Hedgehog inhibitors from Withania somnifera

Yoneyama, Tatsuro; Arai, Midori A.; Sadhu, Samir Kumar; Ahmed, Firoj; Ishibashi, Masami

doi:10.1016/j.bmcl.2015.06.081

Cited by 25 publications

(13 citation statements)

References 27 publications

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“…Additional natural products such as compounds 181 , 182 , and 183 isolated from Artocarpus communis and Hyptis suaveolens (IC 50 = 7.6, 4.7, and 4.0 μM, respectively), compounds 184 , 185 , and 186 isolated from Withania somnifera leaves (IC 50 = 0.5, 0.6, and 1.8 μM, respectively), and compound 187 isolated from C rinum asiaticum (IC 50 = 4.7 μM) were also shown to inhibit Gli1‐mediated transcription . These 7 compounds also exhibited cytotoxic effects against Hh‐Gli activated human PANC1 (IC 50 = 17.9, 15.7, 12.1, 1.6, 1.1, 11.9, and 10.0 μM, respectively) and DU145 cells (IC 50 = 30.3, 18.8, 32.6, 2.5, 1.8, 10.6, and 18.5 μM, respectively) (Figure ).…”

Section: Hh Signaling Pathway Inhibitorsmentioning

confidence: 99%

Strategies to target the Hedgehog signaling pathway for cancer therapy

Xin

Cruz

et al. 2018

Medicinal Research Reviews

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Hedgehog (Hh) signaling is an essential pathway in the human body, and plays a major role in embryo development and tissue patterning. Constitutive activation of the Hh signaling pathway through sporadic mutations or other mechanisms is explicitly associated with cancer development and progression in various solid malignancies. Therefore, targeted inhibition of the Hh signaling pathway has emerged as an attractive and validated therapeutic strategy for the treatment of a wide range of cancers. Vismodegib, a first-in-class Hh signaling pathway inhibitor was approved by the US Food and Drug Administration in 2012, and sonidegib, another potent Hh pathway inhibitor, received FDA's approval in 2015 as a new treatment of locally advanced or metastatic basal cell carcinoma. The clinical success of vismodegib and sonidegib provided strong support for the development of Hh signaling pathway inhibitors via targeting the smoothened (Smo) receptor. Moreover, Hh signaling pathway inhibitors aimed to target proteins, which are downstream or upstream of Smo, have also been pursued based on the identification of additional therapeutic benefits. Recently, much progress has been made in Hh singling and inhibitors of this pathway. Herein, medicinal chemistry strategies, especially the structural optimization process of different classes of Hh inhibitors, are comprehensively summarized. Further therapeutic potentials and challenges are also discussed.

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Section: Hh Signaling Pathway Inhibitorsmentioning

confidence: 99%

Strategies to target the Hedgehog signaling pathway for cancer therapy

Xin

Cruz

et al. 2018

Medicinal Research Reviews

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“…Leaf extract of Withania somnifera was found to contain withaferin A, which targets hedgehog pathway by inhibiting GLI1-DNA complex (Yoneyama et al, 2015) . Treatment of breast CSCs with curcumin was reported to downregulate Shh pathway (D. .…”

Section: Phytomedicines Targeting Hedgehog Signaling Pathwaymentioning

confidence: 99%

Current Perspectives on Phytomedicines targeting Cancer Stem Cells

Saraff

Gahtori

Tripathi

et al. 2021

Preprint

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Studies have established the presence of a small subpopulation of cells within tumor cells, known as cancer stem cells (CSCs). These cells have evidently been the reason for metastasis, chemotherapy or radiotherapy resistance and tumor relapses in several types of cancers. CSCs are prone to epithelial-to-mesenchymal transition (EMT), resulting in aggressive tumors. They modulate various pathways of molecular signaling, including Wnt, Hedgehog and Notch, thus increasing the stem-like characteristics. Elevated expression of ATP binding cassette (ABC) transporter efflux pump as well as suppression of apoptosis has also increased anti-cancer drug resistance. Plants are known to possess bioactive compounds that can modulate these key regulators and hence eliminate CSCs. This review aims to report and summarize preclinical studies about the effects of phytocompounds on CSCs of various tumors. Furthermore, clinical trials carried out for some of these phytoconstituents are reported. Thus, selectively targeting CSCs with plant extracts and herbal preparations may be a promising remedial strategy for cancer.

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“…Yoneyama et al 159 screened the methanolic extract of leaves of Withania somnifera to assess its potential to inhibit Gli1-mediated transcription. After purification, withaferin 18l , 27-deoxywithaferin 18m , 5,6-deoxywithaferin 18n , 2, 3-dihydrowithaferin 18o , 2,3-dihydro-3-methoxywithaferin 18p , and 2,3-dihydro-3- β -O-sulfate withaferin 18q (Figure 18) were isolated, which show potent inhibition of Hh/Gli1-mediated transcriptional activity particularly withaferin 18l and 27-deoxywithaferin 18m .…”

Section: Recent Advances In Design Of Hh Pathway Inhibitorsmentioning

confidence: 99%

“…Many natural products discussed in this section may serve a source of inspiration for the development of new semisynthetic Hh inhibitors. 32,154–157,159–162…”

Section: Recent Advances In Design Of Hh Pathway Inhibitorsmentioning

confidence: 99%

Design of Hedgehog pathway inhibitors for cancer treatment

Bariwal

Kumar

Dong

et al. 2018

Medicinal Research Reviews

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Hedgehog (Hh) signaling is involved in the initiation and progression of various cancers and is essential for embryonic and postnatal development. This pathway remains in the quiescent state in adult tissues but gets activated upon inflammation and injuries. Inhibition of Hh signaling pathway using natural and synthetic compounds has provided an attractive approach for treating cancer and inflammatory diseases. While the majority of Hh pathway inhibitors target the transmembrane protein Smoothened (SMO), some small molecules that target the signaling cascade downstream of SMO are of particular interest. Substantial efforts are being made to develop new molecules targeting various components of the Hh signaling pathway. Here, we have discussed the discovery of small molecules as Hh inhibitors from the diverse chemical background. Also, some of the recently identified natural products have been included as a separate section. Extensive structure-activity relationship (SAR) of each chemical class is the focus of this review. Also, clinically advanced molecules are discussed from the last 5 to 7 years. Nanomedicine-based delivery approaches for Hh pathway inhibitors are also discussed concisely.

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Hedgehog inhibitors from Withania somnifera

Cited by 25 publications

References 27 publications

Strategies to target the Hedgehog signaling pathway for cancer therapy

Strategies to target the Hedgehog signaling pathway for cancer therapy

Current Perspectives on Phytomedicines targeting Cancer Stem Cells

Design of Hedgehog pathway inhibitors for cancer treatment

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