A 83-01 is a potent inhibitor of TGF-β type I receptor ALK5 kinase, type I nodal receptor ALK4 and type I nodal receptor ALK7, with IC50 s of 12 nM,45 nM and 7.5 nM against the transcription induced by ALK5, ALK4 and ALK7, respectively [1].
A 83-01 reduces the level of ALK-5-induced transcription in Mv1Lu cells, also blocks the ALK4-TD and ALK7-TD induced transcription R4-2 cells, and weakly suppresses that induced by constitutively active ALK-6, ALK-2, ALK-3, and ALK-1. A 83-01 (0.03-10 μM) potently prevents the growth-inhibitory effects of TGF-β, and completely inhibits the effect at 3 μM. A 83-01 (1-10 μM) inhibits TGF-β-induced Smad activation in HaCaT cells [1]. A 83-01 (1 μM) decreases cell motility, adhesion and invasion increased by TGF-β1 in HM-1 cells, but does not change cell proliferation [2]. A-83-01-treated retinal pigment epithelium (RPE) failed to differentiate after 7 passages (P7). Exogenous expression of MYCN and OTX2 in conjunction with A 83-01 restored P7-RPE differentiation to a status similar to minimally passaged RPE [5].
When co-administrated F-SL with A 83-01. Intraperitoneally injected A 83-01-induced alterations in the cancer-associated neovasculature were examined by magnetic resonance imaging (MRI) and histological analysis. The targeting efficacy of single intravenous injections of F-SL combined with A 83-01 was evaluated by measurement of the biodistribution and the antitumor effect in mice bearing murine lung carcinoma M109. A 83-01 temporarily changed the tumor vasculature around 3 h post injection. A 83-01 induced 1.7-fold higher drug accumulation of F-SL in the tumor than liposome alone at 24 h post injection. Moreover F-SL co-administrated with A 83-01 showed significantly greater antitumor activity than F-SL alone [3]. A 83-01 treatment significantly increased the number of Nkx2.5(+) cardiomyoblasts at baseline and after myocardial injury, resulting in an increase in newly formed cardiomyocytes [6]. Using transgenic Nkx2.5 enhancer-green fluorescent protein (GFP) reporter mice, and isolated cardiac progenitor cells (CPC). A 83-01 was found to induce proliferation mainly through increasing Birc5 expression in the MEK/ERK-dependent pathway [7]. Treatment of rat dermal fibroblast with A 83-01 inhibited transforming growth factor-β1 (TGF-β1)-dependent induction of α-SMA and collagen type I [4].
参考文献:
[1]: Tojo M, Hamashima Y, et,al. The ALK-5 inhibitor A-83-01 inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-beta. Cancer Sci. 2005 Nov;96(11):791-800. doi: 10.1111/j.1349-7006.2005.00103.x. PMID: 16271073.
[2]: Yamamura S, Matsumura N, et,al. The activated transforming growth factor-beta signaling pathway in peritoneal metastases is a potential therapeutic target in ovarian cancer. Int J Cancer. 2012 Jan 1;130(1):20-8. doi: 10.1002/ijc.25961. Epub 2011 Apr 18. PMID: 21503873.
[3]: Taniguchi Y, Kawano K, et,al. Enhanced antitumor efficacy of folate-linked liposomal doxorubicin with TGF-β type I receptor inhibitor. Cancer Sci. 2010 Oct;101(10):2207-13. doi: 10.1111/j.1349-7006.2010.01646.x. Epub 2010 Jul 1. PMID: 20608940.
[4]: Sun X, Kim YH, et,al. Topical application of ALK5 inhibitor A-83-01 reduces burn wound contraction in rats by suppressing myofibroblast population. Biosci Biotechnol Biochem. 2014;78(11):1805-12. doi: 10.1080/09168451.2014.932666. Epub 2014 Jul 10. PMID: 25351330.
[5]:Shih YH, Radeke MJ, et,al. Restoration of Mesenchymal RPE by Transcription Factor-Mediated Reprogramming. Invest Ophthalmol Vis Sci. 2017 Jan 1;58(1):430-441. doi: 10.1167/iovs.16-20018. PMID: 28118667.
[6]: Chen WP, Liu YH, et,al. Pharmacological inhibition of TGFβ receptor improves Nkx2.5 cardiomyoblast-mediated regeneration. Cardiovasc Res. 2015 Jan 1;105(1):44-54. doi: 10.1093/cvr/cvu229. Epub 2014 Oct 31. PMID: 25362681; PMCID: PMC4342671.
[7]: Ho YS, Tsai WH,et,al. Cardioprotective Actions of TGFβRI Inhibition Through Stimulating Autocrine/Paracrine of Survivin and Inhibiting Wnt in Cardiac Progenitors. Stem Cells. 2016 Feb;34(2):445-55. doi: 10.1002/stem.2216. Epub 2015 Oct 10. PMID: 26418219.
