Bisdemethoxycurcumin

The rhizome of Curcuma longa L.

Bisdemethoxycurcumin(Curcumin III; Didemethoxycurcumin) is a natural derivative of curcumin with anti-inflammatory and anti-cancer activities. IC50 value: Target: Anticancer natural compound in vitro: BDMC-induced apoptosis was mediated by a combinatory inhibition of cytoprotective proteins, such as Bcl2 and heme oxygenase-1 and increased generation of reactive oxygen species. Intriguingly, BDMC-induced apoptosis was reversed with co-treatment of sr144528, a cannabinoid receptor (CBR) 2 antagonist, which was confirmed with genetic downregulation of the receptor using siCBR2 [1]. Induction of cell cycle arrest in HepG2 cells by NB and BDCur in combination was evidenced by accumulation of the G2/M cell population. Further investigation on the molecular mechanism showed that NB and BDCur in combination resulted in a significant decrease in the expression level of Cdc2 and cyclin B [2]. BDMC treatment activated Sirt1/AMPK signaling pathway. Moreover, downregulating Sirt1 by the pharmacological inhibitor nicotianamine or small interfering RNA blocked BDMC-mediated protection against t-BHP-mediated decrease in proliferation [4]. in vivo: human gastric adenocarcinoma xenograft model was generated in vivo using nude mice and BDMC was observed to suppress the growth and activity of tumors, in addition to improving the physical and mental capacity of the mice [3].

References:
[1]. Lee PJ, et al. Bisdemethoxycurcumin Induces Apoptosis in Activated Hepatic Stellate Cells via Cannabinoid Receptor 2. Molecules. 2015 Jan 14;20(1):1277-92. [2]. Chen J, et al. Natural borneol enhances bisdemethoxycurcumin-induced cell cycle arrest in the G2/M phase through up-regulation of intracellular ROS in HepG2 cells. Food Funct. 2014 Dec 24. [3]. Luo C, et al. Bisdemethoxycurcumin attenuates gastric adenocarcinoma growth by inducing mitochondrial dysfunction. Oncol Lett. 2015 Jan;9(1):270-274. [4]. Li YB, et al. Bisdemethoxycurcumin Increases Sirt1 to Antagonize t-BHP-Induced Premature Senescence in WI38 Fibroblast Cells. Evid Based Complement Alternat Med. 2013;2013:851714.

Bisdemethoxycurcumin suppresses MCF-7 cells proliferation by inducing ROS accumulation and modulating senescence-related pathways.[Pubmed:23950593]

Pharmacol Rep. 2013;65(3):700-9.

BACKGROUND: Bisdemethoxycurcumin (BDMC) is a natural derivative of curcumin present in the phenolic components extracted from the dried rhizome of Curcuma longa L. BDMC demonstrated potential chemotherapeutic activities but the underlying mechanisms have not been fully clarified. In the present study, the role of reactive oxidative species (ROS) in the anti-cancer effects of BDMC was investigated. METHODS: MCF-7 cells were exposed to BDMC, and then the cell proliferation, colony formation ability and cell cycle profile were analyzed. Cellular ROS level was determined by flow cytometry and fluorescent microscope observation using specific fluorescent probes. Mitochondrial membrane potential (psim) was assessed using JC-1. In addition, effects of BDMC on senescence-related molecules were analyzed by western blot assay. RESULTS: BDMC significantly inhibited MCF-7 breast cancer cell proliferation, while a rapid rise of the intracellular ROS level accompanied with a reduction of Dym were observed. In addition, BDMC activated the pro-apoptotic protein p53 and its downstream effector p21 as well as the cell cycle regulatory proteins p16 and its downstream effector retinoblastoma protein (Rb). All of these BDMC-induced effects were counteracted with the pre-incubation of the antioxidant N-acetylcysteine (NAC). CONCLUSIONS: These results suggested that BDMC-induced ROS accumulation may contribute to its inhibitory effect on MCF-7 cell viability through regulation of p53/p21 and p16/Rb pathways.

