Cimigenol

Anticancer efficiency of cycloartane triterpenoid derivatives isolated from Cimicifuga yunnanensis Hsiao on triple-negative breast cancer cells.[Pubmed:30584366]

Cancer Manag Res. 2018 Dec 6;10:6715-6729.

Background: The roots and rhizomes of Cimicifuga yunnanensis Hsiao are commonly used as anti-inflammatory, antipyretic, and analgesic remedies and detoxification agents in traditional Chinese medicine (TCM). Although C. yunnanensis has been considered as supplementary medicine for several disorders, the antitumor effect of this herb and its key components has not been explored. Materials and methods: The rhizomes of C. yunnanensis were isolated by chromatographic techniques. Structures of isolated compounds were identified based on spectroscopic methods and comparison with published data. The in vitro anticancer activities of purified components were also performed by MTT experiments. The in vivo anticancer activities were examined by subcutaneous tumor model or a breast cancer liver metastasis model. Results: In this study, we aimed to identify and characterize the effective antitumor components from the rhizomes of C. yunnanensis. By bioassay-guided fractionation techniques and chemical characterization, 12 cycloartane triterpenes and four chromones were isolated, among them, 11 compounds were identified in this genus at first. The identified two compounds showed dramatic inhibitory activities against breast cancer cells: compound 4 (23-epi-26-deoxyactein) and compound 13 (Cimigenol). Then, we examined the antitumor effect of these two selective candidate chemicals on triple-negative breast cancer (TNBC) cells in vivo and found that they could reduce tumor growth in subcutaneous tumor model or breast cancer liver metastasis model. Conclusion: These results suggested that the selective compounds isolated from C. yunnanensis Hsiao could be the promising new agents for TNBC treatment.

[Research progress on cycloartane triterpenoids of Actaea].[Pubmed:30486523]

Zhongguo Zhong Yao Za Zhi. 2018 Oct;43(20):4000-4010.

The genus Actaea plants are widely distributed in China, and the cycloartane triterpenoids are the characteristic constituents of this genus. They are divided into types of Cimigenol, hydroshengmanol, shengmanol, cimiacerogenin, acteol, 16, 23-diketo, foetidonol, dahurinol, etc. Cycloartane triterpenoids show many biological activities, such as cytotoxicity, anti-osteoporosis, antiviral, anti-inflammatory, anti-nucleoside transport, neuroprotective, anti-oxidant, antibacterial activities. The present paper reviewed the distribution of the plant resources of Actaea, chemical structures and biological activities of cycloartane triterpenoids, aiming to provide a reference for the further research in the future.

Soulieoside O, a new cyclolanostane triterpenoid glycoside from Souliea vaginata.[Pubmed:28374633]

J Asian Nat Prod Res. 2017 Dec;19(12):1177-1182.

A new cyclolanostane triterpenoid glycoside, soulieoside O (1), together with 25-O-acetylCimigenol-3-O-beta-d-xylopyranoside (2) and Cimigenol-3-O-beta-d-xylopyranoside (3), was isolated from the rhizomes of Souliea vaginata. Their structures were characterized by spectroscopic analysis and chemical methods. The new compound showed moderate inhibitory activity against three human cancer cell lines with IC50 values of 9.3-22.5 muM.

A novel cycloartane triterpenoid from Cimicifuga induces apoptotic and autophagic cell death in human colon cancer HT-29 cells.[Pubmed:28260002]

Oncol Rep. 2017 Apr;37(4):2079-2086.

