TRAIL-induced HCC cell engraftment is enhanced by rocaglamide. HepG2 and H-7 cell engraftment were 9% and 11%, respectively, after rocaglamide therapy alone. HepG2 and H-7 cell engraftment was 16% and 17%, respectively, after TRAIL treatment. However, it is evident that the combination of Rocaglamide and TRAIL did more than just have an additive effect because it also generated cellular tolerance in 55% of HepG2 and 57% of Huh-7 cells. Injection violet staining was used to measure cell viability, and similar results were achieved. Highly drug- and chemoresistant HepG2 and Huh-7 cells may become more susceptible to TRAIL-based therapy when exposed to rocamide [2].

Compared to the catalyst group, the tumor volume in the rocaramide-treated group was 45 ± 12%. When compared to catalyst, rocamide greatly slowed the growth of tumors. Rocamide was generally well tolerated, as evidenced by the fact that neither weight loss nor evident toxicity was seen consistently in mice during the treatment period in groups treated with the drug [2].

[1]. Tight coordination of protein translation and heat shock factor 1 activation supports the anabolic malignant state. Science. 2013 Jul 19; 341(6143): 1238303.

[2]. 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.

[3]. Rocaglamide derivatives are potent inhibitors of NF-kappa B activation in T-cells. J Biol Chem. 2002 Nov 22;277(47):44791-800.

Rocaglamide is an organic heterotricyclic compound that is 2,3,3a,8b-tetrahydro-1H-benzo[b]cyclopenta[d]furan substituted by hydroxy groups at positions 1 and 8b, methoxy groups at positions 6 and 8, a 4-methoxyphenyl group at position 3a, a phenyl group at position 3 and a N,N-dimethylcarbamoyl group at position 1. Isolated from Aglaia odorata and Aglaia duperreana, it exhibits antineoplastic activity. It has a role as a metabolite, an antineoplastic agent and an antileishmanial agent. It is an organic heterotricyclic compound, a monomethoxybenzene and a monocarboxylic acid amide.
Rocaglamide, also referred to as rocaglamide-A, is the eponymous member of a class of anti-cancer phytochemicals known as rocaglamides. Rocaglamides are secondary metabolites of the plant genus Aglaia, and extracts of the plant have traditionally been used as a form of insect repellant due to its natural insecticidal properties. Reports of Aglaia anti-tumor activity date back as far as 1973, and rocaglamide-A was first isolated in 1982 from the species A. elliptifolia. Rocaglamide and a number of its derivatives (e.g. [didesmethylrocaglamide]) are currently being studied for use as chemotherapeutic agents in the treatment of various leukemias, lymphomas, and carcinomas, as well as adjuvant therapy in the treatment of certain chemotherapy-resistant cancers.
Rocaglamide has been reported in Aglaia formosana, Aglaia elliptifolia, and other organisms with data available.

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Mechanism of Action
Rocaglamide’s anti-tumor activity is driven primarily via inhibition of protein synthesis in tumor cells. Inhibition of protein synthesis is accomplished via inhibition of prohibitin 1 (PHB1) and prohibitin 2 (PHB2) - these proteins are necessary in the proliferation of cancer cells and are implicated in the Ras-mediated CRaf-MEK-ERK signaling pathway responsible for phosphorylating eIF4E, a key factor in the initiation of protein synthesis. The rocaglamide derivative silvestrol has also been observed to act directly on eIF4A, another translation initiation factor of the eIF4F complex ultimately responsible for initiation of protein synthesis. Inhibition of protein synthesis has a number of downstream effects. Many of the proteins that are down-regulated in response to protein synthesis inhibition in tumor cells are short-lived proteins responsible for regulation of the cell cycle, such as Cdc25A. Cdc25A is an oncogene that can become overexpressed in certain cancers and lead to unchecked cell growth. In addition to inhibiting its synthesis via the mechanism described above, rocaglamide promotes degradation of Cdc25A via activation of the ATM/ATR-Chk1/Chk2 checkpoint pathway. This pathway is normally activated in response to DNA damage and serves to reduce the expression of proteins responsible for cell cycle progression, thereby inhibiting proliferation of damaged (i.e. tumour) cells. Rocaglamide’s inhibition of protein synthesis also appears to prevent the actions of the transcription factor heat shock factor 1 (HSF1), leading to an increased expression of thioredoxin-interacting protein (TXNIP) which is negatively regulated by HSF1. TXNIP is a negative regulator of cell glucose uptake, and its increased expression blocks glucose uptake and consequently impairs the proliferation of malignant cells. Rocaglamide also appears to induce apoptosis in tumor cells via activation of the pro-apoptotic proteins p38 and JNK and inhibition of the anti-apoptotic Mcl-1 protein. Similarly, it has been studied as an adjuvant in TRAIL-resistant cancers due to its ability to inhibit the synthesis of c-FLIP and IAP/XIAP - these anti-apoptotic proteins can become elevated in certain cancers, preventing the induction of apoptosis and resulting in resistance to TRAIL-based therapies.

C29H31NO7

505.56

505.21

84573-16-0

Aglafoline;143901-35-3;Didesmethylrocaglamide;177262-30-5

331783

White to off-white solid powder

1.3±0.1 g/cm3

667.3±55.0 °C at 760 mmHg

357.4±31.5 °C

0.0±2.1 mmHg at 25°C

1.634

3.1

2

7

6

37

810

5

CN(C)C(=O)[C@@H]1[C@H]([C@]2([C@@]([C@@H]1O)(C3=C(O2)C=C(C=C3OC)OC)O)C4=CC=C(C=C4)OC)C5=CC=CC=C5

DAPAQENNNINUPW-IDAMAFBJSA-N

InChI=1S/C29H31NO7/c1-30(2)27(32)23-24(17-9-7-6-8-10-17)29(18-11-13-19(34-3)14-12-18)28(33,26(23)31)25-21(36-5)15-20(35-4)16-22(25)37-29/h6-16,23-24,26,31,33H,1-5H3/t23-,24-,26-,28+,29+/m1/s1

(1R,2R,3S,3aR,8bS)-1,8b-dihydroxy-6,8-dimethoxy-3a-(4-methoxyphenyl)-N,N-dimethyl-3-phenyl-2,3-dihydro-1H-cyclopenta[b][1]benzofuran-2-carboxamide

RocA; Rocaglamide A; Rocaglamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~197.80 mM)

Solubility in Formulation 1: ≥ 7.5 mg/mL (14.84 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 75.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 7.5 mg/mL (14.84 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 75.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 4.76 mg/mL (9.42 mM) (saturation unknown) in 5% DMSO + 95% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)