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Rocaglamide (Rocaglamide A) Sale

(Synonyms: 楝酰胺,Rocaglamide A; Roc-A) 目录号 : GC33426

Rocaglamide (Rocaglamide A) is isolated from the genus Aglaia (family Meliaceae). 

Rocaglamide (Rocaglamide A) Chemical Structure

Cas No.:84573-16-0

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10mM (in 1mL DMSO)
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Sample solution is provided at 25 µL, 10mM.

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实验参考方法

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 [2]:

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.

References:

[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.

产品描述

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].

References:
[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]\n

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>.

Chemical Properties

Cas No. 84573-16-0 SDF
别名 楝酰胺,Rocaglamide A; Roc-A
Canonical SMILES O1C2=CC(OC)=CC(OC)=C2[C@]2(O)[C@H](O)[C@H](C(N(C)C)=O)[C@@H](C3=CC=CC=C3)[C@]12C1=CC=C(OC)C=C1 |&1:11,13,15,21,28,r|
分子式 C29H31NO7 分子量 505.56
溶解度 150 mg/mL in DMSO 储存条件 Store at -20°C
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溶解性数据

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1 mM 1.978 mL 9.89 mL 19.78 mL
5 mM 0.3956 mL 1.978 mL 3.956 mL
10 mM 0.1978 mL 0.989 mL 1.978 mL
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Research Update

PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis

Autophagy 2020 Mar;16(3):419-434.PMID:31177901DOI:10.1080/15548627.2019.1628520.

Mitophagy, which is a conserved cellular process for selectively removing damaged or unwanted mitochondria, is critical for mitochondrial quality control and the maintenance of normal cellular physiology. However, the precise mechanisms underlying mitophagy remain largely unknown. Prior studies on mitophagy focused on the events in the mitochondrial outer membrane. PHB2 (prohibitin 2), which is a highly conserved membrane scaffold protein, was recently identified as a novel inner membrane mitophagy receptor that mediates mitophagy. Here, we report a new signaling pathway for PHB2-mediated mitophagy. Upon mitochondrial membrane depolarization or misfolded protein aggregation, PHB2 depletion destabilizes PINK1 in the mitochondria, which blocks the mitochondrial recruitment of PRKN/Parkin, ubiquitin and OPTN (optineurin), leading to an inhibition of mitophagy. In addition, PHB2 overexpression directly induces PRKN recruitment to the mitochondria. Moreover, PHB2-mediated mitophagy is dependent on the mitochondrial inner membrane protease PARL, which interacts with PHB2 and is activated upon PHB2 depletion. Furthermore, PGAM5, which is processed by PARL, participates in PHB2-mediated PINK1 stabilization. Finally, a ligand of PHB proteins that we synthesized, called FL3, was found to strongly inhibit PHB2-mediated mitophagy and to effectively block cancer cell growth and energy production at nanomolar concentrations. Thus, our findings reveal that the PHB2-PARL-PGAM5-PINK1 axis is a novel pathway of PHB2-mediated mitophagy and that targeting PHB2 with the chemical compound FL3 is a promising strategy for cancer therapy.Abbreviations: AIFM1: apoptosis inducing factor mitochondria associated 1; ATP5F1A/ATP5A1: ATP synthase F1 subunit alpha; BAF: bafilomycin A1; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CCCP: chemical reagent carbonyl cyanide m-chlorophenyl hydrazine; FL3: flavaglines compound 3; HSPD1/HSP60: heat shock protein family D (Hsp60) member 1; LC3B/MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MEF: mouse embryo fibroblasts; MPP: mitochondrial-processing peptidase; MT-CO2/COX2: mitochondrially encoded cytochrome c oxidase II; MTS: mitochondrial targeting sequence; OA: oligomycin and antimycin A; OPTN: optineurin; OTC: ornithine carbamoyltransferase; PARL: presenilin associated rhomboid like; PBS: phosphate-buffered saline; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; PHB: prohibitin; PHB2: prohibitin 2; PINK1: PTEN induced kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; Roc-A: Rocaglamide A; TOMM20: translocase of outer mitochondrial membrane 20; TUBB: tubulin beta class I.

Rocaglamide and silvestrol: a long story from anti-tumor to anti-coronavirus compounds

Nat Prod Rep 2021 Jan 1;38(1):18-23.PMID:32699874DOI:10.1039/d0np00024h.

Covering: up to the beginning of 2020Many natural substances have been transformed again and again with regard to their pharmaceutical-medical potential, including new members of a growing class of natural products, the flavaglines. Important representatives are Rocaglamide and silvestrol, isolated from the Aglaia species, which are highlighted here. These products started as potential anti-tumor agents five decades ago and have recently proved to be very promising antiviral agents, especially against RNA viruses. Today they are discussed as potential starting compounds for developing drug candidates and therapeutics.

