Chem Biol. 2007 Jun;14(6):623-34.
The tumor inhibitor and antiangiogenic agent withaferin A targets the intermediate filament protein vimentin.
More on Vimentin
FULL TEXT
Bargagna-Mohan P,
Hamza A,
Kim YE,
Khuan Abby Ho Y,
Mor-Vaknin N,
Wendschlag N,
Liu J,
Evans RM,
Markovitz DM,
Zhan CG,
Kim KB,
Mohan R.
Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA.
Correspondence:
royce.mohan@uky.edu
The natural product withaferin A (WFA) exhibits antitumor and antiangiogenesis activity in vivo, which results from this drug's potent growth inhibitory activities. Here, we show that WFA binds to the intermediate filament (IF) protein, vimentin, by covalently modifying its cysteine residue, which is present in the highly conserved alpha-helical coiled coil 2B domain. WFA induces vimentin filaments to aggregate in vitro, an activity manifested in vivo as punctate cytoplasmic aggregates that colocalize vimentin and F-actin. WFA's potent dominant-negative effect on F-actin requires vimentin expression and induces apoptosis. Finally, we show that WFA-induced inhibition of capillary growth in a mouse model of corneal neovascularization is compromised in vimentin-deficient mice. These findings identify WFA as a chemical genetic probe of IF functions, and illuminate a potential molecular target for withanolide-based therapeutics for treating angioproliferative and malignant diseases.
PMID: 17584610 [PubMed - indexed for MEDLINE]
Int J Cancer. 2011 Jan 20. doi: 10.1002/ijc.25938. [Epub ahead of print]
Withaferin A inhibits breast cancer invasion and metastasis at sub-cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation.
Thaiparambil JT,
Bender L,
Ganesh T,
Kline E,
Patel P,
Liu Y,
Tighiouart M,
Vertino PM,
Harvey RD,
Garcia A,
Marcus AI.
LINK
Source
Winship Cancer Institute of Emory University, Atlanta, GA; Department of Hematology and Medical Oncology, Emory University, Atlanta, GA.
Abstract
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 μM 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.
Copyright © 2011 UICC.
- PMID:
- 21538350
- [PubMed - as supplied by publisher]
Cancer Sci. 2006 Jul;97(7):658-64.
Chemotherapeutic efficacy of paclitaxel in combination with Withania somnifera on benzo(a)pyrene-induced experimental lung cancer.
Senthilnathan P,
Padmavathi R,
Magesh V,
Sakthisekaran D.
Department of Medical Biochemistry, ALM Postgraduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai 600-113, India.
Lung cancer is one of the leading causes of cancer death in the world and is notoriously difficult to treat effectively. In the present study, male Swiss albino mice were divided into five groups of six animals each: group I animals received corn oil orally and served as a control; group II cancer-induced animals received benzo(a)pyrene (50 mg/kg bodyweight dissolved in corn oil, orally) twice weekly for four successive weeks; group III cancer-bearing animals (after 12 weeks of induction) were treated with paclitaxel (33 mg/kg bodyweight, i.p.) once weekly for 4 weeks; group IV cancer-bearing animals were treated with paclitaxel along with Withania somnifera (400 mg/kg bodyweight) orally once weekly for 4 weeks; and group V animals constituted the drug control treated with paclitaxel along with W. somnifera. The serum, lung and liver were investigated biochemically for aryl hydrocarbon hydroxylase, gamma-glutamyl transpeptidase, 5'-nucleotidase, lactate dehydrogenase and protein-bound carbohydrate components (hexose, hexosamine and sialic acid). These enzyme activities were increased significantly in cancer-bearing animals compared with control animals. The elevation of these in cancer-bearing animals was indicative of the persistent deteriorating effect of benzo(a)pyrene in cancer-bearing animals. Our data suggest that paclitaxel, administered with W. somnifera, may extend its chemotherapeutic effect through modulating protein-bound carbohydrate levels and marker enzymes, as they are indicators of cancer. The combination of paclitaxel with W. somnifera could effectively treat the benzo(a)pyrene-induced lung cancer in mice by offering protection from reactive oxygen species damage and also by suppressing cell proliferation.
PMID: 16827807 [PubMed - indexed for MEDLINE]
Chem Biol Interact. 2006 Feb 25;159(3):180-5. Epub 2005 Dec 22.
