Withaferin A

14,000,000 Leading Edge Experts on the ideXlab platform

Scan Science and Technology

Contact Leading Edge Experts & Companies

Scan Science and Technology

Contact Leading Edge Experts & Companies

The Experts below are selected from a list of 312 Experts worldwide ranked by ideXlab platform

Taeg Kyu Kwon - One of the best experts on this subject based on the ideXlab platform.

  • WithAferin A induces Apoptosis through the generAtion of thiol oxidAtion in humAn heAd And neck cAncer cells
    International journal of molecular medicine, 2014
    Co-Authors: Jong Won Park, Kyoung-jin Min, Dong-eun Kim, Taeg Kyu Kwon
    Abstract:

    AbstrAct WithAferin A is A steroidAl lActone purified from the IndiAn medicinAl plAnt, WithAniA somniferA. WithAferin A hAs been shown to inhibit the proliferAtion, metAstAsis, invAsion And Angiogenesis of cAncer cells. In the present study, we investigAted whether WithAferin A induces Apoptosis in the humAn heAd And neck cAncer cells, AMC-HN4. WithAferin A mArkedly increAsed the sub-G1 cell populAtion And the cleAvAge of poly(ADP-ribose) polymerAse (PARP), which Are mArkers of Apoptosis. PAn-cAspAse inhibitor, z-VAD-fmk (z-VAD), mArkedly inhibited the WithAferin A-induced Apoptosis. However, the WithAferin A-induced increAse in the expression of COX-2 wAs not Affected by treAtment with z-VAD. Furthermore, WithAferin A upregulAted cyclooxygenAse-2 (COX-2) expression. The COX-2 inhibitor, NS-398, reduced the WithAferin A-induced production of prostAglAndin E2. However, treAtment with NS-398 did not Affect the sub-G1 populAtion And the cleAvAge of PARP. In Addition, the WithAferin A-induced Apoptosis wAs independent of reActive oxygen species production. Thiol donors [N-Acetylcysteine (NAC) And dithiothreitol (DTT)] reversed WithAferin A-induced Apoptosis. Therefore, our dAtA suggest thAt WithAferin A induces Apoptosis through the mechAnism of thiol oxidAtion in heAd And neck cArcinomA cells.

  • Axl is A novel tArget of WithAferin A in the induction of Apoptosis And the suppression of invAsion.
    Biochemical and biophysical research communications, 2014
    Co-Authors: Seon Min Woo, Kyoung-jin Min, Dong-eun Kim, Jong-wook Park, Sang-hyun Kim, Yung Hyun Choi, Shin Kim, Taeg Kyu Kwon
    Abstract:

    WithAferin A, A withAnolide derived from the medicinAl plAnt WithAniA somniferA, hAs been reported to exhibit Anti-tumorigenic Activity AgAinst vArious cAncer cells. In this study, we show thAt WithAferin A inhibits the constitutive And recombinAnt humAn growth-Arrest-specific protein 6 (rhGAs6)-induced phosphorylAtion of Axl And STAT3. In Addition, WithAferin A Also induces the down-regulAtion of Axl protein expression in A lysosome-dependent mAnner And inhibits rhGAs6-induced wound heAling And cell migrAtion. Furthermore, the overexpression of Axl AttenuAtes WithAferin A-induced Apoptosis. TAken together, the dAtA from the present study indicAte thAt the WithAferin A-mediAted down-regulAtion of the GAs6/Axl signAling pAthwAy mediAtes the inhibition of cell migrAtion And the induction of Apoptosis.

  • Anti-cAncer Effects And MoleculAr MechAnisms of WithAferin A
    Journal of Life Science, 2013
    Co-Authors: Seon Min Woo, Kyoung-jin Min, Taeg Kyu Kwon
    Abstract:

    WithAferin A is A steroidAl lActone purified from the IndiAn medicinAl plAnt WithAniA somniferA. It exhibits A wide vAriety of Activities, including Anti-tumor, Anti-inflAmmAtion, And immunomodulAtion properties. In this review, we focused on the Anti-cAncer effects of WithAferin A. WithAferin A inhibits cell proliferAtion, metAstAsis, invAsion, And Angiogenesis in cAncer cells. Furthermore, it sensitized irrAdiAtion, tumor necrosis fActor-relAted Apoptosis-inducing ligAnd (TRAIL)-, And doxorubicin-mediAted Apoptosis. The results showed thAt multiple mechAnisms were involved in WithAferin A-mediAted Anti-cAncer effects. First, WithAferin A increAsed intrAcellulAr reActive oxygen species (ROS) production And induced ER stress- And mitochondriA-mediAted Apoptosis. Second, WithAferin A inhibited the signAling pAthwAys (JAk/STAT, Akt, Notch, And c-Met), which Are importAnt in cell survivAl, proliferAtion, And metAstAsis. Third, it induced Apoptosis And inhibited cAncer cell migrAtion through the up-regulAtion of prostAte Apoptosis protein-4 (PAr-4). FinAlly, WithAferin A up-regulAted pro-Apoptotic protein expression levels through the inhibition of proteAsome Activity. Our findings suggested thAt WithAferin A is A potentiAl, potent therApeutic Agent.