The extract from Cimicifuga, a genus of flowering plants, has been demonstrated to have mainly therapeutic effects on menstrual and menopausal symptoms and also exhibits immunomodulatory, anti-inflammatory and antimicrobial activity. Moreover, the anticancer effects of Cimicifuga have been reported, but the underlying mechanism causing cancer cell death has been poorly described. The present study was designed to investigate the antitumor effects and underlying molecular mechanisms of Cimigenol (KY17), a novel cycloartane triterpenoid from Cimicifuga. KY17-induced autophagy and apoptotic cell death in human colon cancer cells (HT-29) was investigated. KY17 treatment induced growth inhibition and apoptotic cell death in a concentration-dependent manner. The induction of apoptosis was confirmed by a change in cell morphology, and an increase in the G2/M phase, as well as increased protein levels of cleaved-caspase-8 and -3; cleavage of poly(ADP-ribose) polymerase (PARP) in the HT-29 cells following KY17 treatment. In addition, autophagy was evaluated by the accumulation of acridine orange, the appearance of green fluorescent protein-light-chain 3 (LC3) punctate structures and increased levels of LC3-II protein expression. Furthermore, combination treatment with the autophagy inhibitor bafilomycin A1 enhanced the induction of apoptosis by KY17. Taken together, the present study provides new insight into the role of KY17 as a potential antitumor compound. Combination of KY17 with an autophagy inhibitor may be a valuable strategy for the chemoprevention or treatment of colon cancer.

Induction of mast cell degranulation by triterpenoidal saponins obtained from Cimicifugae rhizoma.[Pubmed:27310149]

Immunopharmacol Immunotoxicol. 2016 Oct;38(5):311-8.

Cimicifugae rhizoma has been widely used as a traditional herbal medicine to treat inflammation and menopausal symptoms. In this study, we found that some of the triterpenoidal saponins purified from the ethanol extract of Cimicifugae rhizoma dramatically induced histamine release. The structure-related induction of mast cell degranulation by them and the mechanism of action were determined. beta-Hexosaminidase release in HMC-1 cells was increased in a concentration-dependent manner, with maximal 6.5- and 8.5-fold increases, by 200 mug/mL 24-epi-7,8-didehydroCimigenol-3-O-xyloside (comp 1) and Cimigenol 3-O-beta-d-xyloside (comp 4) compared with those treated with phorbol 12-myristate 13-acetate and A23187 (PMACI), respectively. However, beta-hexosaminidase release was not changed by 7,8-dihydroCimigenol (comp 3), or 23-OAc-shengmanol-3-O-xyloside (comp 7). These triterpenoidal saponins changed neither the intracellular Ca(2+ )level nor the activation of PKC, both of which play essential roles in histamine release. However, cromolyn and ketotifen, membrane stabilizers, effectively inhibited the beta-hexosaminidase release induced by comp 1 or comp 4 by 39 and 45%, respectively. Collectively, xylose on the Cimigenol-related backbone among triterpene glycosides isolated from Cimicifugae rhizoma may play an important role in activating mast cells and induction of degranulation partly via membrane destabilization of mast cells.

Cytotoxic cycloartane triterpenes of the traditional Chinese medicine "shengma" (Cimicifuga dahurica).[Pubmed:23225366]

Planta Med. 2013 Jan;79(1):60-9.

Twelve new 9,19-cycloartane triterpenes (1-12), together with fourteen known compounds (13-26), were isolated from the roots of Cimicifuga dahurica. Their structures were determined by application of spectroscopic analyses and chemical methods. Biological evaluation of the compounds against human HL-60, SMMC-7721, A549, MCF-7, and SW-480 cell lines indicated that Cimigenol-type glycosides (1-3, 19, and 20) showed broad-spectrum and moderate cytotoxicities, with IC50 values ranging from 4.2 to 14.5 microM. Meanwhile, Cimigenol-type aglycones (6-8, 15, 16, and 18) exhibited broad-spectrum and week cytotoxicities, having IC50 values around 20 microM. In addition, the key points of the structure-activity relationships of aglycones with a Cimigenol skeleton were discussed.

Cycloartane-type triterpene glycosides from the rhizomes of Cimicifuga heracleifolia and their anticomplementary activity.[Pubmed:22753039]

Planta Med. 2012 Aug;78(12):1391-4.