Enhancement of antitumor effect of paclitaxel in combination with immunomodulatory Withania somnifera on benzo(a)pyrene induced experimental lung cancer.
Senthilnathan P,
Padmavathi R,
Banu SM,
Sakthisekaran D.
Department of Medical Biochemistry, Dr. ALM Postgraduate Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai 600113, India.
senthilnpm@rediffmail.com
The current experimental work deals with the immunomodulatory studies on the extract of Withania somnifera (L.) Dunal root powder against benzo(a)pyrene induced lung cancer in male Swiss albino mice. In our previous study, we reported the antioxidant and anticarcinogenic effect of W. somnifera (L.) Dunal along with paclitaxel. Immune dysfunction has been found to be associated with cancer and chemotherapy. Benzo(a)pyrene induced cancer animals were treated with 400mg/kg bodyweight of W. somnifera (L.) Dunal extract for 30 days significantly alters the levels of immunocompetent cells, immune complexes and immunoglobulins. Based on the data, the carcinogen as well as the paclitaxel affects the immune system, the toxic side effects on the immune system is more reversible and more controllable by W. somnifera (L.) Dunal. These results concluded the immunomodulatory activity of W. somnifera (L.) Dunal extract, which is a known immunomodulator in indigenous medicine.
PMID: 16375880 [PubMed - indexed for MEDLINE]
Mol Cancer Ther. 2010 Jan;9(1):202-10. Epub 2010 Jan 6.
Notch-1 inhibition by Withaferin-A: a therapeutic target against colon carcinogenesis.
Koduru S,
Kumar R,
Srinivasan S,
Evers MB,
Damodaran C.
Department of Clinical Sciences, College of Health Sciences, University of Kentucky, Lexington, Kentucky 40536-0200, USA.
Notch signaling plays a crucial role in the development of colon cancer; targeting the Notch pathway may sensitize colon cancers to various adjuvant agents. The focus of our current study is to identify natural compounds that target Notch signaling and that might be beneficial for the prevention and treatment of colon cancer.
Withaferin-A (WA) is a bioactive compound derived from Withania somnifera, which inhibits Notch-1 signaling and downregulates prosurvival pathways, such as Akt/NF-kappaB/Bcl-2, in three colon cancer cell lines (HCT-116, SW-480, and SW-620). In addition, WA downregulated the expression of mammalian target of rapamycin signaling components, pS6K and p4E-BP1, and activated c-Jun-NH(2)-kinase-mediated apoptosis in colon cancer cells. We also established the molecular link between Notch/Akt/mammalian target of rapamycin signaling by complementary approaches (i.e., overexpression of Notch-1 or inhibition of Notch-1 by small interfering RNA). Our results suggest that WA inhibits Notch-mediated prosurvival signaling, which facilitates c-Jun-NH(2)-kinase-mediated apoptosis in colon cancer cell lines. These results underscore the anticancer activity of WA, which exhibits potential for further development for targeted chemotherapy and/or chemoprevention strategies in the context of colon cancer.
PMID: 20053782 [PubMed - in process]
Altern Med Rev. 2006 Dec;11(4):269-77.
Ancient medicine, modern use: Withania somnifera and its potential role in integrative oncology.
Winters M.
Withania somnifera Dunal, commonly known as ashwagandha, has been used for centuries in Ayurvedic medicine to increase longevity and vitality. Western research supports its polypharmaceutical use, confirming antioxidant, anti-inflammatory, immune-modulating, and antistress properties in the whole plant extract and several separate constituents. This article reviews the literature pertaining to Withania somnifera and its botanical constituents as antitumor agents and in conjunction with radiation and chemotherapy treatment. Following a search of MEDLINE and EBSCO databases, it can be concluded that Withania somnifera reduces tumor cell proliferation while increasing overall animal survival time. Furthermore, it has been shown to enhance the effectiveness of radiation therapy while potentially mitigating undesirable side effects. Withania somnifera also reduces the side effects of chemotherapeutic agents cyclophosphamide and paclitaxel without interfering with the tumor-reducing actions of the drugs. These effects have been demonstrated in vitro on human cancer cell lines, and in vivo on animal subjects, but there have been no human trials to date. Given its broad spectrum of cytotoxic and tumor-sensitizing actions, Withania somnifera presents itself as a novel complementary therapy for integrative oncology care.
PMID: 17176166 [PubMed - indexed for MEDLINE]
Indian J Physiol Pharmacol. 2001 Apr;45(2):253-7.
