiosensitivity of NHOK. ATRA increased LDH significantly, but increasing irradiation dose decreased LDH, suggesting that the radiosensitizing effect of ATRA is not directly related with increasing cell necrosis by ATRA. ATRA did not induce appotosis but increased G2 arrest after 10 Gy irradiation, implying that the increased radiosensitivity of NHOK may be due to a decrease in mitosis casued by increasing G2 arrest. ATRA inhibited the reduction of p53 at 3 days after l0Gy irradiation and increased p21 at 1 day after 10 Gy irradiation. Further study is required to determine the precise relationship between this effect and the radiosensitizing effect of A TRA. Conclusion: These results suggested that ATRA increase radiosensitivity by inhibiting mitosis caused by increasing G2 arrest.

• Asian Pacific Journal of Cancer Prevention
• /
• 제15권24호
• /
• pp.10819-10824
• /
• 2015

Aims: To explore the effect and probable mechanism of a synthetic retinoid 4-amino-2-tri-fluoromethylphenyl ester (ATPR) on apoptosis of MDA-MB-231 breast cancer cells. Materials and Methods: MTT assays were performed to measure the proliferation of MDA-MB-231 cells treated with different concentrations of all-trans retinoic acid (ATRA) and ATPR. Morphologic changes were observed by microscopy. The apoptosis rates and cell cycling of MDA-MB-231 cells treated with ATRA or ATPR were assessed using flow cytometry analysis. Expression of retinoic acid receptor and phosphorylation of ERK, JNK, p38 proteins were detected by Western blotting. Results: Treatment of the cells with the addition of $15{\mu}mol/L$ ATPR for 48 h clearly demonstrated reduced cell numbers and deformed cells, whereas no changes in the number and morphology were observed after treatment with ATRA. The apoptosis rate was 33.2% after breast cancer MDA-MB-231 cells were treated by ATPR ($15{\mu}mol/L$) whereas ATRA ($15{\mu}mol/L$) had no apoptotic effect. ATPR inhibited the phosphorylation of ERK, JNK, and p38 while ATRA had no significant effect. ATPR inhibited the expression of BiP and increased the expression of Chop at the protein level compared with control groups, ATRA and ATPR both decreased the protein expression of $RXR{\alpha}$, ATPR reduced the protein expression of $RAR{\beta}$ and $RXR{\beta}$ while ATRA did not decrease $RAR{\beta}$ or $RXR{\beta}$. Conclusions: ATPR could induce apoptosis of breast cancer MDA-MB-231 cells, possible mechanisms being binding to $RAR{\beta}/RXR{\beta}$ heterodimers, then activation of ER stress involving the MAPK pathway.

• Journal of Animal Science and Technology
• /
• 제63권6호
• /
• pp.1397-1410
• /
• 2021

The present study was designed to determine the influence of all-trans retinoic acid (ATRA) on adipogenesis-related gene regulation in bovine intramuscular (IM) and subcutaneous (SC) adipose cells during differentiation. Bovine IM and SC adipocytes were isolated from three 19-mo-old, crossbred steers. Adipogenic differentiation was induced upon cultured IM and SC preadipocytes with various doses (0, 0.001, 0.01, 0.1, 1 µM) of ATRA. After 96 h of incubation, cells were harvested and used to measure the gene expression of CCAAT/Enhancer binding protein β (C/EBPβ), peroxisome proliferator-activated receptor (PPAR) γ, glucose transporter 4 (GLUT4), stearoyl CoA desaturase (SCD), and Smad transcription factor 3 (Smad3) relative to the quantity of ribosomal protein subunit 9 (RPS 9). Retinoic acid receptor (RAR) antagonist also tested to identify the effect of ATRA on PPARγ -RAR related gene expression in IM cells. The addition of ATRA to bovine IM decreased (p < 0.05) expression of PPARγ. The expression of PPARγ was also tended to be downregulated (p < 0.1) in high levels (10 µM) of ATRA treatment in SC cells. The treatment of RAR antagonist increased the expression of PPARγ in IM cells. Expression of C/EBPβ decreased (p < 0.05) in SC, but no change was observed in IM (p > 0.05). Increasing levels of ATRA may block adipogenic differentiation via transcriptional regulation of PPARγ. The efficacy of ATRA treatment in adipose cells may vary depending on the location.