A withanolide coagulin-L inhibits adipogenesis modulating Wnt/β-catenin pathway and cell cycle in mitotic clonal expansion

Beg, Muheeb; Chauhan, Prem M. S.; Varshney, Salil; Shankar, Kripa; Rajan, Sujith; Saini, Deepika; Srivastava, Mukesh; Yadav, Prem P.; Gaikwad, Anil Nilkanth

doi:10.1016/j.phymed.2013.10.009

Cited by 31 publications

(18 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our validated hit, CAP1, is a withanolide steroidal lactone glycoside previously identified as coagulin-L from Withania coagulans [19, 20]. It has been suggested to act as an adipogenic differentiation blocker perhaps enhancing WNT levels [20], as well as to inhibit both NOS production and NFkB signaling in the micromolar range [19].…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested to act as an adipogenic differentiation blocker perhaps enhancing WNT levels [20], as well as to inhibit both NOS production and NFkB signaling in the micromolar range [19]. Our lead, CAP2, is the aglycone of CAP1 and represents withanolide F, which was initially identified from the leaves of Withania adpressa and reported to have cytotoxic activity [9,21].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Long-Lasting WNT-TCF Response Blocking and Epigenetic Modifying Activities of Withanolide F in Human Cancer Cells

et al. 2016

View full text Add to dashboard Cite

The WNT-TCF signaling pathway participates in adult tissue homeostasis and repair, and is hyperactive in a number of human diseases including cancers of the colon. Whereas to date there are no antagonists approved for patient use, a potential problem for their sustained use is the blockade of WNT signaling in healthy tissues, thus provoking potentially serious co-lateral damage. Here we have screened a library of plant and microorganism small molecules for novel WNT signaling antagonists and describe withanolide F as a potent WNT-TCF response blocker. This steroidal lactone inhibits TCF-dependent colon cancer xenograft growth and mimics the effects of genetic blockade of TCF and of ivermectin, a previously reported WNT-TCF blocker. However, withanolide F is unique in that it imposes a long-lasting repression of tumor growth, WNT-TCF targets and cancer stem cell clonogenicity after drug treatment. These findings are paralleled by its modulation of chromatin regulators and its alteration of overall H3K4me1 levels. Our results open up the possibility to permanently repress essential signaling responses in cancer cells through limited treatments with small molecules.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Long-Lasting WNT-TCF Response Blocking and Epigenetic Modifying Activities of Withanolide F in Human Cancer Cells

et al. 2016

View full text Add to dashboard Cite

show abstract

“…While studies have described anti-diabetic activity in withanolides including coagulanolide (Beg et al, 2014;Singh et al, 2012;Maurya et al, 2008), and 4b-hydroxywithanolide E (Takimoto et al, 2014), this is the first study documenting the anti-diabetic activity of withaferin A. Previously implicated as a possible treatment for cancer (Grover et al, 2010), inflammation (Maitra et al, 2009), and for inhibiting angiogenesis (Mohan et al, 2004), withaferin's hypoglycemic activity had not previously been documented.…”

Section: Discussionmentioning

confidence: 85%

Hypoglycemic activity of withanolides and elicitated Withania somnifera

Gorelick¹,

Rosenberg

Smotrich³

et al. 2015

Phytochemistry

View full text Add to dashboard Cite

“…Among various reported biological activities of withanolides, modulation of cell signaling pathways is, in particular, intriguing. Inhibition of adipocyte differentiation mediated by coagulin‐L ( 3 , Scheme ), for instance, has been linked to modulation of the Wnt pathway, whereas withanolide D ( 4 , Scheme ) induces apoptosis in pancreatic ductal adenocarcinoma by abrogating β‐catenin signaling …”

Section: Resultsmentioning

confidence: 99%

Small Molecules Inspired by the Natural Product Withanolides as Potent Inhibitors of Wnt Signaling

et al. 2017

View full text Add to dashboard Cite

Wnt signaling is a fundamental pathway that drives embryonic development and is essential for stem cell maintenance and tissue homeostasis. Dysregulation of Wnt signaling is linked to various diseases, and a constitutively active Wnt pathway drives tumorigenesis. Thus, disruption of the Wnt response is deemed a promising strategy for cancer drug discovery. However, only few clinical drug candidates that target Wnt signaling are available so far, and new small-molecule modulators of Wnt-related processes are in high demand. Here we describe the synthesis of small molecules inspired by withanolide natural products by using a pregnenolone-derived β-lactone as the key intermediate that was transformed into a δ-lactone appended to the D-ring of the steroidal scaffold. This natural-product-inspired compound library contained potent inhibitors of Wnt signaling that act upstream of the destruction complex to stabilize Axin in a tankyrase-independent manner.

show abstract

A withanolide coagulin-L inhibits adipogenesis modulating Wnt/β-catenin pathway and cell cycle in mitotic clonal expansion

Cited by 31 publications

References 42 publications

Long-Lasting WNT-TCF Response Blocking and Epigenetic Modifying Activities of Withanolide F in Human Cancer Cells

Long-Lasting WNT-TCF Response Blocking and Epigenetic Modifying Activities of Withanolide F in Human Cancer Cells

Hypoglycemic activity of withanolides and elicitated Withania somnifera

Small Molecules Inspired by the Natural Product Withanolides as Potent Inhibitors of Wnt Signaling

Contact Info

Product

Resources

About