Reversal of paclitaxel induced neutropenia by Withania somnifera in mice.
Gupta YK,
Sharma SS,
Rai K,
Katiyar CK.
Department of Pharmacology, All India Institute of Medical Sciences, New Delhi-110 029.
The effect of aqueous extract of Withania somnifera (L. Solanaceae) was studied against paclitaxel induced neutropenia in mice. After paclitaxel 1 mg/kg, i.v. administration significant fall in total WBC and absolute neutrophil count was observed on day 3 and day 5. W. Somnifera (200 mg/kg, p.o.) per se produced significant increase in neutrophil counts. W. somnifera (200 mg/kg, p.o.) when administered for 4 days before paclitaxel treatment and continued for 12 days caused significant reversal of neutropenia of paclitaxel. The findings of the study suggest the potential of W. somnifera as an adjuvant during cancer chemotherapy for the prevention of bone marrow depression associated with anticancer drugs.
PMID: 11480235 [PubMed - indexed for MEDLINE]
Clin Cancer Res. 2007 Apr 1;13(7):2298-306.
Selective killing of cancer cells by leaf extract of Ashwagandha: identification of a tumor-inhibitory factor and the first molecular insights to its effect.
Widodo N,
Kaur K,
Shrestha BG,
Takagi Y,
Ishii T,
Wadhwa R,
Kaul SC.
Research Institute for Cell Engineering, GENE Therapeutics, Inc., National Institute of Advanced Industrial Science and Technology, Higashi, Tsukuba, Japan.
PURPOSE: Ashwagandha is regarded as a wonder shrub of India and is commonly used in Ayurvedic medicine and health tonics that claim its variety of health-promoting effects. Surprisingly, these claims are not well supported by adequate studies, and the molecular mechanisms of its action remain largely unexplored to date. We undertook a study to identify and characterize the antitumor activity of the leaf extract of ashwagandha. EXPERIMENTAL DESIGN: Selective tumor-inhibitory activity of the leaf extract (i-Extract) was identified by in vivo tumor formation assays in nude mice and by in vitro growth assays of normal and human transformed cells. To investigate the cellular targets of i-Extract, we adopted a gene silencing approach using a selected small hairpin RNA library and found that p53 is required for the killing activity of i-Extract. RESULTS: By molecular analysis of p53 function in normal and a variety of tumor cells, we found that it is selectively activated in tumor cells, causing either their growth arrest or apoptosis. By fractionation, purification, and structural analysis of the i-Extract constituents, we have identified its p53-activating tumor-inhibiting factor as with a none. CONCLUSION: We provide the first molecular evidence that the leaf extract of ashwagandha selectively kills tumor cells and, thus, is a natural source for safe anticancer medicine.
PMID: 17404115 [PubMed - indexed for MEDLINE]
Cancer Lett. 2008 Jan 9. [Epub ahead of print]
Selective killing of cancer cells by leaf extract of Ashwagandha: Components, activity and pathway analyses.
Widodo N,
Takagi Y,
Shrestha BG,
Ishii T,
Kaul SC,
Wadhwa R.
National Institute of Advanced Industrial Science & Technology (AIST), Central 4, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8562, Japan; Department of Molecular and Cellular Physiology, University of Tsukuba, Ibaraki 305-8575, Japan.
Ashwagandha, also called as "Queen of Ayurveda" and "Indian ginseng", is a commonly used plant in Indian traditional medicine, Ayurveda. Its roots have been used as herb remedy to treat a variety of ailments and to promote general wellness. However, scientific evidence to its effects is limited to only a small number of studies. We had previously identified anti-cancer activity in the leaf extract (i-Extract) of Ashwagandha and demonstrated withanone as a cancer inhibitory factor (i-Factor). In the present study, we fractionated the i-Extract to its components by silica gel column chromatography and subjected them to cell based activity analyses. We found that the cancer inhibitory leaf extract (i-Extract) has, at least, seven components that could cause cancer cell killing; i-Factor showed the highest selectivity for cancer cells and i-Factor rich Ashwagandha leaf powder was non-toxic and anti-tumorigenic in mice assays. We undertook a gene silencing and pathway analysis approach and found that i-Extract and its components kill cancer cells by at least five different pathways, viz. p53 signaling, GM-CFS signaling, death receptor signaling, apoptosis signaling and G2-M DNA damage regulation pathway. p53 signaling was most common. Visual analysis of p53 and mortalin staining pattern further revealed that i-Extract, fraction F1, fraction F4 and i-Factor caused an abrogation of mortalin-p53 interactions and reactivation of p53 function while the fractions F2, F3, F5 work through other mechanisms.