Chinese herb derived-Rocaglamide A is a potent inhibitor of pancreatic cancer cells

Am J Transl Res 2016 Feb 15;8(2):1047-54.PMID:27158390doi

Pancreatic cancer ranks No.1 in mortality rate worldwide. This study aims to identify the novel anti-pancreatic cancer drugs. Human pancreatic carcinoma cell lines were purchased from ATCC. CPE-based screening assay was used to examine the cell viability. Patient derived tumor xenografts in SCID mice was established. The Caspase-3 and 7 activities were measured using the Caspase Glo 3/7 Assay kit. Soft agar colony formation assay was used to evaluate the colony formation. Wound healing assay was employed to determine the cell migration. We screened a Chinese herbal product library and found three "hits" that kill cancer cells at nanomolar to micromolar concentrations. One of these compounds, Rocaglamide, was found to be potent inhibitors of a wide spectrum of pancreatic cancer cell lines. Furthermore, Rocaglamide reduced the tumor size in a patient-derived pancreatic cancer xenograft mouse model without noticeable toxicity in vivo. Rocaglamide also inhibits pancreatic cancer cell migration and invasion. In conclusion, these data support that Rocaglamide may be a promising anti-pancreatic cancer drug.

Rocaglamide promotes the infiltration and antitumor immunity of NK cells by activating cGAS-STING signaling in non-small cell lung cancer

Int J Biol Sci 2022 Jan 1;18(2):585-598.PMID:35002511DOI:10.7150/ijbs.65019.

Background: Natural killer (NK) cell-based immunotherapy is clinically limited due to insufficient tumor infiltration in solid tumors. We have previously found that the natural product Rocaglamide (RocA) can enhance NK cell-mediated killing of non-small cell lung cancer (NSCLC) cells by inhibiting autophagy, and autophagic inhibition has been shown to increase NK cell tumor infiltration in melanoma. Therefore, we hypothesized that RocA could increase NK cell infiltration in NSCLC by autophagy inhibition. Methods: Flow cytometry, RNA-sequencing, real-time PCR, Western blotting analysis, and xenograft tumor model were utilized to assess the infiltration of NK cells and the underlying mechanism. Results: RocA significantly increased the infiltration of NK cells and the expressions of CCL5 and CXCL10 in NSCLC cells, which could not be reversed by the inhibitions of autophagy/ULK1, JNK and NF-κB. However, such up-regulation could be suppressed by the inhibitions of TKB1 and STING. Furthermore, RocA dramatically activated the cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) signaling pathway, and the inhibition/depletion of STING ablated the up-regulation of CCL5 and CXCL10, NK cell infiltration, and tumor regression induced by RocA. Besides, RocA damaged mitochondrial DNA (mtDNA) and promoted the cytoplasmic release of mtDNA. The mPTP inhibitor cyclosporin A could reverse RocA-induced cytoplasmic release of mtDNA. Conclusions: RocA could promote NK cell infiltration by activating cGAS-STING signaling via targeting mtDNA, but not by inhibiting autophagy. Taken together, our current findings suggested that RocA was a potent cGAS-STING agonist and had a promising potential in cancer immunotherapy, especially in NK cell-based immunotherapy.

Rocaglamide and a XIAP inhibitor cooperatively sensitize TRAIL-mediated apoptosis in Hodgkin's lymphomas

Int J Cancer 2012 Aug 15;131(4):1003-8.PMID:21952919DOI:10.1002/ijc.26458.

Although most of the patients with Hodgkin's lymphoma (HL) can be cured by the current regimen of high-dose multiagent chemotherapy, the treatment causes high risks of later toxicities including secondary malignancies. Therefore, new rational strategies are needed for HL treatment. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent due to its tumor selectivity and its lack of toxicity for normal cells. Unfortunately, many cancers remain resistant to TRAIL including HL. HL is characterized by enhanced expression of cellular caspase-8 (FLICE)-inhibitory protein (c-FLIP) and X-linked inhibitor of apoptosis (XIAP), which block receptor-mediated apoptosis by inhibiting caspase-8 and caspase-3, respectively. We have recently discovered the herbal compound Rocaglamide, which breaks TRAIL-resistance in acute T cell leukemia through inhibition of c-FLIP expression. We have also shown that small molecule XIAP inhibitors can sensitize TRAIL-mediated apoptosis in several resistant tumors. However, whether targeting XIAP or c-FLIP is also a suitable strategy to prime HL cells for TRAIL-induced apoptosis has not yet been investigated. In our study, we show that Rocaglamide suppresses c-FLIP expression in HL cells in a dose- and time-dependent manner. However, downregulation of c-FLIP alone was not sufficient to sensitize TRAIL-induced apoptosis in HL cells. Similarly, treatment of HL cells with a small molecule XIAP inhibitor resulted in a moderate induction of apoptosis. However, inhibition of XIAP alone was also not sufficient to enhance TRAIL-induced cell death. Synergistic increase in TRAIL-mediated killing of HL cells was only obtained by combination of Rocaglamide and XIAP inhibitors. Our study demonstrates that targeting both c-FLIP and XIAP are necessary for an efficient treatment of HL.