Notch-1 Inhibition by Withaferin-A: A Therapeutic Target against Colon Carcinogenesis

Koduru, Srinivas; Kumar, Raj; Srinivasan, Sudarshan; Evers, Mark; Damodaran, Chendil

doi:10.1158/1535-7163.mct-09-0771

Cited by 196 publications

(152 citation statements)

References 53 publications

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“…[29][30][31][32] WFA binds covalently to annexin II and stimulates its basal F-actin cross-linking activity 29 ; however, at the low nanomolar concentrations, we did not observe significant actin defects (Fig. 2a).…”

Section: Cancer Therapymentioning

confidence: 64%

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Withaferin A inhibits breast cancer invasion and metastasis at sub‐cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation

Thaiparambil

Bender

Ganesh

et al. 2011

Intl Journal of Cancer

236

208

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Withaferin A (WFA) is purified from the plant Withania somnifera and inhibits the vimentin cytoskeleton. Vimentin overexpression in cancer correlates with metastatic disease, induction of epithelial to mesenchymal transition and reduced patient survival. As vimentin functions in cell motility, we wanted to test the hypothesis that WFA inhibits cancer metastasis by disrupting vimentin function. These data showed that WFA had weak cytotoxic and apoptotic activity at concentrations less than or equal to 500 nM, but retained potent anti-invasive activity at these low doses. Imaging of breast cancer cell lines revealed that WFA induces perinuclear vimentin accumulation followed by rapid vimentin depolymerization. A concomitant induction of vimentin ser56 phosphorylation was observed, which is consistent with vimentin disassembly. Structure activity relationships were established using a set of chemically modified WFA analogs and showed that the predicted vimentin-binding region of WFA is necessary to induce vimentin ser56 phosphorylation and for its anti-invasive activity. Pharmacokinetic studies in mice revealed that WFA reaches peak concentrations up to 2 lM in plasma with a half-life of 1.36 hr following a single 4 mg/kg dose. In a breast cancer metastasis mouse model, WFA showed dose-dependent inhibition of metastatic lung nodules and induced vimentin ser56 phosphorylation, with minimal toxicity to lung tissue. Based upon these studies, we conclude that WFA is a potent breast cancer anti-metastatic agent and the anti-metastatic activity of WFA is, at least in part, mediated through its effects on vimentin and vimentin ser56 phosphorylation.Metastatic disease is the major cause of death in almost all cancer types; however, most treatments are developed to target the primary tumor and not the metastases. This is due to metastatic cells being difficult to detect, highly aggressive, chemoresistant and experimentally challenging to model. 1 At present, there is no agent in clinical use that effectively prevents metastasis and most patients ultimately succumb to metastatic disease.The metastatic process can be broadly categorized into three stages-tumor cell invasion into surrounding tissue, intravasation into blood or lymphatic vessels and extravasation into a new host environment. These events are triggered by genetic and epigenetic alterations that transform stationary epithelial cells into migratory cells, a process termed epithelialmesenchymal transition (EMT). 2,3 Recent data suggests that cancer cells can re-trigger EMT to migrate into surrounding tissue. 3,4 A classical EMT protein is vimentin; numerous reports show that vimentin is overexpressed in invasive human tumors but is nearly undetectable in non-invasive, stationary tumors. 3,[5][6][7] Vimentin is a Type III intermediate filament 8 and its overexpression correlates with metastatic disease, EMT induction, poor prognosis and reduced patient survival. 7,[9][10][11] Similar correlations between vimentin overexpression and invasion are observed in cancer ce...