Seven known triterpene glycosides, 23-O-acetylshengmanol 3-O-alpha-L-arabinopyranoside (1), 23-O-acetylshengmanol 3-O-beta-D-xylopyranoside (2), 24-epi-24-O-acetylhydroshengmanol 3-O-beta-D-xylopyranoside (3), cimiaceroside B (4), (23R,24S)-Cimigenol 3-O-beta-D-xylopyranoside (5), (23R,24R)-25-O-acetylCimigenol 3-O-beta-D-xylopyranoside (6) and (23R,24S)-25-O-anhydroCimigenol 3-O-beta-D-xylopyranoside (7) were isolated from the rhizomes of Cimicifuga heracleifolia. Their chemical structures were determined on the basis of spectroscopic analyses including 2D NMR. All isolates were investigated for their inhibitory effects on the classical pathway of the complement system. Among them, compound 6 showed strong inhibitory activity with an IC(5)(0) value of 7.7 microM while compound 3 was moderately active with an IC(5)(0) value of 195.6 microM.

Studies on the constituents of Cimicifuga foetida collected in Guizhou Province and their cytotoxic activities.[Pubmed:22689393]

Chem Pharm Bull (Tokyo). 2012;60(5):571-7.

Two new triterpenoids and a chromone glycoside, namely, 24-epi-Cimigenol-3-one (1), foetinoside (2), cimifugin-4'-O-[6''-feruloyl]-beta-D-glucopyranoside (3), together with 18 known compounds, were isolated from the rhizomes of Cimicifuga foetida L. collected in Guizhou Province, China. All of the compounds were identified by spectroscopic methods, as well as chemical methods. In the in vitro cytotoxicity evaluation of these compounds against 5 human cancer cell lines, Cimigenol (8) exerted the most potent cytotoxic activity against SMMC-7721 (7.87 microM) and A-549 (12.16 microM), while cimiacerin B (9) also showed obvious cytotoxicity against the A-549 cell line, with an IC(50) value of 16.77 microM.

Simultaneous determination of cimicifugoside H-2, cimicifugoside H-1, 23-epi-26-deoxyactein, cimigenol xyloside and 25-O-acetylcimigenoside in beagle dog plasma by LC-MS/MS.[Pubmed:22285707]

J Pharm Biomed Anal. 2012 Mar 25;62:87-95.

A selective and sensitive LC-MS/MS method was developed and validated for the simultaneous determination of five constituents (cimicifugoside H-2, cimicifugoside H-1, 23-epi-26-deoxyactein, Cimigenol xyloside and 25-O-acetylcimigenoside) of Cimicifuga foetida L. in beagle dog plasma. The quantitation was performed on a LC-MS/MS with negative electrospray ionization in selected reaction monitoring (SRM) mode. A gradient mobile phase composed of methanol and water was used at a flow rate of 0.4 ml/min. All the analytes and internal standard (20 (S)-ginsenoside Rg3) were isolated from plasma samples by a liquid-liquid extraction method. The average extraction recoveries were 73-74% for cimicifugoside H-2, 89-94% for cimicifugoside H-1, 73-80% for 23-epi-26-deoxyactein, 89-91% for Cimigenol xyloside, 87-96% for 25-O-acetylcimigenoside, respectively. The method showed good linearity and no endogenous material interfered with all the five compounds and I.S. peaks. The lower limit of quantification (LLOQ) of all analytes was 0.5 ng/ml. The intra- and inter-day precision of analysis was less than 15% for each analyte at concentrations of 2.0, 50, 500 ng/ml, and the accuracy ranged from 85.8% to 107%. This method was successfully applied to reveal the pharmacokinetic properties of cimicifugoside H-2, cimicifugoside H-1, 23-epi-26-deoxyactein, Cimigenol xyloside and 25-O-acetylcimigenoside after oral administration.

Cycloartane triterpenoids from the aerial parts of Cimicifuga foetida Linnaeus.[Pubmed:21565371]

Phytochemistry. 2011 Aug;72(11-12):1473-81.

