14-Deoxy-11,12-didehydroandrographolide

J Nat Med. 2014 Apr;68(2):387-94.

14-Deoxy-11,12-didehydroandrographolide inhibits proliferation and induces GSH-dependent cell death of human promonocytic leukemic cells.[Pubmed: 24458985]

14-Deoxy-11,12-didehydroandrographolide (AND2), an analogue of andrographolide, showed more potent cytotoxicity against human promonocytic leukemia (THP-1) cells than adherent cancer cell lines.
METHODS AND RESULTS:
In this study 14-Deoxy-11,12-didehydroandrographolide was isolated from the plant Andrographis paniculata and it was characterized. The antiproliferative effect of 14-Deoxy-11,12-didehydroandrographolide on both adherent (PC-3 and MDAMB) and non-adherent (THP-1 and Jurkat) cancer cell lines was evaluated by MTT assay. The effect of intracellular reduced glutathione (GSH) on 14-Deoxy-11,12-didehydroandrographolide-induced cytotoxicity was studied by conducting cell viability assays on GSH-pretreated cells. The effect of 14-Deoxy-11,12-didehydroandrographolide on the redox status of THP-1 cells was determined by analyzing the endogenous reduced GSH content. Apoptosis induction was confirmed by DNA laddering assay and Western blot analysis using anti-caspase-3 protein antibody. 14-Deoxy-11,12-didehydroandrographolide showed antiproliferative action on both THP-1 and Jurkat cancer cell lines with low IC50 values. Cytotoxicity of AND2 was reversed by GSH pretreatment. AND2 treatment decreased the GSH content by 19.76 % (p < 0.001) in the THP-1 cancer cell line and reduced the cell clumping between the THP-1 cells. Expression of procaspase-3 varied in THP-1 cells during the time course of 14-Deoxy-11,12-didehydroandrographolide treatment. Procaspase-3 expression reached a maximum in treated cells at 32 h and was markedly reduced at 48 h but no procaspase-3 cleavage was observed. The obtained results suggest that 14-Deoxy-11,12-didehydroandrographolide is more effective against leukemia cells. 14-Deoxy-11,12-didehydroandrographolide induced a redox-mediated cell death in THP-1 cells.
CONCLUSIONS:
As 14-Deoxy-11,12-didehydroandrographolide temporarily increased the procaspase-3 expression during treatment, this study encourages the preclinical testing of 14-Deoxy-11,12-didehydroandrographolide against promonocytic leukemia cells in combination with small molecules that directly activate procaspase-3 to caspase-3.

Life Sci. 2012 Feb 13;90(7-8):257-66.

Effects of andrographolide and 14-deoxy-11,12-didehydroandrographolide on cultured primary astrocytes and PC12 cells.[Pubmed: 22154981]

To test the effects of andrographolide (AP1) and 14-Deoxy-11,12-didehydroandrographolide (AP2) on pheochromocytoma cell line 12 (PC12) cells in an astrocyte-rich environment.
METHODS AND RESULTS:
The abilities of AP1 and 14-Deoxy-11,12-didehydroandrographolide to reduce the secretion of pro-inflammatory cytokines Interleukin (IL)-1, IL-6, and Tumor necrosis factor (TNF)-α from stimulated astrocytes were tested. In addition, the abilities of AP1 and 14-Deoxy-11,12-didehydroandrographolide to reduce oxidative stress in astrocytes were tested using an oxidative-sensitive fluorescent dye. The reduction of chondroitin sulfate proteoglycan (CSPG) in stimulated astrocytes was tested using the dot blot method. Reduction of H(2)O(2)-induced death was tested in PC12 cells. Astrocyte-conditioned medium (ACM) and TNF-α-stimulated astrocyte-conditioned medium (SACM) were used to assess the effects of 14-Deoxy-11,12-didehydroandrographolide on PC12 cells treated with H(2)O(2). AP1 and 14-Deoxy-11,12-didehydroandrographolide reduced pro-inflammatory cytokines, reactive oxygen species (ROS), and CSPG in TNF-α stimulated astrocytes. AP1 protected H(2)O(2)-treated PC12 cells cultured in ACM. Co-incubation of PC12 cells in H(2)O(2), and ACM collected from AP1 treated astrocytes did not prevent cell death.
CONCLUSIONS:
AP1 and 14-Deoxy-11,12-didehydroandrographolide effectively ameliorated astrocytic pro-inflammatory reactions and prevented PC12 cell death with different efficacies. These compounds may be candidates for treatment of spinal-cord injury and neurodegeneration.

Pharmacol Res. 1998 Dec;38(6):413-7.

