Rhizomes Of Cimicifuga Foetida Research Articles

Development of actein derivatives as potent anti-triple negative breast cancer agents

Actein is a natural triterpenoid glycoside, isolated from the rhizomes of Cimicifuga foetida, which have been demonstrated to be potential in the treatment of breast cancer previously. Herein, we described the design and synthesis of a series of actein derivatives as anti-triple negative breast cancer (TNBC) inhibitors. Of which, the most promising derivative 27 exhibited significant inhibitory activity against human TNBC cell lines HCC1806 and MDA-MB-231, with IC50 values of 2.78 and 9.11 μM, respectively. Structure-activity relationships of actein derivatives were also discussed. Moreover, preliminary mechanism investigation revealed that 27 significantly inhibited cancer cell proliferation via cell cycle arrest at S phase. In addition, western blot analysis showed that the activation of MAPK signaling pathway might contribute to derivative 27 induced cell death. Overall, these results indicate that 27 has the potential to be developed as a lead compound and compounds with the actein scaffold are a promising novel class of inhibitors to treat TNBC.

Actein Antagonizes Oral Squamous Cell Carcinoma Proliferation through Activating FoxO1

Background: Oral squamous cell carcinoma (OSCC) is among the most prevalent head and neck malignancies globally, and it is associated with high mortality rates. Actein is one of the primary active components extractable from the rhizomes of Cimicifuga foetida. This study aimed to evaluate the anti-OSCC effects of actein and evaluate the potential underlying mechanisms. Methods and Results: CCK-8 cell proliferation experiments demonstrated significant dose- and time-dependent anti-OSCC effects of actein, while actein had weak cytotoxic effects on normal oral cell lines. Flow cytometry for cell cycle evaluation revealed that actein could induce cell cycle arrest at the G1 phase among OSCC cell lines. In our Annexin V/PI double staining apoptosis analysis, actein induced significant apoptosis among OSCC cells, with upregulation of Bax and downregulation of Bcl-2. Our mechanistic study implicated the involvement of the Akt/FoxO1 pathway in the anti-OSCC effects of actein. Akt1 and Akt2 expression significantly decreased in association with the FoxO1 upregulation. Furthermore, Bim and p21 were significantly upregulated, while survivin expression was downregulated. Finally, actein treatment was associated with significant p-Akt downregulation and p-FoxO1 upregulation in OSCC cells, demonstrating the validated roles of Akt/FoxO1 in actein-mediated OSCC cell apoptosis and cell cycle arrest. FoxO1 knockdown significantly reversed the anti-OSCC effects of actein. Additionally, a xenograft model indicated that actein could inhibit OSCC cell growth in vivo. Conclusions: Our findings demonstrated that actein could be a strong anti-OSCC candidate. Further evaluations of its safety and effectiveness are necessary before it can be considered for clinical use.

Actein antagonizes colorectal cancer through blocking PI3K/Akt pathways by downregulating IMPDH2.

Actein, a triterpene glycoside, isolated from rhizomes of Cimicifuga foetida, was reported to exhibit anticancer effects in vitro and in vivo. However, the effects of actein on colorectal cancer (CRC) remains unclear. As one of the most popular cancers all over the world, CRC ranked third place in both men and women. Recently, we investigated the potential anti-CRC effects of actein and its mechanisms. The Cell counting kit-8 cell proliferation assays, cell cycle detection, apoptosis detection, reactive oxygen species and mitochondrial membrane potential evaluation, western blot, as well as SW480 xenograft mice model were conducted to illustrate the mechanisms of action on anti-CRC effects of actein. Actein could significantly inhibit the human CRC cell lines SW480 and HT-29 proliferation, whereas less antiproliferation effects were found in normal colorectal cell lines HCoEpiC and FHC. Administration of actein resulted in G1 phase cell cycle arrest in both SW480 and HT-29 cells. Moreover, mitochondria-mediated apoptosis was also observed after treatment with actein in SW480 and HT-29 cell lines. Further investigation of mechanisms of action on actein-mediated anti-CRC proliferation effects indicated that the phosphoinositide 3-kinases (PI3K)/Akt pathways were involved. Actein significantly downregulated the phosphorylation of key molecules in PI3K/Akt pathways, including mTOR, glycogen synthesis kinase 3β (GSK-3β), as well as FOXO1. In addition, inosine 5'-monophosphate dehydrogenase type II (IMPDH2) was also observed decreasing in both SW480 and HT-29 cell lines after actein treatment, suggesting that actein may inhibit the PI3K/Akt pathways by decreasing IMPDH2. Finally, our SW480 xenograft model verified the anti-CRC effects and the safety of actein in vivo. Our findings suggest actein is worthy of further investigation as a novel drug candidate for the treatment of CRC.