Cycloartane triterpenoids, 2',24-O-diacetylisodahurinol-3-O-alpha-L-arabinopyranoside, 24-O-acetylisodahurinol-3-O-alpha-L-arabinopyranoside, 12beta-hydroxy-25-anhydroCimigenol, Cimigenol-12-one, 12beta-hydroxy-15-deoxyCimigenol, 2'-O-acetyl-24-epi-Cimigenol-3-O-alpha-L-arabinopyranoside, 2'-O-acetylCimigenol-3-O-beta-D-xylopyranoside, 25-anhydroCimigenol-3-O-alpha-L-arabinopyranoside, 2',23-O-diacetylshengmanol-3-O-alpha-L-arabinopyranoside, and 2',24-O-diacetyl-25-anhydrohydroshengmanol-3-O-alpha-L-arabinopyranoside, together with eight known compounds, were isolated from aerial parts of Cimicifuga foetida. Their structures were determined by application of spectroscopic analyses and chemical methods. Biological evaluation of the compounds against human HL-60, SMMC-7721, A549, SK-BR-3, and PANC-1 cell lines indicated that three of these compounds exhibited broad-spectrum and moderate cytotoxic activities, with IC(5)(0) values ranging from 6.20 to 22.74 muM. By comparing previous cytotoxic testing data and bioassay results from this study, preliminary structure-activity relationships of compounds with a c imigenol-skeleton can be proposed.

Bioactivity-guided isolation of GABA(A) receptor modulating constituents from the rhizomes of Actaea racemosa.[Pubmed:21082802]

J Nat Prod. 2010 Dec 27;73(12):2024-8.

Black cohosh (Actaea racemosa) is a frequently used herbal remedy for the treatment of mild climacteric symptoms. In the present study, the modulation of gamma-aminobutryic acid (GABA)-induced chloride currents (I(GABA)) through GABA type A (GABA(A)) receptors by black cohosh extracts and isolated compounds was investigated. GABA(A) receptors, consisting of alpha(1), beta(2), and gamma(2S) subunits, were expressed in Xenopus laevis oocytes, and potentiation of I(GABA) was measured using the two-microelectrode voltage clamp technique. In a bioactivity-guided isolation procedure the positive modulation of I(GABA) could be restricted to the plant terpenoid fractions, resulting in the isolation of 11 cycloartane glycosides, of which four significantly (p < 0.05) enhanced I(GABA). The most efficient effect was observed for 23-O-acetylshengmanol 3-O-beta-d-xylopyranoside (4, 100 muM), enhancing I(GABA) by 1692 +/- 201%, while actein (1), Cimigenol 3-O-beta-d-xylopyranoside (6), and 25-O-acetylCimigenol 3-O-alpha-l-arabinopyranoside (8) were significantly less active. In the absence of GABA, only 4 induced small (not exceeding 1% of I(GABA-max)) chloride inward currents through GABA(A) receptors. It is hypothesized that the established positive allosteric modulation of GABA(A) receptors may contribute to beneficial effects of black cohosh extracts in the treatment of climacteric symptoms.

Quantitative analysis of cycloartane glycosides in black cohosh rhizomes and dietary supplements by RRLC-ELSD and RRLC-qTOF-MS.[Pubmed:20694806]

Anal Bioanal Chem. 2011 Jun;400(8):2597-605.

In this study, a fast and reproducible RRLC-ELSD method for the quantitative analysis of 17 cycloartane glycosides and the aglycone Cimigenol in black cohosh rhizomes and dietary supplements has been developed. Separation of the 18 triterpenes was achieved within 16 min using reversed phase material and a gradient elution system consisting of water, acetonitrile and methanol. The method was validated for accuracy (recovery rates from 96.79% to 102.86%), precision (intra-day variation

Cycloartane triterpenoids from Cimicifuga yunnanensis induce apoptosis of breast cancer cells (MCF7) via p53-dependent mitochondrial signaling pathway.[Pubmed:20564500]

Phytother Res. 2011 Jan;25(1):17-24.