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Section: Cancer Therapymentioning

confidence: 64%

“…25 Moreover, WFA has proapoptotic and anti-tumor activity in breast and prostate cancers. [26][27][28] There are several other documented targets of WFA including NF-Kb, BCL-2, FOXO3A, Hsp90, phosphorylated STAT3 and annexin II 27,[29][30][31][32][33] ; however, the mechanisms by which this leads to anti-tumor activity are not fully understood.…”

mentioning

confidence: 99%

Withaferin A inhibits breast cancer invasion and metastasis at sub‐cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation

Thaiparambil

Bender

Ganesh

et al. 2011

Intl Journal of Cancer

236

208

View full text Add to dashboard Cite

show abstract

“…Withaferin-A (WA) is a bioactive compound derived from Withaniasomnifera, which inhibits Notch-1 signaling and downregulates pro-survival pathways, such as Akt/ NF-kappaB/Bcl-2, in colon cancer cell lines (Koduru et al, 2010). Green tea catechin, eipgallocatechin-3-gallate inhibits notch signaling (Singh et al, 2011).…”

Section: Notch Signaling and Colon Cancermentioning

confidence: 99%

Dietary Non-nutritive Factors in Targeting of Regulatory Molecules in Colorectal Cancer: An Update

Pandurangan

Esa²

2013

Asian Pacific Journal of Cancer Prevention

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Colorectal cancer (CRC), a complex multi-step process involving progressive disruption of homeostatic mechanisms controlling intestinal epithelial proliferation/inflammation, differentiation, and programmed cell death, is the third most common malignant neoplasm worldwide. A number of promising targets such as inducible nitric acid (iNOS), cyclooxygenase (COX)-2, NF-E2-related factor 2 (Nrf2), Wnt/β-catenin, Notch and apoptotic signaling have been identified by researchers as useful targets to prevent or therapeutically inhibit colon cancer development. In this review article, we aimed to explore the current targets available to eliminate colon cancer with an update of dietary and non-nutritional compounds that could be of potential use for interaction with regulatory molecules to prevent CRC.

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“…Most of these pharmacological activities are attributed to a novel group of naturally occurring triterpenoid C-28 steroidal lactones called withanolides. One of the well known withanolides, Withaferin A emerged as an important therapeutic molecule of W. ashwagandha due its anticancer properties ( Koduru et al, 2010, Lee et al, 2010, Mayola et al, 2011and Yang et al, 2011.…”

Section: Introductionmentioning

confidence: 99%

Reproductive biology of Withania ashwagandha sp. novo (Solanaceae)

Mir

Koul

Soodan

2013

Industrial Crops and Products

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Withania ashwagandha Kaul (Solanaceae) is an annual plant species of immense medicinal importance. It is a repository of a large number of pharmacologically active secondary metabolites known as withanolides. Evidence for the delimitation of the species from W. somnifera has been provided by our group using multidisciplinary approaches. Knowledge of reproductive biology of medicinal plants is crucial for improvement, effective conservation and management plans to evolve genetically superior varieties. The present paper reports our findings on the floral biology, pollination behavior and breeding system of W. ashwagandha in natural populations grown at our experimental field under near natural conditions. Flowering (peak) takes place during April-July and anthesis occurs between 08:00 and 11:00 h. The period of stigma receptivity coincides with anther dehiscence. Fruit set on pollination treatments ranged from 90.8% (passive autogamy), 72% (assisted autogamy), 30.30% (xenogamy), and 56.50% (geitonogamy) through 50.40% (open pollination). Xenogamy brings about very low fruit set, seed-set and seed germination percentages. It is inferred that W. ashwagandha is predominantly an autogamous and self-compatible species. Self-compatibility is mainly accomplished due to close proximity of stigma and anthers. This work is the first report on the reproductive biology of W. ashwagandha and will be useful for conservation and development of improved varieties of this multipurpose herb. Highlights► Reproductive biology of W. ashwagandha Kaul was reported first time.► We report the species to be highly self compatible due to close proximity of stigma and anthers.► The period of stigma receptivity coincides with anther dehiscence. ► Fruit set on pollination treatments ranged between 90.8% (passive autogamy) and 30.30% (xenogamy).► Xenogamy brings about very low fruit set, seed-set and seed germination percentages.

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Notch-1 Inhibition by Withaferin-A: A Therapeutic Target against Colon Carcinogenesis

Cited by 196 publications

References 53 publications

Withaferin A inhibits breast cancer invasion and metastasis at sub‐cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation

Withaferin A inhibits breast cancer invasion and metastasis at sub‐cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation

Dietary Non-nutritive Factors in Targeting of Regulatory Molecules in Colorectal Cancer: An Update

Reproductive biology of Withania ashwagandha sp. novo (Solanaceae)

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