Withanone-Rich Combination of Ashwagandha Withanolides Restricts Metastasis and Angiogenesis through hnRNP-K

Gao, Ran; Shah, Navjot; Lee, Jung-Sun; Katiyar, Shashank P.; Li, Ling; Oh, Eonju; Sundar, Durai; Yun, Chae Ok; Wadhwa, Renu; Kaul, Sunil C.

doi:10.1158/1535-7163.mct-14-0324

Cited by 64 publications

(70 citation statements)

References 46 publications

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“…VEGF expression was significantly reduced in ASH-WEX-fed rats as compared to PBS-fed animals. This is in line with previous studies which have shown ashwagandha to inhibit VEGF expression leading to restricted angiogenesis [41,42]. Taken together, these results strongly support that ASH-WEX has the potential to block in vivo invasion of gliomas and angiogenesis.…”

Section: Discussionsupporting

confidence: 91%

Withania somnifera Suppresses Tumor Growth of Intracranial Allograft of Glioma Cells

et al. 2015

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Gliomas are the most frequent type of primary brain tumor in adults. Their highly proliferative nature, complex cellular composition, and ability to escape therapies have confronted investigators for years, hindering the advancement toward an effective treatment. Agents that are safe and can be administered as dietary supplements have always remained priority to be most feasible for cancer therapy. Withania somnifera (ashwagandha) is an essential ingredient of Ayurvedic preparations and is known to eliminate cancer cells derived from a variety of peripheral tissues. Although our previous studies have addressed the in vitro anti-proliferative and differentiation-inducing properties of ashwagandha on neuronal cell lines, in vivo studies validating the same are lacking. While exploring the mechanism of its action in vitro, we observed that the ashwagandha water extract (ASH-WEX) induced the G2/M phase blockade and caused the activation of multiple pro-apoptotic pathways, leading to suppression of cyclin D1, bcl-xl, and p-Akt, and reduced the expression of polysialylated form of neural cell adhesion molecule (PSA-NCAM) as well as the activity of matrix metalloproteinases. ASH-WEX reduced the intracranial tumor volumes in vivo and suppressed the tumor-promoting proteins p-nuclear factor kappa B (NF-κB), p-Akt, vascular endothelial growth factor (VEGF), heat shock protein 70 (HSP70), PSA-NCAM, and cyclin D1 in the rat model of orthotopic glioma allograft. Reduction in glial fibrillary acidic protein (GFAP) and upregulation of mortalin and neural cell adhesion molecule (NCAM) expression specifically in tumor-bearing tissue further indicated the anti-glioma efficacy of ASH-WEX in vivo. Combining this enhanced understanding of the molecular mechanisms of ASH-WEX in glioma with in vivo model system offers new opportunities to develop therapeutic strategy for safe, specific, and effective formulations for treating brain tumors.

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Section: Discussionsupporting

confidence: 91%

Withania somnifera Suppresses Tumor Growth of Intracranial Allograft of Glioma Cells

et al. 2015

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“…An alternative mechanism of action of withaferin A, obtained from Withania somnifera, was also presented by another study, where withaferin A was shown to inhibit NF-kB activity in HUVEC cells [165]. Additionally, Gao et al [166], studied the combination of withanone and withaferin A, verifying that this combination showed significant antimigratory and antiangiogenic activities, both in vitro or in vivo assays. Furthermore, the authors demonstrated, by using bioinformatic and biochemical approaches, that withanone and withaferin A caused downregulation of VEGF and MMPs.…”