Bisdemethoxycurcumin attenuates gastric adenocarcinoma growth by inducing mitochondrial dysfunction.[Pubmed:25435973]

Oncol Lett. 2015 Jan;9(1):270-274.

Bisdemethoxycurcumin (BDMC) is a demethoxy derivative of curcumin. In this study, a human gastric adenocarcinoma xenograft model was generated in vivo using nude mice and BDMC was observed to suppress the growth and activity of tumors, in addition to improving the physical and mental capacity of the mice. An increased number of apoptotic cells, decreased ratio of B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein and increased caspase-3 expression was also observed following treatment with BDMC, indicating that BDMC may promote apoptosis in tumors via mitochondrial modulation. The growth of SGC 7901 gastric cancer cells was inhibited and arrested at G1 phase. Specific indicators of mitochondrial dysfunction, a reduction in adenosine triphosphate generation, the inner mitochondrial membrane potential, augmentation of reactive oxygen species production and cytochrome c were also detected in the mitochondria following treatment with BDMC. These results indicate that BDMC attenuates gastric adenocarcinoma growth by inducing mitochondrial dysfunction.

Comparative antiulcer effect of bisdemethoxycurcumin and curcumin in a gastric ulcer model system.[Pubmed:19188055]

Phytomedicine. 2009 Apr;16(4):342-51.

The antiulcer effect of Bisdemethoxycurcumin, a yellow pigment found mainly in rhizomes of Curcuma longa, was compared with curcumin in gastric ulcer model systems to validate its clinical application as a remedy for peptic ulcer. Western blot analysis of mouse macrophage cell line RAW 264.7 activated with lipopolysaccharide showed that Bisdemethoxycurcumin inhibited inducible nitric oxide synthase (iNOS) production significantly but had no effect on tumor necrosis factor-alpha (TNF-alpha) production, whereas curcumin showed stronger suppression of iNOS protein production and inhibited TNF-alpha protein production significantly. However, Bisdemethoxycurcumin and curcumin possessed similar potency in scavenging nitric oxide generated from mouse macrophage cell line RAW 264.7. Reverse-transcriptase polymerase chain reaction (RT-PCR) analysis showed that both curcuminoids inhibited the induction of iNOS dose-dependently at the transcriptional level and curcumin also appeared to inhibit the induction of TNF-alpha at post-transcriptional level. In an animal model, intraduodenal administration of Bisdemethoxycurcumin (5-80 mg/kg body wt.) showed a strong inhibitory effect on gastric acid secretion in pylorus-ligated rats whereas curcumin (5-20 mg/kg body wt.) showed a less inhibitory effect, with maximum potency at a dose of 20mg/kg body wt. Moreover, oral administration of Bisdemethoxycurcumin at doses of 20-80 mg/kg body wt. twice daily for 10 days showed a significant curative efficacy in accelerating the healing of acetic acid-induced chronic gastric ulcer and promotion of mucosal regeneration in the ulcerated portion in a dose-related manner with potency equal to curcumin. In contrast, the curative potency of curcumin tended to decrease at doses over 160 mg/kg body wt./day. Western blot analysis in ulcerated gastric mucosa showed that Bisdemethoxycurcumin dose-dependently reduced the increased protein expression level of iNOS but not TNF-alpha. These results indicated that Bisdemethoxycurcumin directly accelerates gastric ulcer healing with potency equal to curcumin. Its antiulcer effect might be due to its properties of decreasing gastric acid secretion and enhancing the mucosal defensive mechanism through suppression of iNOS-mediated inflammation.

Bisdemethoxycurcumin Induces apoptosis in activated hepatic stellate cells via cannabinoid receptor 2.[Pubmed:25594342]

Molecules. 2015 Jan 14;20(1):1277-92.

