Withangulatin I, a New Cytotoxic Withanolide from Physalis angulata

Lee, Shwu-Woan; Pan, Min‐Hsiung; Chen, Chiu-Ming; Chen, Zong‐Tsi

doi:10.1248/cpb.56.234

Cited by 29 publications

(14 citation statements)

References 25 publications

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“…These are major constituents identified from the important medicinal plant, Withania somnifera, and the related Solanaceae family (30). A number of biological properties of withanolides have been reported, including anti-inflammatory, antitumor, antibacterial, antidepressant, antioxidant, antiulcer, cytotoxic, quinone reductase inducive, antileishmanial, antitrypanosomal, immunosuppressive, cognition-enhancing and memory-improving effects, as well as hypotensive, bradycardic and respiratory-stimulating properties (31)(32)(33). Withanolides have been studied extensively, and >130 withanolides are known and >40 withanolides have been isolated (34).…”

Section: Discussionmentioning

confidence: 99%

Antiproliferation potential of withaferin A on human osteosarcoma cells via the inhibition of G2/M checkpoint proteins

Wang

2015

Experimental and Therapeutic Medicine

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Abstract. Withaferin A (WA) is a well-known steroidal lactone of the medicinally important plant, Withania somnifera. This secondary metabolite has been noted for its anticancer effects against a number of human cancer cell lines. However, there are a limited number of studies investigating the growth inhibitory potential of WA against human osteosarcoma cells and the underlying molecular mechanisms. Thus, in the present study, the antiproliferative activities of WA, along with the underlying mechanisms of action, were investigated using flow cytometry for cell cycle distribution and western blot analysis for the assessment of various checkpoint proteins. In addition, the antiproliferative activity was evaluated using a sulforhodamine B assay, where MG-63 and U2OS human osteosarcoma cell lines were treated with different concentrations of WA. Furthermore, the mRNA expression levels of the checkpoint proteins in the WA-treated MG-63 and U2OS cells were examined. The results obtained corresponded with the western blot analysis results. Furthermore, WA was shown to significantly inhibit the proliferation of the two types of treated cell lines (MG-63 and U2OS). Flow cytometric analysis revealed that WA induced cell cycle arrest at the G2/M phase, which was associated with the inhibition of cyclin B1, cyclin A, Cdk2 and p-Cdc2 (Tyr15) expression and an increase in the levels of p-Chk1 (Ser345) and p-Chk2 (Thr68). In conclusion, the present study found that the antiproliferative potential of WA was associated with the induction of cell cycle arrest at the G2/M phase, which was a result of the attenuation of the expression levels of G2/M checkpoint proteins.

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Section: Discussionmentioning

confidence: 99%

Antiproliferation potential of withaferin A on human osteosarcoma cells via the inhibition of G2/M checkpoint proteins

Wang

2015

Experimental and Therapeutic Medicine

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“…The withanolides are demonstrated to have antitumor, antibacterial, anti-inflammatory, antidepressant, antioxidant, antiulcer, cytotoxic, quinone reductase induction, antileishmanial, antitrypanosomal, immunosuppressive, cognition-enhancing and memory-improving effects, as well as hypotensive, bradycardic and respiratory-stimulant action [65–67]. As a prototype of the withanolides, Withaferin A has been studied extensively.…”

Section: Discussionmentioning

confidence: 99%

Withaferin A targets heat shock protein 90 in pancreatic cancer cells

Hamza

Zhang

et al. 2010

Biochemical Pharmacology

265

224

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The purpose of this study is to investigate the efficacy and the mechanism of Hsp90 inhibition of Withaferin A (WA), a steroidal lactone occurring in Withania somnifera, in pancreatic cancer in vitro and in vivo. Withaferin A exhibited potent antiproliferative activity against pancreatic cancer cells in vitro (with IC50s of 1.24, 2.93 and 2.78 μM) in pancreatic cancer cell lines Panc-1, MiaPaca2 and BxPc3, respectively. Annexin V staining showed that WA induced significant apoptosis in Panc-1 cells in a dose dependent manner. Western blotting demonstrated that WA inhibited Hsp90 chaperone activity to induce degradation of Hsp90 client proteins (Akt, Cdk4 and glucocorticoid receptor), which was reversed by the proteasomal inhibitor, MG132. WA-Biotin pull-down assay of Hsp90 using Panc-1 cancer cell lysates and purified Hsp90 showed that WA-biotin binds to C-terminus of Hsp90, which was competitively blocked by unlabeled WA. Co-immunoprecipitation exhibited that WA (10 μM) disrupted Hsp90-Cdc37 complexes from 1–24 hour post treatment, while it neither blocked ATP binding to Hsp90, nor changed Hsp90-P23 association. WA (3, 6 mg/kg) inhibited tumor growth in pancreatic Panc-1 xenografts by 30% and 58%, respectively. These data demonstrate that Withaferin A binds Hsp90, inhibits Hsp90 chaperone activity through an ATP independent mechanism, results in Hsp90 client protein degradation, and exhibits in vivo anticancer activity against pancreatic cancer.

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“…Accordingly, these bioactivity results should be considered with caution. Among the Physalis withanolides with an unmodified skeleton, potent cytotoxic activity has been reported for withangulatins A (511), B (94), and I (102), physangulin B (512), phyperunolide A (101), withaphysacarpin (195), philadelphicalactones A (197) and B (198), 18-hydroxywithanolide D (128), and withanone (513) (50,55,56,58,104,247).…”

Section: Cytotoxicitymentioning

confidence: 99%