Section: Antiangiogenic Potential Of Other Natural Compoundsmentioning

confidence: 84%

Antiangiogenic compounds: well-established drugs versus emerging natural molecules

et al. 2018

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a b s t r a c tAngiogenesis is the natural and physiologic process of growing blood vessels from pre-existing ones. Pathological angiogenesis occurs when the precise balance of all the molecular pathways that regulate angiogenesis is disrupted, and this process is a critical step in many diseases, including cancer. A limited number of antiangiogenic synthetic drugs have been developed. However, due to toxicity and side effects issues, the search for alternative to existing drugs is ongoing. In this sense, natural molecules obtained from plants or macrofungi, have demonstrated extraordinary potential in the treatment of angiogenesisrelated pathologies, specially taking into consideration its absence or very low toxicity, when compared to synthetic drugs. Using natural compounds as potential angiogenesis modulators is thus a promising field of research, supporting the creation of novel therapies able to reduce the use of drugs and associated side effects. In this review, the current status of antiangiogenic drugs and the wide variety of natural extracts and molecules with antiangiogenic capacities, as well as the angiogenesis molecular pathways and therapeutic targets, are presented. Finally, the challenges that need to be overcome in order to increase the use of natural compounds for clinical purposes are discussed.

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“…It was shown to cause selective cytotoxicity on cancer cells by irreversibly damaging DNA repair mechanisms, disturbing the cellular assembly and organization, and mortalin-p53 function [18,19,24]. Several studies have suggested anti-inflammatory and anti-stress potential of Wi-N [38,39]; they have attributed this property to the oxidized 5-7 carbons in its chemistry [40] that translates into weak binding affinity to target proteins [19].…”

Section: Discussionmentioning

confidence: 99%

“…We have earlier demonstrated that ashwagandha (Indian ginseng)-derived withanolides possess significant anticancer activity in in vitro and in vivo [18][19][20][21][22][23][24][25] [26,27]. Molecular studies have demonstrated activation of tumor suppressor function, oxidative and DNA damage selectively in cancer cells [21,24].…”

Section: Introductionmentioning

confidence: 99%

Anti-Stress and Glial Differentiation Effects of a Novel Combination of Cucurbitacin B and Withanone (CucWi-N): Experimental Evidence

2018

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Background: Natural extracts and compounds used in traditional home medicine are known for their safety and a variety of health promoting and therapeutic potentials. In contrast to the single molecule mediated targets, the combinational therapies are preferred for their multi-functional and limited toxic regimens and may be useful for disease therapeutics as well as to increase the quality of life during a variety of environmental stresses. Purpose: We aimed to combine the active ingredients of Chinese (Helicteres angustifolia) and Indian (Withania somnifera) ginsengs to develop a natural, efficient, and welfare combinatorial mixture with high anti-stress and glial differentiation potentials. Methods: Using cultured cells as a model system, we developed a combination of active ingredients of Chinese (Cucurbitacin B [Cuc]) and Indian (Withanone [Wi-N]) ginsengs. Eleven chemical models of environmental stresses were used. Cytotoxicity studies were performed using human skin fibroblast for anti-stress and rat glioma cells for glial differentiation effects. Results: We demonstrate that the novel combination of Cuc and Wi-N, CucWi-N, was non-toxic to normal cells. It caused stress protection in assays using normal human fibroblasts subjected to a variety of stresses. Of note, cells showed remarkable protection against oxidative and UV stresses and marked by decrease in DNA damage and reactive oxygen species. We examined and found the glial differentiation potential of CucWi-N in rat glioblastoma cells. CucWi-N clearly induced differentiation phenotype, well-marked with upregulation of GAP43, MAP2, and GFAP, which have been shown to play a key role in glial differentiation. Conclusion: These data demonstrate anti-stress and glial differentiation potential of CucWi-N (a novel combination of Cuc and Wi-N) that could be recruited in nutraceutical and pharmaceutical avenues and hence warrant further evaluation and mechanistic studies.

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Withanone-Rich Combination of Ashwagandha Withanolides Restricts Metastasis and Angiogenesis through hnRNP-K

Cited by 64 publications

References 46 publications

Withania somnifera Suppresses Tumor Growth of Intracranial Allograft of Glioma Cells

Withania somnifera Suppresses Tumor Growth of Intracranial Allograft of Glioma Cells

Antiangiogenic compounds: well-established drugs versus emerging natural molecules

Anti-Stress and Glial Differentiation Effects of a Novel Combination of Cucurbitacin B and Withanone (CucWi-N): Experimental Evidence

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