Activated Hepatic Stellate Cells (HSCs), major fibrogenic cells in the liver, undergo apoptosis when liver injuries cease, which may contribute to the resolution of fibrosis. Bisdemethoxycurcumin (BDMC) is a natural derivative of curcumin with anti-inflammatory and anti-cancer activities. The therapeutic potential of BDMC in hepatic fibrosis has not been studied thus far in the context of the apoptosis in activated HSCs. In the current study, we compared the activities of BDMC and curcumin in the HSC-T6 cell line and demonstrated that BDMC relatively induced a potent apoptosis. BDMC-induced apoptosis was mediated by a combinatory inhibition of cytoprotective proteins, such as Bcl2 and heme oxygenase-1 and increased generation of reactive oxygen species. Intriguingly, BDMC-induced apoptosis was reversed with co-treatment of sr144528, a cannabinoid receptor (CBR) 2 antagonist, which was confirmed with genetic downregulation of the receptor using siCBR2. Additionally, incubation with BDMC increased the formation of death-induced signaling complex in HSC-T6 cells. Treatment with BDMC significantly diminished total intracellular ATP levels and upregulated ATP inhibitory factor-1. Collectively, the results demonstrate that BDMC induces apoptosis in activated HSCs, but not in hepatocytes, by impairing cellular energetics and causing a downregulation of cytoprotective proteins, likely through a mechanism that involves CBR2.

Thiol Reactivity of Curcumin and Its Oxidation Products.[Pubmed:29569909]

Chem Res Toxicol. 2018 Apr 16;31(4):269-276.

The polypharmacological effects of the turmeric compound curcumin may be partly mediated by covalent adduction to cellular protein. Covalent binding to small molecule and protein thiols is thought to occur through a Michael-type addition at the enone moiety of the heptadienedione chain connecting the two methoxyphenol rings of curcumin. Here we show that curcumin forms the predicted thiol-Michael adducts with three model thiols, glutathione, N-acetylcysteine, and beta-mercaptoethanol. More abundant, however, are respective thiol adducts of the dioxygenated spiroepoxide intermediate of curcumin autoxidation. Two electrophilic sites at the quinone-like ring of the spiroepoxide are identified. Addition of beta-mercaptoethanol at the 5'-position of the ring gives a 1,7-dihydroxycyclopentadione-5' thioether, and addition at the 1'-position results in cleavage of the aromatic ring from the molecule, forming methoxyphenol-thioether and a tentatively identified cyclopentadione aldehyde. The curcuminoids demethoxy- and Bisdemethoxycurcumin do not form all of the possible thioether adducts, corresponding with their increased stability toward autoxidation. RAW264.7 macrophage-like cells activated with phorbol ester form curcumin-glutathionyl and the 1,7-dihydroxycyclopentadione-5'-glutathionyl adducts. These studies indicate that the enone of the parent compound is not the only functional electrophile in curcumin, and that its oxidation products provide additional electrophilic sites. This suggests that protein binding by curcumin may involve oxidative activation into reactive quinone methide and spiroepoxide electrophiles.

Molecular Modelling reveals the inhibition mechanism and structure-activity relationship of curcumin and its analogues to Staphylococcal aureus Sortase A.[Pubmed:29546799]

J Biomol Struct Dyn. 2019 Mar;37(5):1220-1230.

Previous studies found that the activity of Sortase A, a bacterial surface protein from Staphylococcus aureus, was inhibited by curcumin and its analogues. To explore this inhibitory mechanism, Sortase A and its inhibitors in complex systems were studied by molecular docking, molecular modelling, binding energy decomposition calculation and steered molecular dynamics simulations. Energy decomposition analysis indicated that PRO-163, LEU-169, GLN-172, ILE-182 and ILE-199 are key residues in Sortase A-inhibitor complexes. Furthermore, interactions between the methoxyl group on the benzene ring in the conjugated molecule (curcumin, demethoxycurcumin, Bisdemethoxycurcumin) and VAL-168, LEU-169 and GLN-172 induce the inhibitory activity based on the energy decomposition and distance analyses between the whole residues and inhibitors. However, because of its coiled structure, the non-conjugated molecule, tetrahydrocurcumin, with key residues in the binding sites of Sortase A, interacted weakly with SrtA, leading to the loss of inhibitory activity. Based on these results, the methoxyl group on the benzene ring in the conjugated molecule largely influenced the inhibitory activity of the Sortase A inhibitors.