PMID: 18191020 [PubMed - as supplied by publisher]
J Ethnopharmacol. 2006 May 24;105(3):336-41. Epub 2006 Jan 10.
Evaluation of the effect of Withania somnifera root extracts on cell cycle and angiogenesis.
Mathur R,
Gupta SK,
Singh N,
Mathur S,
Kochupillai V,
Velpandian T.
Department of Pharmacology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India.
In the Indian System of Medicine, the medicinal plant, Withania somnifera Dunal (Solanaceae) finds application for numerous ailments including cancer. This study explores the mechanism(s) underlying this property. The hydroalcoholic extract of the roots (WS) was partitioned between chloroform (WS-chloroform) and water (WS-water). Further, WS-chloroform was fractionated (A1-A12) by reverse-phase column chromatography and their withanolide content was quantified by high-performance liquid chromatography (HPLC). Preliminarily, the anti-proliferative activity of all the extracts and fractions was screened against human laryngeal carcinoma (Hep2) cells by microculture tetrazolium assay (MTT). Two extracts (WS and WS-chloroform) and three fractions (A4, A5 and A6) negatively affected Hep2 viability at the concentration of 25 microg/ml and these were further investigated pharmacologically. Flow cytometry revealed cell cycle block and accumulation of hypoploid (sub G1) cells as the mode of anti-proliferative activity of all but A4. Their anti-angiogenic potential was investigated by a chickchorio-allantoic membrane (CAM) wherein a significant inhibition (p<0.0001) of vascular endothelium growth factor (VEGF), induced neovascularization was recorded. The effect was confirmed in vivo by mouse sponge implantation method. These findings suggest that the roots of Withania somnifera possess cell cycle disruption and anti-angiogenic activity, which may be a critical mediator for its anti-cancer action.
PMID: 16412596 [PubMed - indexed for MEDLINE]
Cancer Res. 2008 Sep 15;68(18):7661-9.
Nutr Cancer. 2008;60 Suppl 1:51-60.
Ayurvedic medicine constituent withaferin a causes G2 and M phase cell cycle arrest in human breast cancer cells.
FREE TEXT
Stan SD,
Zeng Y,
Singh SV.
University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Withaferin A (WA) is derived from the medicinal plant Withania somnifera that has been safely used for centuries in the Indian Ayurvedic medicine for treatment of various ailments. We now demonstrate that WA treatment causes G2 and mitotic arrest in human breast cancer cells. Treatment of MDA-MB-231 (estrogen-independent) and MCF-7 (estrogen-responsive) cell lines with WA resulted in a concentration- and time-dependent increase in G2-M fraction, which correlated with a decrease in levels of cyclin-dependent kinase 1 (Cdk1), cell division cycle 25C (Cdc25C) and/or Cdc25B proteins, leading to accumulation of Tyrosine15 phosphorylated (inactive) Cdk1. Ectopic expression of Cdc25C conferred partial yet significant protection against WA-mediated G2-M phase cell cycle arrest in MDA-MB-231 cells. The WA-treated MDA-MB-231 and MCF-7 cells were also arrested in mitosis as judged by fluorescence microscopy and analysis of Ser10 phosphorylated histone H3. Mitotic arrest resulting from exposure to WA was accompanied by an increase in the protein level of anaphase promoting complex/cyclosome substrate securin. In conclusion, the results of this study suggest that G2-M phase cell cycle arrest may be an important mechanism in antiproliferative effect of WA against human breast cancer cells.
PMID: 19003581 [PubMed - indexed for MEDLINE]
Phytother Res. 2009 Jul;23(7):987-92.
Withanolide sulfoxide from Aswagandha roots inhibits nuclear transcription factor-kappa-B, cyclooxygenase and tumor cell proliferation.
Mulabagal V,
Subbaraju GV,
Rao CV,
Sivaramakrishna C,
Dewitt DL,
Holmes D,
Sung B,
Aggarwal BB,
Tsay HS,
Nair MG.
Bioactive Natural Products and Phytoceuticals, Department of Horticulture and National Food, Safety and Toxicology Center, Michigan State University, East Lansing, Michigan, USA.