Cycloartane triterpene glycosides from rhizomes of Cimicifuga foetida L. with lipid-lowering activity on 3T3-L1 adipocytes

Six previously undescribed cycloartane triterpenes glycosides, cimimanols A–F (1–6), together with thirteen known analogues (7–19) were isolated from the rhizomes of Cimicifuga foetida. Among them, cimimanol A (1) was the first example of cycloartane triterpene glycoside featuring a unique cyclic carbonate, and cimimanol B (2) was a rare trinortriterpene glycoside. The chemical structures and absolute configurations of new compounds were determined on the basis of comprehensive spectroscopic analysis, chemical method, and X-ray crystal diffraction, as well as quantum chemistry calculations. Finally, all these compounds were evaluated for their lipid-lowering effect on 3T3-L1 adipocytes. Compounds 1–3, 6–10, 12–16, 18–19 could significantly reduce the fat accumulation in 3T3-L1 adipocytes, especially compounds 8, 9, 14, and 15 exhibited strong lipid-lowering effect at the concentration of 10 μM, with inhibition rates ranging from 8.35% to 12.07%.

Cimitriteromone A-G, Macromolecular Triterpenoid-Chromone Hybrids from the Rhizomes of Cimicifuga foetida.

Seven unprecedented high molecular weight hybrids of cycloartane triterpenoid saponins and chromone glycosides, namely, Cimitriteromone A-G (1-7), and three known biogenetic precursors (8-10) were isolated from the rhizomes of Cimicifuga foetida by using the HPLC-UV/MS method. The structures of the new compounds were determined by NMR analysis and HRESIMS data. The absolute configurations of sugar moieties were established by a chemical method. The new compounds 2 and 4 showed antiproliferative activities against Taxol-resistant human lung cancer A-549/Taxol with IC50 values of 15.73 ± 0.59 and 24.21 ± 0.61 μM, respectively, while the positive control groups cisplatin and Taxol gave IC50 values of 25.80 ± 1.15 and 0.60 ± 0.09 μM. Notably, compound 4 showed comparable cytotoxicity to the positive control, cisplatin, whereas the corresponding biogenetic precursors compounds 8 and 10 were inactive (IC50 > 40 μM).

Iron oxide magnetic nanoparticles combined with actein suppress non-small-cell lung cancer growth in a p53-dependent manner.

Actein (AT) is a triterpene glycoside isolated from the rhizomes of Cimicifuga foetida that has been investigated for its antitumor effects. AT treatment leads to apoptosis in various cell types, including breast cancer cells, by regulating different signaling pathways. Iron oxide (Fe3O4) magnetic nanoparticles (MNPs) are nanomaterials with biocompatible activity and low toxicity. In the present study, the possible benefits of AT in combination with MNPs on non-small-cell lung cancer (NSCLC) were explored in in vitro and in vivo studies. AT-MNP treatment contributed to apoptosis in NSCLC cells, as evidenced by activation of the caspase 3-signaling pathway, which was accompanied by downregulation of the antiapoptotic proteins Bcl2 and BclXL, and upregulation of the proapoptotic signals Bax and Bad. The death receptors of TRAIL were also elevated following AT-MNP treatment in a p53-dependent manner. Furthermore, a mouse xenograft model in vivo revealed that AT-MNP treatment exhibited no toxicity and suppressed NSCLC growth compared to either AT or MNP monotherapies. In conclusion, this study suggests a novel therapy to induce apoptosis in suppressing NSCLC growth in a p53-dependent manner by combining AT with Fe3O4 MNPs.