Bisdemethoxycurcumin inhibits PDGF-induced vascular smooth muscle cell motility and proliferation.[Pubmed:23554078]

Mol Nutr Food Res. 2013 Sep;57(9):1611-8.

SCOPE: A key event in the development of plaque in the arteries is the migration and proliferation of smooth muscle cells (SMCs) from the media to the intima of the blood vessel. This study was conducted to evaluate the effects of Bisdemethoxycurcumin (BC), a naturally occurring structural analog of curcumin (CC), on platelet-derived growth factor (PDGF)-stimulated migration and proliferation of SMCs. METHODS AND RESULTS: CC and BC were synthesized by condensing acetyl acetone with vanillin and 4-hydroxybenzaldehyde, respectively. SMCs isolated from adult rat aorta were stimulated with PDGF in the presence or absence of CC or BC following which, cell migration and proliferation were assessed by monolayer wound healing assay and [(3) H]-thymidine incorporation respectively. PDGF-stimulated phosphorylation of PDGF receptor-beta and its downstream effectors Akt and ERK were assessed by Western blotting. Intracellular reactive oxygen species was assessed using the fluorescent dye 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate. BC elicited a concentration-dependent inhibition of PDGF-stimulated phosphorylation of PDGF receptor-beta, Akt and Erk as well as the PDGF-stimulated SMC migration and proliferation. BC was more potent than CC in inhibiting migration and proliferation and suppressing PDGF-signaling in SMCs. Both compounds were equipotent in inhibiting PDGF-stimulated generation of intracellular reactive oxygen species. CONCLUSION: BC may be of potential use in the prevention or treatment of vascular disease.

Curcuminoids combined with gefitinib mediated apoptosis and autophagy of human oral cancer SAS cells in vitro and reduced tumor of SAS cell xenograft mice in vivo.[Pubmed:29717538]

Environ Toxicol. 2018 May 2.

Gefitinib has been used for cancer patients and curcumin (CUR), demethoxycurcumin (DMC), or Bisdemethoxycurcumin (BDMC) also shown to induce cancer cell apoptosis. However, no report shows the combination of gefitinib with, CUR, DMC, or BDMC induce cell apoptosis and autophagy in human oral cancer cells. In this study, we investigated the effects of gefitinib with or without CUR, DMC, or BDMC co-treatment on the cell viability, apoptotic cell death, autophagy, mitochondria membrane potential (MMP), and caspase-3 activities by flow cytometry assay and autophagy by acridine orange (AO) staining in human oral cancer SAS cells. Results indicated that gefitinib co-treated with CUR, DMC, or BDMC decreased total viable cell number through the induction of cell apoptosis and autophagy and decreased the levels of MMP and increased caspase-3 activities in SAS cells. Western blotting indicated that gefitinib combined with CUR, DMC, or BDMC led to decrease Bcl-2 protein expression which is an antiapoptotic protein and to increase ATG5, Beclin 1, p62/SQSTM1, and LC3 expression that associated with cell autophagy in SAS cells. Gefitinib combined with CUR and DMC led to significantly reduce the tumor weights and volumes in SAS cell xenograft nude mice but did not affect the total body weights. Based on those observations, we suggest that the combination of gefitinib with CUR, DMC, and BDMC can be a potential anticancer agent for human oral cancer in future.

Synthesis of curcuminoid-imprinted polymers applied to the solid-phase extraction of curcuminoids from turmeric samples.[Pubmed:29568669]

J Pharm Anal. 2018 Feb;8(1):60-68.