A 83-01 是 TGF-β I 型受体 ALK5 激酶、I 型淋巴结受体 ALK4 和 I 型淋巴结受体 ALK7 的有效抑制剂，IC50 s 分别为 12 nM、45 nM和 7.5 nM 分别抑制 ALK5、ALK4 和 ALK7 诱导的转录[1]。
A 83-01 降低 Mv1Lu 细胞中 ALK-5 诱导的转录水平，还阻断 ALK4-TD 和 ALK7-TD 诱导的转录 R4-2 细胞，并弱抑制由组成型活性 ALK-6 诱导的转录， ALK-2、ALK-3 和 ALK-1。 A 83-01 (0.03-10 μM) 有效阻止 TGF-β 的生长抑制作用，并在 3 μM 时完全抑制该作用。 A 83-01 (1-10 μM) 抑制 HaCaT 细胞中 TGF-β 诱导的 Smad 激活 [1]。 A 83-01 (1 μM) 降低 HM-1 细胞中 TGF-β1 增加的细胞运动性、粘附和侵袭，但不改变细胞增殖[2]。 A-83-01 处理的视网膜色素上皮细胞 (RPE) 在 7 代后无法分化 (P7)。 MYCN 和 OTX2 的外源表达与 A 83-01 一起将 P7-RPE 分化恢复到类似于最小传代 RPE 的状态[5]。
当 F-SL 与 A 83-01 共同给药时。通过磁共振成像 (MRI) 和组织学分析检查腹膜内注射 A 83-01 诱导的癌症相关新生血管的改变。单次静脉内注射 F-SL 联合 A 83-01 的靶向功效通过测量生物分布和荷载肺癌 M109 小鼠的抗肿瘤作用来评估。 83-01 在注射后 3 小时左右暂时改变了肿瘤脉管系统。在注射后 24 小时，83-01 诱导的 F-SL 在肿瘤中的药物积累比单独的脂质体高 1.7 倍。此外，F-SL 与 A 83-01 联合给药显示出比单独使用 F-SL 显着更高的抗肿瘤活性[3]。 83-01 治疗显着增加了基线和心肌损伤后 Nkx2.5(+) 心肌细胞的数量，导致新形成的心肌细胞增加[6]。使用转基因 Nkx2.5 增强子-绿色荧光蛋白 (GFP) 报告小鼠和分离的心脏祖细胞 (CPC)。发现 A 83-01 主要通过增加 MEK/ERK 依赖通路中 Birc5 的表达来诱导增殖[7]。 A 83-01 处理大鼠真皮成纤维细胞可抑制转化生长因子-β1 (TGF-β1) 依赖的 α-SMA 和 I 型胶原的诱导[4]。
| Cell experiment [1]: | |
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Cell lines |
Mv1Lu and C2C12 cells |
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Preparation Method |
Cells were pretreated for 1 h with 1uM small molecule inhibitors A 83-01 and then cultured with TGF-β. |
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Reaction Conditions |
1uM A-83-01, 1 h |
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Applications |
The effects of TGF-β inhibitors on cell proliferation were examined. A 83-01 efficiently prevented the growth-inhibitory effects of TGF-β, A-83-01 prevented inhibition of growth of Mv1Lu cells by TGF-β in a dose-dependent fashion. Treatment with 0.3 uM A 83-01 completely blocked the growth-inhibitory effect of TGF-β. |
| Animal experiment [2]: | |
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Animal models |
M109 cells were inoculated subcutaneously into CDF1 female mice (5 weeks old) |
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Preparation Method |
When the tumor volume reached approximately 100-200 mm3, SL, F-SL, or free DXR was injected intravenously at 8 mg/kg, with or without intraperitoneal injection of 0.5 mg A 83-01/kg. The control group was injected intravenously with saline (0.2 mL/20 g body weight) with intraperitoneal injection of the vehicle (0.1 mL/20 g body weight). |
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Dosage form |
0.5?mg A-83-01/kg,16day |
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Applications |
The liposomal DXR injected group showed a strong antitumor effect in comparison with saline with or without A 83-01 and free DXR treated groups. A 83-01 alone did not show an antitumor effect. F-SL with A 83-01 showed a significantly stronger antitumor effect than F-SL alone on day 7 and days 13 and 16, SL alone on day 7 and days 10 and 13, or SL with A 83-01 on days 7 and 10. |
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参考文献: [1]. Tojo M, Hamashima Y, et,al. The ALK-5 inhibitor A-83-01 inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-beta. Cancer Sci. 2005 Nov;96(11):791-800. doi: 10.1111/j.1349-7006.2005.00103.x. PMID: 16271073. [2]. Taniguchi Y, Kawano K, et,al. Enhanced antitumor efficacy of folate-linked liposomal doxorubicin with TGF-β type I receptor inhibitor. Cancer Sci. 2010 Oct;101(10):2207-13. doi: 10.1111/j.1349-7006.2010.01646.x. Epub 2010 Jul 1. PMID: 20608940. |
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