Cimicifoetones A and B, Dimeric Prenylindole Alkaloids as Black Pigments of Cimicifuga foetida.

Two dimeric prenylindole alkaloids with a unique indole-benzoindolequinone skeleton, cimicifoetones A (1) and B (2), were isolated as black pigments from the rhizomes of Cimicifuga foetida. The structures were elucidated by spectroscopic methods including HRMS and 2D NMR, as well as single-crystal X-ray diffraction and computational chemical modeling techniques. Cimicifoetones A and B represented the first examples of dimeric indole alkaloids generated through [4+2] Diels-Alder cycloaddition between the prenyl side chain in one 3-prenylindole and the aromatic ring in another. The two compounds showed promising anti-proliferative activity on seven tumor cell lines with IC50 values in the range of 1.36-21.09 μm. Flow cytometric and western blot analysis revealed that compound 2 induced cell apoptosis via death receptor-mediated extrinsic and mitochondrial-mediated intrinsic pathways.

New potential beneficial effects of actein, a triterpene glycoside isolated from Cimicifuga species, in breast cancer treatment.

Actein is a triterpene glycoside isolated from the rhizomes of Cimicifuga foetida (Chinese herb “shengma”) which could inhibit the growth of breast cancer cells. Nevertheless, the effect of actein on angiogenesis, which is an essential step for tumor growth and metastasis, has never been reported. Hence, this study aimed to investigate the in vitro and in vivo effects of actein on angiogenesis using human microvascular endothelial cells (HMEC-1), matrigel plug and tumor-bearing mouse models. Our results showed that actein significantly inhibited the proliferation, reduced the migration and motility of endothelial cells, and it could suppress the protein expressions of VEGFR1, pJNK and pERK, suggesting that JNK/ERK pathways were involved. In vivo results showed that oral administration of actein at 10 mg/kg for 7 days inhibited blood vessel formation in the growth factor-containing matrigel plugs. Oral actein treatments (10–15 mg/kg) for 28 days resulted in decreasing mouse 4T1 breast tumor sizes and metastasis to lungs and livers. The apparent reduced angiogenic proteins (CD34 and Factor VIII) expressions and down-regulated metastasis-related VEGFR1 and CXCR4 gene expressions were observed in breast tumors. Our novel findings provide insights into the use of actein for development of anti-angiogenic agents for breast cancer.

Abstract 3798: KHF16, a new cycloartane triterpenoid isolated from Cimicifuga foetida, suppresses triple-negative breast cancer by inhibiting the NF-κB signaling pathway

Abstract Triterpenoids extracted from Cimicifuga foetida were reported to inhibit cancers by inducing cell cycle arrest and apoptosis. In this study, KHF16 (24-acetylisodahurinol-3-O-b-D-xylopyranoside), a new cycloartane triterpenoid isolated from the rhizomes of Cimicifuga foetida, showed potent anti-cancer activity in multiple ERa/PR/HER2 triple-negative breast cancer (TNBC) cell lines. KHF16 significantly induces cell cycle G2/M phase arrest and apoptosis in both MDA-MB-468 and SW527 TNBC cell lines. KHF16 reduces the expression levels of XIAP, Mcl-1, Survivin, Bcl-2 and Cyclin B1/D1 proteins. Importantly, KHF16 inhibits TNFα-induced IKKa/b phosphorylation, IKBa phosphorylation, p65 nuclear translocation and NF-κB downstream target gene induction in TNBC cells. These results suggest that KHF16 may inhibit TNBC through blocking the NF-κB signaling pathway. Citation Format: Yanjie Kong, Ceshi Chen. KHF16, a new cycloartane triterpenoid isolated from Cimicifuga foetida, suppresses triple-negative breast cancer by inhibiting the NF-κB signaling pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3798. doi:10.1158/1538-7445.AM2015-3798