Investigation of the methanol extract of Aswagandha (Withania somnifera) roots for bioactive constituents yielded a novel withanolide sulfoxide compound (1) along with a known withanolide dimer ashwagandhanolide (2) with an S-linkage. The structure of compound 1 was established by extensive NMR and MS experiments. Compound 1 was highly selective in inhibiting cyclooxygenase-2 (COX-2) enzyme by 60% at 100 microm with no activity against COX-1 enzyme. The IC(50) values of compound 1 against human gastric (AGS), breast (MCF-7), central nervous system (SF-268) and colon (HCT-116) cancer cell lines were in the range 0.74-3.63 microm. Both S-containing dimeric withanolides, 1 and 2, completely suppressed TNF-induced NF-kappaB activation when tested at 100 microm. The isolation of a withanolide sulfoxide from W. somnifera roots and its ability to inhibit COX-2 enzyme and to suppress human tumor cell proliferation are reported here for the first time. In addition, this is the first report on the abrogation of TNF-induced NF-kappaB activation for compounds 1 and 2. Copyright 2009 John Wiley & Sons, Ltd.
PMID: 19152372 [PubMed - indexed for MEDLINE]
Pharmazie. 2007 Apr;62(4):305-7.
Study of the anticancer potential of Yemeni plants used in folk medicine.
Mothana RA,
Grünert R,
Lindequist U,
Bednarski PJ.
Department of Pharmacognosy, Faculty of Pharmacy, Sana'a-University, Yemen.
r_mothana@yahoo.com
The present work evaluated the anticancer activity of methanol extracts from 24 plants used in Yemeni traditional medicine. To evaluate the in vitro cytotoxic potency of the investigated extracts, an established microtiter plate assay based on cellular staining with crystal violet was used with 5 human cancer cell lines: two lung cancer (A-427 and LCLC-103H), two urinary bladder carcinoma (5637 and RT-112) and one breast cancer (MCF-7) line. The methanolic extracts of
Dendrosicyos socotrana, Withanina aduensis, Withania riebeckii, Dracena cinnabari and Buxus hildebrandtii exhibited the highest toxicity on all tumor cell lines with IC50 values ranging between 0.29 and 5.54 microg/ml. The extracts of Jatropha unicostata and Punica protopunica showed a moderate potency on the most tumor cell lines.
PMID: 17484289 [PubMed - indexed for MEDLINE]
Withaferin A causes FOXO3a- and Bim-dependent apoptosis and inhibits growth of human breast cancer cells in vivo.
Stan SD,
Hahm ER,
Warin R,
Singh SV.
Department of Pharmacology and Chemical Biology, and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Withaferin A (WA) is derived from the medicinal plant Withania somnifera, which has been safely used for centuries in Indian Ayurvedic medicine for treatment of different ailments. We now show, for the first time, that WA exhibits significant activity against human breast cancer cells in culture and in vivo. The WA treatment decreased viability of MCF-7 (estrogen-responsive) and MDA-MB-231 (estrogen-independent) human breast cancer cells in a concentration-dependent manner. The WA-mediated suppression of breast cancer cell viability correlated with apoptosis induction characterized by DNA condensation, cytoplasmic histone-associated DNA fragmentation, and cleavage of poly-(ADP-ribose)-polymerase. On the other hand, a spontaneously immortalized normal mammary epithelial cell line (MCF-10A) was relatively more resistant to WA-induced apoptosis compared with breast cancer cells. The WA-mediated apoptosis was accompanied by induction of Bim-s and Bim-L in MCF-7 cells and induction of Bim-s and Bim-EL isoforms in MDA-MB-231 cells. The cytoplasmic histone-associated DNA fragmentation resulting from WA exposure was significantly attenuated by knockdown of protein levels of Bim and its transcriptional regulator FOXO3a in both cell lines. Moreover, FOXO3a knockdown conferred marked protection against WA-mediated induction of Bim-s expression. The growth of MDA-MB-231 cells implanted in female nude mice was significantly retarded by 5 weekly i.p. injections of 4 mg WA/kg body weight. The tumors from WA-treated mice exhibited reduced cell proliferation and increased apoptosis compared with tumors from control mice. These results point toward an important role of FOXO3a and Bim in regulation of WA-mediated apoptosis in human bre
Studies Suggest Potent Anti-Cancer Activity
http://www.lef.org/magazine/mag2006/...t_ashwa_01.htm
In addition to ashwagandha’s documented neuroprotective effects, exciting recent evidence suggests that it also has the potential to stop cancer cells in their tracks. For example,
a recent analysis showed that ashwagandha extract inhibited the growth of human breast, lung, and colon cancer cell lines in the laboratory. This inhibition was comparable to that achieved with the common cancer chemotherapy drug doxorubicin (Caelyx®, Myocet®). In fact, researchers reported that withaferin A, a specific compound extracted from ashwagandha, was more effective than doxorubicin in inhibiting breast and colon cancer cell growth.11,14
Scientists in India recently conducted cell studies showing that ashwagandha extract disrupts cancer cells’ ability to reproduce—a key step in fighting cancer. Additionally, laboratory analysis indicates that ashwagandha extract possesses anti-angiogenic activity, also known as the ability to prevent cancer from forming new blood vessels to support its unbridled growth. These findings lend further support to ashwagandha’s potential role in fighting cancer.15 Based on these studies, research in this area continues.
