Arglabin

Arglabin is a sesquiterpene gamma-lactone is isolated from Artemisia glabella; anticancer natural compound. IC50 value: Target: anticancer in vitro: Arglabin-stimulated macrophages displayed a strong cytotoxic activity and the lowest doses (1.25 micrograms/mL and 0.125 micrograms/mL) induced a significant stimulation of cell mitochondrial metabolism, which correlated with [3H]TdR uptake by J774.1 cells under the same experimental conditions. Arglabin triggered the production of the three cytokines from J774-1 cells. However, the pattern of cytokine secretion differed to some extent, according to the methodology used for cytokine measurement: either traditional bioassay or specific immunoassay (ELISA) [1]. Arglabin exhibits antiexudative and antiproliferative properties on the models of acute aseptic inflammation caused by formalin, carrageenan, and histamine, and on the model of proliferative inflammation accompanying cotton-pellet granuloma [2]. Arglabin is able to reduce the proportion of AML stem cells (CD34+CD38-) in primary AML cells [3].

References:
[1]. Bottex-Gauthier C, et al. In vitro biological activities of arglabin, a sesquiterpene lactone from the Chinese herb Artemisia myriantha Wall. (Asteraceae). Biotechnol Ther. 1993;4(1-2):77-98. [2]. Abil'daeva AZh, et al. Anti-inflammatory effect of arglabin and 11,13-dihydro-13-dimethylaminoarglabin hydrochloride. Eksp Klin Farmakol. 2004 Jan-Feb;67(1):37-9. [3]. Zhang Q, et al. Guaianolide sesquiterpene lactones, a source to discover agents that selectively inhibit acute myelogenous leukemia stem and progenitor cells. J Med Chem. 2012 Oct 25;55(20):8757-69.

Inhibition of the Inflammasome NLRP3 by Arglabin Attenuates Inflammation, Protects Pancreatic beta-Cells from Apoptosis, and Prevents Type 2 Diabetes Mellitus Development in ApoE2Ki Mice on a Chronic High-Fat Diet.[Pubmed:27044804]

J Pharmacol Exp Ther. 2016 Jun;357(3):487-94.

Intraperitoneal injection of Arglabin (2.5 ng/g of body weight, twice daily, 13 weeks) into female human apolipoprotein E2 gene knock-in (ApoE2Ki) mice fed a high-fat Western-type diet (HFD) reduced plasma levels of glucose and insulin by approximately 20.0% +/- 3.5% and by 50.0% +/- 2.0%, respectively, in comparison with vehicle-treated mice. Immunohistochemical analysis revealed the absence of active caspase-3 in islet sections from ApoE2Ki mice fed a HFD and treated with Arglabin. In addition, Arglabin reduced interleukin-1beta (IL-1beta) production in a concentration-dependent manner in Langerhans islets isolated from ApoE2Ki mice treated with lipopolysaccharide (LPS) and with cholesterol crystals. This inhibitory effect is specific for the inflammasome NOD-like receptor family, pyrin domain-containing 3 (NLRP3) because IL-1beta production was abolished in Langerhans islets isolated from Nlrp3(-/-) mice. In the insulin-secreting INS-1 cells, Arglabin inhibited, in a concentration-dependent manner, the maturation of pro-IL-1beta into biologically active IL-1beta probably through the inhibition of the maturation of procaspase-1 into active capsase-1. Moreover, Arglabin reduced the susceptibility of INS-1 cells to apoptosis by increasing Bcl-2 levels. Similarly, autophagy activation by rapamycin decreased apoptosis susceptibility while autophagy inhibition by 3-methyladenin treatment promoted apoptosis. Arglabin further increased the expression of the autophagic markers Bcl2-interacting protein (Beclin-1) and microtubule-associated protein 1 light chain 3 II (LC3-II) in a concentration-dependent manner. Thus, Arglabin reduces NLRP3-dependent inflammation as well as apoptosis in pancreatic beta-cells in vivo and in the INS-1 cell line in vitro, whereas it increases autophagy in cultured INS-1 cells, indicating survival-promoting properties of the compound in these cells. Hence, Arglabin may represent a new promising compound to treat inflammation and type 2 diabetes mellitus development.

Anti-inflammatory and antiatherogenic effects of the NLRP3 inflammasome inhibitor arglabin in ApoE2.Ki mice fed a high-fat diet.[Pubmed:25613820]

Circulation. 2015 Mar 24;131(12):1061-70.