Four New 9,19‐Cyclolanostane Triterpenes from the Rhizomes of Cimicifuga foetida Collected in Yulong

AbstractFour new 9,19‐cyclolanostane‐type triterpenes (1–4), were isolated from the rhizomes of Cimicifuga foetida. On the basis of spectroscopic analysis, their chemical structures were elucidated as 1,7‐dien‐cimigenol‐3,12‐dione (1), 1‐en‐cimigenol‐3,11‐dione (2), 11(‐hydroxy‐7‐en‐cimigenol‐3‐one (3), and (20R,24R)‐24,25‐epoxy‐11(‐hydroxy‐7‐en‐9,19‐cyclolanost‐3,16,23‐trione (4).

Three New Cycloartane (=9,19‐Cyclolanostane) Glycosides from Cimicifuga foetida

AbstractThree new cycloartane glycosides, 24‐epicimigenol 3‐(α‐L‐arabinopyranoside) (1), (3β,16β)‐cycloartane‐3,16,22,24,25‐pentol 3‐(β‐D‐xylopyranoside) (2), and (3β,15α,16β)‐cycloartane‐3,15,16,24,25‐pentol 3‐(β‐D‐xylopyranoside) (3), together with five known compounds, including four cycloartane glycosides and bergenin, were isolated from the rhizomes of Cimicifuga foetida. Their structures were elucidated by spectroscopic methods.

ChemInform Abstract: Five New Triterpene Bisglycosides with Acyclic Side Chains from the Rhizomes of Cimicifuga foetida L.

Abstractisolation, structure and cytotoxicity of one lanostane bisglycoside, foetidinoside A (I), one seco‐cycloartane type bisglycoside, foetidinoside B (II), and three new cycloartane‐type bisglycosides, foetidinoside C (III), D and E

Five New Triterpene Bisglycosides with Acyclic Side Chains from the Rhizomes of Cimicifuga foetida L.

Five new triterpene bisglycosides, foetidinosides A (1), B (2), C (3), D (4) and E (5), including three of the cycloartane type, one of its derivative, and one of the lanostane type were isolated from the rhizomes of Cimicifuga foetida. Their structures were elucidated on the basis of spectroscopic data and chemical evidence. They were the first bisglycosides with acyclic side chains which were different from the typical triterpenes with side chains epoxidized with ring D in Cimicifuga species.

Cimicifine A: A Novel Triterpene Alkaloid from the Rhizomes of Cimicifuga foetida.

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Cimicifine A: A Novel Triterpene Alkaloid from the Rhizomes of Cimicifuga foetida

AbstractCimicifine A (1), the first cycloartane triterpene alkaloid, was isolated from the rhizomes of Cimicifuga foetida, together with the known compound cimicifugoside H‐1 (2). Their chemical structures were established by extensive NMR and MS analyses and by comparison with literature.

Cimicifoetisides A and B, two cytotoxic cycloartane triterpenoid glycosides from the rhizomes of Cimicifuga foetida, inhibit proliferation of cancer cells.

Two new cycloartane-type triterpene glycosides, namely cimicifoetisides A (1) and B (2), along with seven known compounds cimigenol, 25-O-acetylcimigenol, cimigenol 3-O-β-D-xylopyranoside, 12β-hydroxycimigenol 3-O-β-D-xylopyranoside, cimigenol 3-O-α-L-arabinopyranoside, 25-deoxyshengmanol 3-O-β-D-xylopyranoside and cimilactone A, were isolated from the rhizomes of Cimicifuga foetida. Their structures were elucidated as cimigenol 3-O-(2'-O-acetyl)-α-L-arabinopyranoside (1) and 25-O-acetylcimigenol 3-O-(2'-O-acetyl)-α-L-arabinopyranoside (2). Both compounds 1 and 2 exhibited potent cytotoxicity against rat EAC (Ehrlich ascites carcinoma) and MDA-MB-A231 (human breast cancer) cells with IC50 values of 0.52 and 6.74 μM for 1, and 0.19 and 10.21 μM for 2, suggesting their potential for further investigation as anti-cancer agents.