In another study,
orally administered ashwagandha extract significantly inhibited experimentally induced stomach cancer in laboratory animals. Tumor incidence was reduced by 60% and tumor multiplicity (number) by 92%. Similarly,
in a rodent model of skin cancer, ashwagandha inhibited tumor incidence and multiplicity by 45% and 71%, respectively.16 Ashwagandha’s protective effect against skin cancer has been shown in other studies as well.17
A recent experiment demonstrated that ashwagandha extract produced a marked increase in life span and a decrease in tumor weight in animals with experimentally induced cancer of the lymphatic system.18 This is an exciting finding, suggesting that ashwagandha could enhance survival in individuals with cancer.
Ashwagandha extract may also have applications as an adjunct to cancer chemotherapy treatment. One of the consequences of chemotherapy is neutropenia, a decrease in white blood cells called neutrophils that can leave patients dangerously vulnerable to infection. A
study of animals demonstrated that orally administered ashwagandha extract protected against this decline in infection-fighting neutrophils. While further human studies are needed, these findings suggest that ashwagandha may be an excellent adjunctive therapy to chemotherapy.19
Another animal study investigated ashwagandha extract’s effects in normalizing the immune-suppressing effects of chemotherapy.
When test animals received a common chemotherapy drug, levels of the desirable immune factors interferon-gamma and interleukin-2 decreased.
When the animals also received orally administered ashwagandha extract, however, their immune system parameters remained normal. These findings add support to the idea that ashwagandha may help protect immune function during chemotherapy treatment.20
Bad with cyclophosphamide??:
J Ethnopharmacol. 1998 Oct;62(3):209-14.
Suppressive effect of cyclophosphamide-induced toxicity by Withania somnifera extract in mice.
Davis L,
Kuttan G.
Professor Amala Cancer Research Centre, Amala Nagar P.O., Kerala, India.
Administration of Withania somnifera extract (Solanaceae) was found to significantly reduce leucopenia induced by cyclophosphamide (CTX) treatment. The total WBC count on the 12th day of the CTX-treated group was 3720 cells/mm3 and that of CTX along with Withania was 6120 cells/mm3. Treatment of Withania along with CTX was found to significantly (P < 0.001) increase the bone marrow cellularity (13.1 x 10(6) cells/femur) compared to CTX alone treated group (8 x 10(6) cells/femur). Administration of Withania extract increased the number of alpha-esterase positive cells (1130/4000 cells) in the bone marrow of CTX treated animals, compared to the CTX-alone treated group (687/4000 cells). The major activity of Withania somnifera may be the stimulation of stem cell proliferation. These studies indicate that Withania somnifera could reduce the cyclophosphamide induced toxicity and its usefulness in cancer therapy.
PMID: 9849630 [PubMed - indexed for MEDLINE]
Biochem Pharmacol. 2010 Feb 15;79(4):542-51.
Withaferin A targets heat shock protein 90 in pancreatic cancer cells.
Yu Y,
Hamza A,
Zhang T,
Gu M,
Zou P,
Newman B,
Li Y,
Gunatilaka AA,
Zhan CG,
Sun D.
Department of Pharmaceutical Sciences, College of Pharmacy, The University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA.
