Cytotoxic withanolides from Physalis angulata var. villosa and the apoptosis-inducing effect via ROS generation and the activation of MAPK in human osteosarcoma cells

Ma, Ting; Zhang, Wenna; Yang, Lei; Zhang, Chao; Lin, Rong; Shan, Si‐Ming; Zhu, Mengdi; Luo, Jian‐Guang; Kong, Ling–Yi

doi:10.1039/c6ra08574a

Cited by 31 publications

(49 citation statements)

References 29 publications

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“…Similarly, a recent study on W. somnifera extracts reported its therapeutic role in stroke repair through its anti-apoptotic and anti-oxidant properties [9]. Chemically, it is a rich source of withanolides, which possess diverse pharmacological properties, including anti-inflammatory, anti-microbial, anti-tumor, hepatoprotective, and immunosuppressive effects [10][11][12][13][14][15][16]. In addition, alkaloids, steroidal saponins, lignanamides [17], and phenolics [18] have also been reported, and some of them were found to have anti-tumor activities [19].…”

Section: Introductionmentioning

confidence: 99%

Withaninsams A and B: Phenylpropanoid Esters from the Roots of Indian Ginseng (Withania somnifera)

Baek

Lee

Kim

et al. 2019

Plants

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Withania somnifera (L.) Dunal (Solanaceae), known as Indian ginseng or ashwagandha, has been used in Indian Ayurveda for the treatment of a variety of disorders, such as diabetes and reproductive and nervous system disorders. It is particularly used as a general health tonic, analgesic, and sedative. As part of continuing projects to discover unique bioactive natural products from medicinal plants, phytochemical investigation of the roots of W. somnifera combined with a liquid chromatography–mass spectrometry (LC/MS)-based analysis has led to the isolation of two novel phenylpropanoid esters, Withaninsams A (1) and B (2), as an inseparable mixture, along with three known phenolic compounds (3, 4, and 6) and a pyrazole alkaloid (5). The structures of the new compounds were elucidated using a combination of spectroscopic methods, including one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectroscopy (HR-ESIMS). Withaninsams A (1) and B (2) are phenylpropanoid esters that contain a side chain, 4-methyl-1,4-pentanediol unit. To the best of our knowledge, the present study is the first to report on phenylpropanoid esters with 4-methyl-1,4-pentanediol unit. The anti-inflammatory activity of the isolated compounds (1–6) was evaluated by determining their inhibitory effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, where compound 3 inhibited LPS-induced NO production (IC50 = 33.3 μM) and TNF-α production, a pro-inflammatory cytokine (IC50 = 40.9 μM). The anti-inflammatory mechanism through the inhibition of transcriptional iNOS protein expression was confirmed by western blotting experiments for the active compound 3, which showed decreased iNOS protein expression.

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Section: Introductionmentioning

confidence: 99%

Withaninsams A and B: Phenylpropanoid Esters from the Roots of Indian Ginseng (Withania somnifera)

Baek

Lee

Kim

et al. 2019

Plants

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“…Withagulatin A (WA) was isolated from Physalis angulata var. villosa in our previous study [ 24 ]. NCI–H1975 (H1975) non-small cell lung cancer cells and human embryonic kidney 293T cells (HEK293T cells) were purchased from the Cell Bank of Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences (Shanghai, China).…”

Section: Methodsmentioning

confidence: 99%

“…Withangulatin A (WA), a withanolide isolated from Physalis angulata var. villosa , has been reported to inhibit the proliferation of various cancer cells [ 24 ]. Herein, we first report that WA, a natural small molecule, is a novel covalent inhibitor of PRDX6.…”

Section: Introductionmentioning

confidence: 99%

Identification of peroxiredoxin 6 as a direct target of withangulatin A by quantitative chemical proteomics in non-small cell lung cancer

et al. 2021

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Peroxiredoxin 6 (PRDX6), as a bifunctional enzyme with glutathione peroxidase activity (GPx) and Ca2 + -independent phospholipase A2 (iPLA2) activity, has a higher expression in various cancer cells, which leads to the increase of antioxidant properties and promotes tumorigenesis. However, only a few inhibitors of PRDX6 have been discovered to date, especially the covalent inhibitors of PRDX6. Here, we firstly identified Withangulatin A (WA), a natural small molecule, as a novel covalent inhibitor of PRDX6. SILAC-ABPP identified that WA could directly bind to PRDX6 and inactivate the enzyme activity of PRDX6 by the α, β-unsaturated ketone moiety. Moreover, WA also facilitated the generation of ROS, and inhibited the GPx and iPLA2 activities. However, WA-1, with a reduced α, β-unsaturated ketone moiety, had no significant inhibition of the GPx and iPLA2 activities. Biolayer interferometry and LC-MS/MS analysis further demonstrated the selectively covalent binding of WA to the cysteine 47 residue (Cys47) of PRDX6, while mutation of Cys47 blocked the binding of WA to PRDX6. Notably, WA-mediated cytotoxicity and inhibition of the GPx and iPLA2 activities were almost abolished by the deficiency of PRDX6. Therefore, this study indicates that WA is a novel PRDX6 covalent inhibitor, which could covalently bind to the Cys47 of PRDX6 and holds great potential in developing anti-tumor agents for targeting PRDX6.

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“…angulata var. villosa . Withaneomexolides D ( 135 ) and C ( 142 ) were isolated from the aerial parts of P .…”

Section: The Phytochemical Classificationmentioning

confidence: 99%

Withanolides from the genus Physalis: a review on their phytochemical and pharmacological aspects

Huang

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives Withanolides are a group of modified C28 ergostane‐type steroids with a C‐22, C‐26 δ‐lactone side chain or a C‐23, C‐26 γ‐lactone side chain. They enjoy a limited distribution in the plant kingdom and predominantly occur in several genera of Solanaceae. Of which, the genus Physalis is an important resource for this type of natural molecules. The present review aims to comprehensively illustrate the structural characteristics and classification of withanolides, and particularly focus on the progression on phytochemical and pharmacological aspects of withanolides from Physalis ranging from January 2015 to June 2019. Key findings Approximately 351 natural withanolides with novel and unique structures have so far been identified from genus Physalis, mainly isolated from the species of P. angulata and P. peruviana. Withanolides demonstrated diverse biological activity, such as anticancer, anti‐inflammatory, antimicrobial, immunoregulatory, trypanocidal and leishmanicidal activity. Their observed pharmacological functions supported the uses of Physalis species in traditional or folk medicines. Summary Due to their unique structure skeleton and potent bioactivities, withanolides are regarded to be promising drug candidates, particularly for developing anticancer and anti‐inflammatory agents. Further investigations for discovering novel withanolides of genus Physalis, exploiting their pharmacological values and evaluating their potency as therapeutic agents are significant work.

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Cytotoxic withanolides from Physalis angulata var. villosa and the apoptosis-inducing effect via ROS generation and the activation of MAPK in human osteosarcoma cells

Abstract: Physagulide I induced apoptosis and cell cycle arrest via ROS generation and the activation of MAPK in human osteosarcoma cells.

Cited by 31 publications

References 29 publications

Withaninsams A and B: Phenylpropanoid Esters from the Roots of Indian Ginseng (Withania somnifera)

Withaninsams A and B: Phenylpropanoid Esters from the Roots of Indian Ginseng (Withania somnifera)

Identification of peroxiredoxin 6 as a direct target of withangulatin A by quantitative chemical proteomics in non-small cell lung cancer

Withanolides from the genus Physalis: a review on their phytochemical and pharmacological aspects

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