Cardiovascular activity of 14-deoxy-11,12-didehydroandrographolide in the anaesthetised rat and isolated right atria.[Pubmed: 9990649 ]

METHODS AND RESULTS:
The cardiovascular activity of 14-Deoxy-11,12-didehydroandrographolide (DDA) from Andrographis paniculata (Burm.f.) Nees (Acanthaceae) was elucidated in anaesthetised Sprague-Dawley (SD) rats and isolated rat right atria. In anaesthetised rats, DDA produced significant falls in mean arterial blood pressure (MAP) and heart rate in a dose-dependent manner with the maximum decrease of 37.6 +/- 2.6% and 18.1 +/- 4.8%, respectively. The ED50 value for MAP was 3.43 mmol kg-1. Pharmacological antagonist studies were done using this dose. The hypotensive action of DDA was not mediated through effects on the alpha-adrenoceptor, muscarinic cholinergic and histaminergic receptors, for it was not affected by phentolamine, atropine as well as pyrilamine and cimetidine. However, it seems to work via adrenoceptors, autonomic ganglia receptor and angiotensin-converting enzyme, since the hypotensive effect of DDA was negated or attenuated in the presence of propranolol, hexamethonium and captopril. In the isolated right atria, DDA caused negative chronotropic action and antagonised isoproterenol-induced positive chronotropic actions in a non-competitive and dose-dependent manner.
CONCLUSIONS:
These results further supported the bradycardia-inducing and beta-adrenoceptor antagonistic properties of DDA in vivo.

Food Chem Toxicol. 2012 Feb;50(2):431-44.

Identification of genes involved in the regulation of 14-deoxy-11,12-didehydroandrographolide-induced toxicity in T-47D mammary cells.[Pubmed: 22101062]

14-Deoxy-11,12-didehydroandrographolide is one of the principle compounds of the medicinal plant, Andrographis paniculata Nees.
METHODS AND RESULTS:
This study explored the mechanisms of 14-Deoxy-11,12-didehydroandrographolide-induced toxicity and non-apoptotic cell death in T-47D breast carcinoma cells. Gene expression analysis revealed that 14-Deoxy-11,12-didehydroandrographolide exerted its cytotoxic effects by regulating genes that inhibit the cell cycle or promote cell cycle arrest. This compound regulated genes that are known to reduce/inhibit cell proliferation, induce growth arrest and suppress cell growth. The growth suppression activities of this compound were demonstrated by a downregulation of several genes normally found to be over-expressed in cancers. Microscopic analysis revealed positive monodansylcadaverine (MDC) staining at 8h, indicating possible autophagosomes. TEM analysis revealed that the treated cells were highly vacuolated, thereby suggesting that 14-Deoxy-11,12-didehydroandrographolide may cause autophagic morphology in these cells.
CONCLUSIONS:
This morphology may be correlated with the concurrent expression of genes known to affect lysosomal activity, ion transport, protein degradation and vesicle transport. Interestingly, some apoptotic-like bodies were found, and these bodies contained multiple large vacuoles, suggesting that this compound is capable of eliciting a combination of apoptotic and autophagic-like morphological characteristics.

J Nat Prod. 2011 Jun 24;74(6):1484-90.

Protective role of 14-deoxy-11,12-didehydroandrographolide, a noncytotoxic analogue of andrographolide, in allergic airway inflammation.[Pubmed: 21598983]

Our group recently reported novel anti-inflammatory effects of andrographolide (2), a bioactive molecule isolated from Andrographis paniculata, in a mouse asthma model. However, 2 has been shown to possess cytotoxic activity. 14-Deoxy-11,12-didehydroandrographolide (1) is an analogue of 2 that can be isolated from A. paniculata.
METHODS AND RESULTS:
We hypothesized that 14-Deoxy-11,12-didehydroandrographolide retains the anti-inflammatory effects for asthma but is devoid of cytotoxicity. In contrast to 2, 14-Deoxy-11,12-didehydroandrographolide did not elicit any cytotoxic activity in A549 and BEAS-2B human lung epithelial cells and rat basophilic leukemia (RBL)-2H3 cells using a MTS assay. Compound 14-Deoxy-11,12-didehydroandrographolide dose-dependently inhibited ovalbumin (OVA)-induced increases in total and eosinophil counts, IL-4, IL-5, and IL-13 levels in lavage fluid, and serum OVA-specific IgE level in a mouse asthma model. 14-Deoxy-11,12-didehydroandrographolide attenuated OVA-induced airway eosinophilia, mucus production, mast cell degranulation, pro-inflammatory biomarker expression in lung tissues, and airway hyper-responsiveness. This substance also blocked p65 nuclear translocation and DNA-binding activity in the OVA-challenged lung and in TNF-α-stimulated human lung epithelial cells.
CONCLUSIONS:
The present findings reveal for the first time that 14-Deoxy-11,12-didehydroandrographolide retains the anti-inflammatory activities of 2 for asthma probably through the inhibition of NF-κB. 14-Deoxy-11,12-didehydroandrographolide (1) may be considered as a safer analogue of 2 for the potential treatment of asthma.