BACKGROUND: This study was designed to evaluate the effect of Arglabin on the NLRP3 inflammasome inhibition and atherosclerotic lesion in ApoE2Ki mice fed a high-fat Western-type diet. METHODS AND RESULTS: Arglabin was purified, and its chemical identity was confirmed by mass spectrometry. It inhibited, in a concentration-dependent manner, interleukin (IL)-1beta and IL-18, but not IL-6 and IL-12, production in lipopolysaccharide and cholesterol crystal-activated cultured mouse peritoneal macrophages, with a maximum effect at approximately 50 nmol/L and EC50 values for both cytokines of approximately 10 nmol/L. Lipopolysaccharide and cholesterol crystals did not induce IL-1beta and IL-18 production in Nlrp3(-/-) macrophages. In addition, Arglabin activated autophagy as evidenced by the increase in LC3-II protein. Intraperitoneal injection of Arglabin (2.5 ng/g body weight twice daily for 13 weeks) into female ApoE2.Ki mice fed a high-fat diet resulted in a decreased IL-1beta plasma level compared with vehicle-treated mice (5.2+/-1.0 versus 11.7+/-1.1 pg/mL). Surprisingly, Arglabin also reduced plasma levels of total cholesterol and triglycerides to 41% and 42%, respectively. Moreover, Arglabin oriented the proinflammatory M1 macrophages into the anti-inflammatory M2 phenotype in spleen and arterial lesions. Finally, Arglabin treatment markedly reduced the median lesion areas in the sinus and whole aorta to 54% (P=0.02) and 41% (P=0.02), respectively. CONCLUSIONS: Arglabin reduces inflammation and plasma lipids, increases autophagy, and orients tissue macrophages into an anti-inflammatory phenotype in ApoE2.Ki mice fed a high-fat diet. Consequently, a marked reduction in atherosclerotic lesions was observed. Thus, Arglabin may represent a promising new drug to treat inflammation and atherosclerosis.

Arglabin: From isolation to antitumor evaluation.[Pubmed:26327249]

Chem Biol Interact. 2015 Oct 5;240:180-98.

Arglabin belongs to guaianolide class of sesquiterpene lactones, isolated from Artemisia species. The molecule bears a 5,7,5-tricyclic ring system having five contiguous stereo centers in which the two five membered rings are trans-annulated. Arglabin shows promising antitumor activity against different tumor cell lines. The antitumor activity of Arglabin proceeds through its inhibition of farnesyl transferase which leads to the activation of RAS proto-oncogene, a process that is believed to play a pivotal role in 20-30% of all human tumors. It actually inhibits the incorporation of farnesyl pyrophosphate into human H-ras proteins by the enzyme farnesyl transferase (FTase). The present review is an attempt to summarize the chemistry and biology of this molecule since its isolation in 1982. It embodies the isolation, structure elucidation, stereo chemical description, structural classification, chemical synthesis, structural modifications and antitumor evaluation reported till date.

Arglabin-DMA, a plant derived sesquiterpene, inhibits farnesyltransferase.[Pubmed:11115593]

Oncol Rep. 2001 Jan-Feb;8(1):173-9.

Arglabin [1(R),10(S)-epoxy-5(S),5(S),7(S)-guaia-3(4),11(13)-dien-6, 12-olide], a sesquiterpene gamma-lactone is isolated from Artemisia glabella, a species of wormwood endemic to the Karaganda region of Kazakstan. The compound has been modified to render it water-soluble through addition of a dimethylaminohydrochloride group to the C(13) carbohydride moiety to yield Arglabin-DMA. Arglabin-DMA is a registered antitumor substance in the Republic of Kazakstan. Previously, we have shown that this compound prevents protein farnesylation without altering geranylgeranylation. We now report that Arglabin-DMA inhibits the incorporation of [(3)H]farnesylpyrophosphate into human H-ras protein by FTase with an IC(50) of no greater than 25 microM. Kinetic studies show that the phosphorylated form of this compound competitively inhibits the binding of farnesyl diphosphate to FTase. This mechanism of action is different from other reported peptidomimetic FTIs which lower the affinity of ras protein to FTase. Our in vitro studies confirm that Arglabin-DMA inhibits post-translational modification of ras protein in cells. Arglabin-DMA inhibits anchorage-dependent proliferation of NB cells (IC50=10 microg/ml) and inhibits anchorage-independent growth of NB and KNRK cells with about the same IC(50). Soft-agar colony formation assay of H-ras and K-ras transformed cells show IC(50)s to be 2 and 5 microg/ml, respectively. In primary cultures of human tumor cells, Arglabin-DMA inhibits cell proliferation of a variety of tumor types with IC(90)s in the range of 0.85 to 5.0 microg/ml. Because of these pharmacologic properties, we propose that Arglabin-DMA is suitable for the treatment of ras related malignancies.