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 IC(50)s of 1.24, 2.93 and 2.78 microM) 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 microM) disrupted Hsp90-Cdc37 complexes from 1 to 24h post-treatment, while it neither blocked ATP binding to Hsp90, nor changed Hsp90-P23 association.
WA (3, 6mg/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.
PMID: 19769945 [PubMed - in process]
Angiogenesis. 2004;7(2):115-22.
Withaferin A is a potent inhibitor of angiogenesis.
Mohan R,
Hammers HJ,
Bargagna-Mohan P,
Zhan XH,
Herbstritt CJ,
Ruiz A,
Zhang L,
Hanson AD,
Conner BP,
Rougas J,
Pribluda VS.
Discovery Research, EntreMed, Inc., Rockville, Maryland, USA.
Royce.Mohan@uky.edu
The medicinal plant Withania somnifera is widely researched for its anti-inflammatory, cardioactive and central nervous system effects. In Ayurveda , the major Traditional Indian medicine system, extracts from W. somnifera are distinctively employed for the treatment of arthritis and menstrual disorders. Because these conditions involve angiogenic processes we hypothesized that the W. somnifera extracts might contain angiogenesis inhibitors. We employed an endothelial cell-sprouting assay to monitor the purification of substances from W. somnifera root extracts and isolated as the active principle the previously known natural product withaferin A. We show that withaferin A inhibits human umbilical vein endothelial cell (HUVEC) sprouting in three-dimensional collagen-I matrix at doses which are relevant to NF-kappa B-inhibitory activity. Withaferin A inhibits cell proliferation in HUVECs (IC50 =12 nM) at doses that are significantly lower than those required for tumor cell lines through a process associated with inhibition of cyclin D1 expression. We propose that the inhibition of NF-kappa B by withaferin A in HUVECs occurs by interference with the ubiquitin-mediated proteasome pathway as suggested by the increased levels of poly-ubiquitinated proteins. Finally, withaferin A is shown to exert potent anti-angiogenic activity in vivo at doses that are 500-fold lower than those previously reported to exert anti-tumor activity in vivo. In conclusion, our findings identify a novel mode of action of withaferin A, which highlights the potential use of this natural product for cancer treatment or prevention.
PMID: 15516832 [PubMed - indexed for MEDLINE]
http://www.raysahelian.com/ashwagandha.html
Ashwagandha, Withania somnifera, is an herb that is extensively used in Ayurveda, the traditional health care system in India. This herb is used as a general tonic and "adaptogen," helping the body adapt to stress. In addition, this herb has been shown to possess antioxidant activity as well as an ability to support a healthy immune system. Ashwagandha - also known as Indian Winter Cherry - is a shrub cultivated in India and North America whose roots have been used for thousands of years by Ayurvedic practitioners. The root contains flavonoids and many active ingredients of the withanolide class. Several studies over the past few years have looked into whether this herb has anti-inflammatory, anti-tumor, anti-stress, antioxidant, mind-boosting, immune-enhancing, and rejuvenating properties (see studies at bottom of page). Historically ashwagandha root has also been noted to have sex-enhancing properties. Many people notice a relaxing effect within hours of taking a 500 mg pill.
Anticarcinogenic activity of Withania somnifera Dunal against Dalton's Ascitic Lymphoma.
J Ethnopharmacol. 2004 Aug;93(2-3):359-61.
The effect of ethanolic extract of ashwagandha root against Dalton's Ascitic Lymphoma has been evaluated in Swiss albino mice. A significant increase in the life span and a decrease in the cancer cell number and tumour weight were noted in the tumour-induced mice after treatment with ashwagandha extract. These observations are suggestive of the protective effect of ashwagandha extract in Dalton's Ascitic Lymphoma.
http://www.ethnoleaflets.com/leaflets/withafer.htm
Conclusion: The studies so far indicate that W. somnifera could prove to be a good natural source of a potent and relatively safe radiosensitizer/chemotherapeutic agent.
http://www.drugs.com/npp/ashwaganda.html
Cancer
Withaferin A was first isolated as a cytotoxic agent,
3 and a considerable amount of investigation followed. The compound produced mitotic arrest in Ehrlich ascites carcinoma cells in vitro
31 while in vivo effects were mediated by macrophage activation.
26 ,
32 Further investigations on peripheral blood lymphocytes determined that withaferin A destroyed spindle microtubules of cells in metaphase.