A molecular imprinting polymer technique was successfully applied to precipitation polymerization by using styrene as a functional monomer, curcuminoids as templates, acetonitrile as a porogenic solvent, benzoyl peroxide as the initiator, and ethylene glycol dimethacrylate as the crosslinker. The effects of interaction on the adsorption capacity of the molecularly imprinted polymer (MIP) and non-imprinted polymer (NIP) were investigated. A comparison of the adsorption capacity for MIP and NIP indicated that the NIP had the lowest adsorption capacity. The curcuminoid-imprinted polymer (Cur-MIP) was synthesized from 0.0237 mmol of styrene, 47.0 g of acetonitrile, 1.0238 mmol of ethylene glycol dimethacrylate, 0.0325 mmol of curcuminoids, and 0.2480 mmol of benzoyl peroxide. A high-performance liquid chromatography method with fluorescence detection was developed and validated for various chromatographic conditions for the determination of the curcuminoids in turmeric samples. The sample solution was separated using the Cur-MIP via solid-phase extraction and analyzed on a Brownlee analytical C18 column (150 mm x 6 mm, 5 microm) using an isocratic elution consisting of acetonitrile and 0.1% trichloroacetic acid (40:60, v/v). The flow rate was maintained at 1.5 mL/min. The fluorescence detector was set to monitor at lambdaex = 426 nm and lambdaem = 539 nm. The quantification limit values were found to be 16.66, 66.66, and 33.33 microg/L for curcumin, demethoxycurcumin, and Bisdemethoxycurcumin, respectively. Thus, we concluded that the Cur-MIP and high-performance liquid chromatographic-fluorescence method could be applied to selective extraction and could be used as a rapid tool for the determination of curcuminoids in medicinal herbal extracts.

Curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and turmerones differentially regulate anti-inflammatory and anti-proliferative responses through a ROS-independent mechanism.[Pubmed:17522064]

Carcinogenesis. 2007 Aug;28(8):1765-73.

Curcumin, a component of turmeric (Curcuma longa), has been shown to exhibit chemopreventive activity. Whether analogs of curcumin (Cur), such as demethoxycurcumin (DMC), Bisdemethoxycurcumin (BDMC), tetrahydrocurcumin (THC) and turmerones, modulate inflammatory signaling and cell proliferation signaling to same extent as curcumin was investigated. The results indicate that the relative potency for suppression of tumor necrosis factor (TNF)-induced nuclear factor-kappaB (NF-kappaB) activation was Cur > DMC > BDMC; thus suggesting the critical role of methoxy groups on the phenyl ring. THC, which lacks the conjugated bonds in the central seven-carbon chain, was completely inactive for suppression of the transcription factor. Turmerones also failed to inhibit TNF-induced NF-kappaB activation. The suppression of NF-kappaB activity correlated with inhibition of NF-kappaB reporter activity and with down-regulation of cyclooxygenase-2, cyclin D1 and vascular endothelial growth factor, all regulated by NF-kappaB. In contrast to NF-kappaB activity, the suppression of proliferation of various tumor cell lines by Cur, DMC and BDMC was found to be comparable; indicating the methoxy groups play minimum role in the growth-modulatory effects of curcumin. THC and turmerones were also found to be active in suppression of cell growth but to a much lesser extent than curcumin, DMC and BDMC. Whether suppression of NF-kappaB or cell proliferation, no relationship of any of the curcuminoid was found with reactive oxygen species (ROS) production. Overall, our results demonstrated that different analogs of curcumin present in turmeric exhibit variable anti-inflammatory and anti-proliferative activities, which do not correlate with their ability to modulate the ROS status.

[Research on standard decoction of processed Curcumae Longae Rhizoma containing volatile oil].[Pubmed:29676082]

Zhongguo Zhong Yao Za Zhi. 2018 Mar;43(5):879-884.

