Rocaglamide (Rocaglamide A)|84573-16-0|安捷凯

Background

Rocaglamide (Rocaglamide A) is isolated from the genus Aglaia (family Meliaceae). Rocaglamide (Rocaglamide A)(IC50 of 50 nM) inhibits the function of the translation initiation factor eIF4A, a DEAD box RNA helicase ^[1，2].

Rocaglamide (Rocaglamide A) (100 nM;24h) significantly enhanced TRAIL induced apoptosis^[4]. Rocaglamide (Rocaglamide A) (20- 100 nM;48h)can induce 10-30% apoptosis of L1236 and KM-H2 cells ^[3]. Rocaglamide (Rocaglamide A) are able to suppress the PMA-induced expression of NF-kappaB target genes and sensitize leukemic T cells to apoptosis induced by TNFalpha, cisplatin, and gamma-irradiation ^[5]. Rocaglamide (Rocaglamide A)( 30/50 nM;21d) prevented TNF-α mediated inhibition of osteoblast differentiation, and promoted osteoblast differentiation directly, in both C2C12 and primary mesenchymal stromal cells ^[6].

Rocaglamide (Rocaglamide A)( 2.5 mg/kg; i.p.; 32 days) induced tumor cell apoptosis in a SCID mouse model (Huah-7 cells) without causing weight loss in mice, and no significant signs of toxicity were observed during treatment, suggesting that Rocaglamide is generally well tolerated in vivo^[4]. Rocaglamide (Rocaglamide A)( 0.5 mg/kg; i.p.; five times per week for two weeks) overcomes CPT resistance in U266 in vitro and significant increases in anti-tumor efficacies of CPT in mice xenografted with U266^[7].

参考文献:
[1]. Santagata S, Mendillo ML, et,al. Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state. Science. 2013 Jul 19;341(6143):1238303. doi: 10.1126/science.1238303. PMID: 23869022; PMCID: PMC3959726.
[2]. Kim S, Salim AA, Swanson SM and Kinghorn AD: Potential of cyclopenta[b]benzofurans from Aglaia species in cancer chemotherapy. Anticancer Agents Med Chem. 6:319-345. 2006.
[3]. Giaisi M, K?hler R, et,al. Rocaglamide and a XIAP inhibitor cooperatively sensitize TRAIL-mediated apoptosis in Hodgkin's lymphomas. Int J Cancer. 2012 Aug 15;131(4):1003-8. doi: 10.1002/ijc.26458. Epub 2011 Nov 8. PMID: 21952919.
[4]. Luan Z, He Y, et,al. Rocaglamide overcomes tumor necrosis factor-related apoptosis-inducing ligand resistance in hepatocellular carcinoma cells by attenuating the inhibition of caspase-8 through cellular FLICE-like-inhibitory protein downregulation. Mol Med Rep. 2015 Jan;11(1):203-11. doi: 10.3892/mmr.2014.2718. Epub 2014 Oct 21. PMID: 25333816; PMCID: PMC4237083.
[5]. Baumann B, Bohnenstengel F, et,al. Rocaglamide derivatives are potent inhibitors of NF-kappa B activation in T-cells. J Biol Chem. 2002 Nov 22;277(47):44791-800. doi: 10.1074/jbc.M208003200. Epub 2002 Sep 16. PMID: 12237314.
[6]. Li A, Yang L, et,al. Rocaglamide-A Potentiates Osteoblast Differentiation by Inhibiting NF-κB Signaling. Mol Cells. 2015 Nov;38(11):941-9. doi: 10.14348/molcells.2015.2353. Epub 2015 Nov 6. PMID: 26549505; PMCID: PMC4673408.
[7]. Wu Y, Giaisi M, et,al. Rocaglamide breaks TRAIL-resistance in human multiple myeloma and acute T-cell leukemia in vivo in a mouse xenogtraft model. Cancer Lett. 2017 Mar 28;389:70-77. doi: 10.1016/j.canlet.2016.12.010. Epub 2016 Dec 18. PMID: 27998762.