The present study was carried out to investigate the antitumor activity of five cycloartane triterpenoids isolated from Cimicifuga yunnanensis on the breast cancer cell line MCF7 and its corresponding drug resistant subline R-MCF7, including Cimigenol-3-O-beta-D-xylopyranoside (compound 1), 25-O-acetylCimigenol-3-O-beta-D-xylopyranoside (compound 2), 25-chlorodeoxyCimigenol-3-O-beta-D-xylopyranoside (compound 3), 25-O-acetylCimigenol-3-O-alpha-L-arabinopyranoside (compound 4) and 23-O-acetylCimigenol-3-O-beta-D-xylopyranoside (compound 5). The results showed that compounds 2-5 have relatively high antitumor activity on both MCF7 and R-MCF7 cells. The involvement of apoptosis as a major cause of cycloartane triterpenoids-induced cell death was further confirmed. The results of RT-PCR showed that compounds 2-5 increased the expression of p53 and bax, which led to the loss of mitochondrial potential and then resulted in the activation of caspase-7. These findings collectively demonstrated that compounds 2-5 induced apoptosis of MCF7 via p53-dependent mitochondrial pathway.

Six new cycloartane triterpene glycosides from Actaea asiatica.[Pubmed:20183295]

J Asian Nat Prod Res. 2009 Jul;11(7):588-96.

Six new cycloartane triterpene glycosides, (3',12beta)-O-diacetyl-Cimigenol-3-O-beta-D-xylopyranoside (1), (4',25)-O-diacetyl-Cimigenol-3-O-beta-D-xylopyranoside (2), 2'-O-acetyl-25-O-methyl-Cimigenol-3-O-beta-D-xylopyranoside (3), 2'-O-acetyl-25-O-ethyl-Cimigenol-3-O-beta-D-xylopyranoside (4), 3'-O-acetyl-cimicifugoside (5), and 4'-O-acetyl-23-epi-26-deoxycimifugoside (6), were isolated from the rhizomes of Actaea asiatica. Their structures were elucidated on the basis of chemical methods and spectroscopic analysis. Compounds 1, 2, 4-6 exhibited positive cytotoxic activities.

Aqueous extracts of Cimicifuga racemosa and phenolcarboxylic constituents inhibit production of proinflammatory cytokines in LPS-stimulated human whole blood.[Pubmed:19935904]

Can J Physiol Pharmacol. 2009 Nov;87(11):963-72.

Cimicifuga racemosa (black cohosh) is commonly used in traditional medicines as treatment for menopausal symptoms and as an antiinflammatory remedy. To clarify the mechanism of action and active principle for the antiinflammatory action, the effects of aqueous C. racemosa root extracts (CRE) and its major constituents on the release of the proinflammatory cytokines IL-6, TNF-alpha, IFN-gamma, and the chemokine IL-8 were investigated in lipopolysaccharide (LPS)-stimulated whole blood of healthy volunteers. CRE (3 microg/microL and 6 microg/microL) reduced LPS-induced release of IL-6 and TNF-alpha in a concentration- and time-dependent manner and almost completely blocked release of IFN-gamma into the plasma supernatant. Except for IFN-gamma, these effects were attenuated at longer incubation periods. IL-8 secretion was stimulated by CRE. As shown by quantitative real-time RT-PCR, effects on cytokines were based on preceding changes in mRNA levels except for IL-8. According to their content in CRE, the phenolcarboxylic compounds caffeic acid, ferulic acid, and isoferulic acid, as well as the triterpene glycosides 23-epi-26-deoxyactein and Cimigenol-3-O-xyloside, were tested at representative concentrations. Among these, isoferulic acid was the prominent active principle in CRE, responsible for the observed inhibition of IL-6, TNF-alpha, and IFN-gamma, but not for IL-8 stimulation. The effect of this compound may explain the antiinflammatory activities of CRE and its beneficial actions in rheumatism and other inflammatory diseases.