33
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Despite a large volume of basic scientific studies on the plant, there is minimal evidence for a proper dose of this herb. A single study in which W. somnifera was the principal component of a polyherbal mixture administered 450 mg of root powder 4 times per day for arthritis.
49
The protective effect of a purified extract of Withania somnifera against doxorubicin-induced cardiac toxicity in rats 2007 LINK
Eur J Cancer. 2009 May;45(8):1494-509. Epub 2009 Mar 5.
Immune modulation and apoptosis induction: Two sides of antitumoural activity of a standardised herbal formulation of Withania somnifera.
Malik F,
Kumar A,
Bhushan S,
Mondhe DM,
Pal HC,
Sharma R,
Khajuria A,
Singh S,
Singh G,
Saxena AK,
Suri KA,
Qazi GN,
Singh J.
Division of Pharmacology, Indian Institute of Integrative Medicine (Council of Scientific and Industrial Research), Canal Road, Jammu 180001, India.
Deregulated apoptosis and suppressed tumour reactive immunity render tumour cells to grow amok in the host body. Traditionally used botanicals may offer potential anticancer chemo-immunotherapeutic leads. We report in this study a chemically standardised herbal formulation (WSF) of Withania somnifera possessing anticancer and Th1 immune up-regulatory activities. WSF produced cytotoxicity in a panel of human cancer cell lines in vitro. The molecular mechanism of cell cytotoxicity, IC(50) 48h approximately 20mug/ml, was investigated in HL-60, where it induced apoptosis by activating both intrinsic and extrinsic signalling pathways. It induced early generation of reactive nitrogen and oxygen species (RNOS), thus producing oxidative stress mediated mitochondrial membrane potential (MMP) loss leading to the release of cytochrome c, the translocation of Bax to mitochondria and apoptosis-inducing factor to the nuclei. These events paralleled the activation of caspase-9, -3 and PARP cleavage. WSF also activated caspase-8 through enhanced expression of TNF-R1 and DR-4, suggesting also the involvement of extrinsic pathway of apoptosis. WSF at 150mg/kg, i.p., inhibited >50% tumour growth in the mouse tumour models. In tumour-bearing mice, WSF inhibited the expression of pStat-3, with a selective stimulation of Th1 immunity as evidenced by enhanced secretion of IFN-gamma and IL-2. In parallel, it enhanced the proliferation of CD4(+)/CD8(+) and NK cells along with an increased expression of CD40/CD40L/CD80. In addition, WSF also enhanced T cell activation in camptothecin treated tumour-bearing mice. WSF being safe when given orally up to 1500mg/kg to rats for 6 months may be found useful in the management of malignancy by targeting at multiple pathways.
PMID: 19269163 [PubMed - indexed for MEDLINE]
Cancer Sci. 2009 Sep;100(9):1740-7. Epub 2009 May 31.
Effect of the alcoholic extract of Ashwagandha leaves and its components on proliferation, migration, and differentiation of glioblastoma cells: combinational approach for enhanced differentiation.
Shah N,
Kataria H,
Kaul SC,
Ishii T,
Kaur G,
Wadhwa R.
National Institute of Advanced Industrial Science and Technology, University if Tsukuba, Ibaraki, Japan.
Ashwagandha (Withania somnifera) is widely used in the Indian traditional system of medicine, Ayurveda. Although it is claimed to have a large variety of health-promoting effects, including therapeutic effects on stress and disease, the mechanisms of action have not yet been determined. In the present study, we aimed to investigate the growth inhibition and differentiation potential of the alcoholic extract of Ashwagandha leaves (i-Extract), its different constituents (Withaferin A, Withanone, Withanolide A) and their combinations on glioma (C6 and YKG1) cell lines. Withaferin A, Withanone, Withanolide A and i-Extract markedly inhibited the proliferation of glioma cells in a dose-dependent manner and changed their morphology toward the astrocytic type. Molecular analysis revealed that the i-Extract and some of its components caused enhanced expression of glial fibrillary acidic protein, change in the immunostaining pattern of mortalin from perinuclear to pancytoplasmic, delay in cell migration, and increased expression of neuronal cell adhesion molecules. The data suggest that the i-Extract and its components have the potential to induce senescence-like growth arrest and differentiation in glioma cells. These assays led us to formulate a unique combination formula of i-Extract components that caused enhanced differentiation of glial cells.
PMID: 19575749 [PubMed - indexed for MEDLINE]
Re: Ashwagandha (Withania somnifera)
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