To prepare processed Curcumae Longae Rhizoma standard decoction, establish its quality standard, provides quality reference for formulated Jianghuang granules and lay a foundation for standard decoction research for the pieces containing volatile oil. Thirteen batches of processed Curcumae Longae Rhizoma standard decoctions were prepared according to the preparation requirements for standard decoction of Chinese herbal medicine containing volatile oil. With curcumin as the detection index, the transfer rate and extraction ratio were calculated; the pH value was determined and HPLC fingerprint analysis method was established. The results showed that the transfer rate ranged from 0.67% to 2.24%; the extraction rate was at a range of 9.95% to 18.36% and pH value was 3.86 to 6.05. Then the Similarity Evaluation System for Chromatographic Fingerprint of Traditional Chinese Medicine (2012A) was used to analyze and compare the fingerprint. Sixteen common peaks were determined and three were identified including Bisdemethoxycurcumin (peak 7), demethoxycurcumin (peak 8) and curcumin (peak 9). Moreover, the similarity was over 0.78 in the similarity evaluation of 13 batches of samples. HPLC fingerprint analysis method of processed Curcumae Longae Rhizoma standard decoction was established, showing good precision, stability and repeatability with certain identification effect, suitable for the quality control of formulated Jianghuang granules.

Simultaneous quantification of free curcuminoids and their metabolites in equine plasma by LC-ESI-MS/MS.[Pubmed:29529492]

J Pharm Biomed Anal. 2018 May 30;154:31-39.

The human health benefits attributed to turmeric/curcumin spice has resulted in its wide utilization as a dietary supplement for companion pets and other animals including horses. While the quantification of free curcuminoids (curcumin, demethoxycurcumin, Bisdemethoxycurcumin) and their phase-2 metabolites (curcumin-O-sulfate, curcumin-O-glucuronide) have been extensively investigated in human and rodent biological samples (primarily plasma and serum), there is lack of similar data for horses. Herein, we report a validated LC-ESI-MS/MS method for the simultaneous quantification of the aforementioned free curcuminoids and their metabolites in equine plasma. The linearity of the aforementioned curcuminoids and curcumin-O-sulfate was in the range of 0.5-1000ng/mL and 1-1000ng/mL for curcumin-O-glucuronide with 85-115% accuracy and <15% precision in equine plasma. The method was validated based on US FDA criteria and applied to characterize the pharmacokinetics of curcumin-O-sulfate in equine plasma.

Curcumin and its demethoxy derivatives possess p300 HAT inhibitory activity and suppress hypertrophic responses in cardiomyocytes.[Pubmed:29602708]

J Pharmacol Sci. 2018 Apr;136(4):212-217.

The natural compound, curcumin (CUR), possesses several pharmacological properties, including p300-specific histone acetyltransferase (HAT) inhibitory activity. In our previous study, we demonstrated that CUR could prevent the development of cardiac hypertrophy by inhibiting p300-HAT activity. Other major curcuminoids isolated from Curcuma longa including demethoxycurcumin (DMC) and Bisdemethoxycurcumin (BDMC) are structural analogs of CUR. In present study, we first confirmed the effect of these three curcuminoid analogs on p300-HAT activity and cardiomyocyte hypertrophy. Our results showed that DMC and BDMC inhibited p300-HAT activity and cardiomyocyte hypertrophy to almost the same extent as CUR. As the three compounds have structural differences in methoxy groups at the 3-position of their phenol rings, our results suggest that these methoxy groups are not involved in the inhibitory effects on p300-HAT activity and cardiac hypertrophy. These findings provide useful insights into the structure-activity relationship and biological activity of curcuminoids for p300-HAT activity and cardiomyocyte hypertrophy.

Bisdemethoxycurcumin(Curcumin III; Didemethoxycurcumin) is a natural derivative of curcumin with anti-inflammatory and anti-cancer activities.

Bisdemethoxycurcumin,33171-05-0,24939-16-0;Curcumin III; Didemethoxycurcumin,Natural Products, buy Bisdemethoxycurcumin , Bisdemethoxycurcumin supplier , purchase Bisdemethoxycurcumin , Bisdemethoxycurcumin cost , Bisdemethoxycurcumin manufacturer , order Bisdemethoxycurcumin , high purity Bisdemethoxycurcumin