Rocaglamide (Rocaglamide A) 是从 Aglaia 属（楝科）中分离出来的。 Rocaglamide (Rocaglamide A)(IC50为50 nM)抑制翻译起始因子eIF4A的功能，eIF4A是一种DEAD box RNA解旋酶^[1，2]。

Rocaglamide (Rocaglamide A) (100 nM;24h) 显着增强 TRAIL 诱导的细胞凋亡^[4]。 Rocaglamide (Rocaglamide A) (20- 100 nM;48h) 可诱导 L1236 和 KM-H2 细胞 10-30% 的凋亡^[3]。 Rocaglamide (Rocaglamide A) 能够抑制 PMA 诱导的 NF-kappaB 靶基因表达，并使白血病 T 细胞对 TNFalpha、顺铂和伽马射线照射诱导的细胞凋亡敏感^[5]。 Rocaglamide (Rocaglamide A)( 30/50 nM;21d) 在 C2C12 和原代间充质基质细胞中阻止 TNF-α 介导的成骨细胞分化抑制，并直接促进成骨细胞分化^[6]。

Rocaglamide (Rocaglamide A)（2.5 mg/kg；i.p.；32 天）在 SCID 小鼠模型（Huah-7 细胞）中诱导肿瘤细胞凋亡，而不会导致小鼠体重减轻，并且在治疗期间未观察到明显的毒性迹象治疗，表明 Rocaglamide 在体内通常具有良好的耐受性^[4]。 Rocaglamide (Rocaglamide A)（0.5 mg/kg；腹腔注射；每周 5 次，持续两周）在体外克服了 U266 的 CPT 耐药性，并显着提高了 U266 异种移植小鼠的 CPT 抗肿瘤功效^{[7]< /sup>.}

Protocol

Cell experiment [1]:

Cell lines

HepG2 and Huh-7 cells

Preparation Method

HepG2 and Huh-7 cells were seeded in 96-well plates in complete culture medium and incubated for 24 h. The cells were then exposed to 100 nM Rocaglamide (Rocaglamide A) and TRAIL for 24 h.

Reaction Conditions

100 nM;24h

Applications

Rocaglamide (Rocaglamide A) significantly enhanced TRAIL induced apoptosis.

Animal experiment [1]:

Animal models

Female SCID mice (6-week-old)

Preparation Method

The Huh-7 cells, suspended in 100 μl mix, were implanted subcutaneously into the right flank of 10 female SCID mice (6-week-old) and then randomly divided into two equal groups, one of which received an intraperitoneal injection of Rocaglamide (Rocaglamide A) (2.5 mg/kg in 80 μl olive oil; n=5) and the other, used as a vehicle contro. These treatments were performed once daily for 32 days and the tumor volumes and body weights of the animals were measured twice a week.

Dosage form

2.5 mg/kg; i.p.; 32 days

Applications

Rocaglamide (Rocaglamide A) induced tumor cell apoptosis in a SCID mouse model (Huah-7 cells) without causing weight loss in mice, and no significant signs of toxicity were observed during treatment, suggesting that Rocaglamide is generally well tolerated in vivo.

参考文献:

[1]. Luan Z, He Y, et,al. Rocaglamide overcomes tumor necrosis factor-related apoptosis-inducing ligand resistance in hepatocellular carcinoma cells by attenuating the inhibition of caspase-8 through cellular FLICE-like-inhibitory protein downregulation. Mol Med Rep. 2015 Jan;11(1):203-11. doi: 10.3892/mmr.2014.2718. Epub 2014 Oct 21. PMID: 25333816; PMCID: PMC4237083.

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信号通路

生命科学

有机化学

无机化学

材料科学

Rocaglamide (Rocaglamide A)

Rocaglamide (Rocaglamide A)详情

Background

Protocol

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