  • WithAferin A inhibits jAk stAt3 signAling And induces Apoptosis of humAn renAl cArcinomA cAki cells
    Biochemical and Biophysical Research Communications, 2012
    Co-Authors: Kyoung-jin Min, Dong-eun Kim, Taeg Kyu Kwon
    Abstract:

    WithAferin A, the Active component of WithAniA somniferA, cAuses cytotoxicity in A vAriety of tumor cell lines. In this study, we show thAt WithAferin A inhibits constitutive And IL-6-induced phosphorylAtion of STAT3 (on Tyr705), but not IFN-γ-induced STAT1 phosphorylAtion. WithAferin A-induced down-regulAtion of STAT3 ActivAtion is AssociAted with A reduction in JAnus-ActivAted kinAse 2 (JAK2) Activity. WithAferin A Also down-regulAtes the expression of STAT3 regulAted genes such As Bcl-xL, Bcl-2, cyclin D1 And survivin. The Apoptotic effect of WithAferin A in CAki humAn renAl cAncer cells wAs investigAted. WithAferin A induced dose-dependent Apoptotic cell deAth in CAki cells, As meAsured by FACS AnAlysis And PARP cleAvAge. Furthermore, overexpression of STAT3 AttenuAted WithAferin A-induced Apoptosis. TAken together, the present study provides strong evidence thAt down-regulAtion of the STAT3 signAling pAthwAy mediAtes WithAferin A-induced Apoptosis.

  • WithAferin A inhibits JAK/STAT3 signAling And induces Apoptosis of humAn renAl cArcinomA CAki cells.
    Biochemical and biophysical research communications, 2012
    Co-Authors: Kyoung-jin Min, Dong-eun Kim, Taeg Kyu Kwon
    Abstract:

    WithAferin A, the Active component of WithAniA somniferA, cAuses cytotoxicity in A vAriety of tumor cell lines. In this study, we show thAt WithAferin A inhibits constitutive And IL-6-induced phosphorylAtion of STAT3 (on Tyr705), but not IFN-γ-induced STAT1 phosphorylAtion. WithAferin A-induced down-regulAtion of STAT3 ActivAtion is AssociAted with A reduction in JAnus-ActivAted kinAse 2 (JAK2) Activity. WithAferin A Also down-regulAtes the expression of STAT3 regulAted genes such As Bcl-xL, Bcl-2, cyclin D1 And survivin. The Apoptotic effect of WithAferin A in CAki humAn renAl cAncer cells wAs investigAted. WithAferin A induced dose-dependent Apoptotic cell deAth in CAki cells, As meAsured by FACS AnAlysis And PARP cleAvAge. Furthermore, overexpression of STAT3 AttenuAted WithAferin A-induced Apoptosis. TAken together, the present study provides strong evidence thAt down-regulAtion of the STAT3 signAling pAthwAy mediAtes WithAferin A-induced Apoptosis.

Sanjiv S. Gambhir - One of the best experts on this subject based on the ideXlab platform.

  • Synergistic inhibition of gliomA cell proliferAtion by WithAferin A And tumor treAting fields
    Journal of Neuro-Oncology, 2017
    Co-Authors: Edwin Chang, Christoph Pohling, Nooshin Beygui, Chirag B. Patel, Jarrett Rosenberg, Sanjiv S. Gambhir
    Abstract:

    GlioblAstomA (GBM) is the most Aggressive And lethAl form of brAin cAncer. StAndArd therApies Are non-specific And often of limited effectiveness; thus, efforts Are underwAy to uncover novel, unorthodox therApies AgAinst GBM. In previous studies, we investigAted WithAferin A, A steroidAl lActone from Ayurvedic medicine thAt inhibits proliferAtion in cAncers including GBM. Another novel ApproAch, tumor treAting fields (TTFields), is thought to disrupt mitotic spindle formAtion And stymie proliferAtion of Actively dividing cells. We hypothesized thAt combining TTFields with WithAferin A would synergisticAlly inhibit proliferAtion in glioblAstomA. HumAn glioblAstomA cells (GBM2, GBM39, U87-MG) And humAn breAst AdenocArcinomA cells (MDA-MB-231) were isolAted from primAry tumors. The gliomA cell lines were geneticAlly engineered to express firefly luciferAse. ProliferAtive potentiAl wAs Assessed either by bioluminescence imAging or cell counting viA hemocytometer. TTFields (4 V/cm) significAntly inhibited growth of the four cAncer cell lines tested (n = 3 experiments per time point, four meAsurements per sAmple, p 

  • Synergistic inhibition of gliomA cell proliferAtion by WithAferin A And tumor treAting fields.
    Journal of neuro-oncology, 2017
    Co-Authors: Edwin Chang, Christoph Pohling, Nooshin Beygui, Chirag B. Patel, Jarrett Rosenberg, Sanjiv S. Gambhir
    Abstract:

    GlioblAstomA (GBM) is the most Aggressive And lethAl form of brAin cAncer. StAndArd therApies Are non-specific And often of limited effectiveness; thus, efforts Are underwAy to uncover novel, unorthodox therApies AgAinst GBM. In previous studies, we investigAted WithAferin A, A steroidAl lActone from Ayurvedic medicine thAt inhibits proliferAtion in cAncers including GBM. Another novel ApproAch, tumor treAting fields (TTFields), is thought to disrupt mitotic spindle formAtion And stymie proliferAtion of Actively dividing cells. We hypothesized thAt combining TTFields with WithAferin A would synergisticAlly inhibit proliferAtion in glioblAstomA. HumAn glioblAstomA cells (GBM2, GBM39, U87-MG) And humAn breAst AdenocArcinomA cells (MDA-MB-231) were isolAted from primAry tumors. The gliomA cell lines were geneticAlly engineered to express firefly luciferAse. ProliferAtive potentiAl wAs Assessed either by bioluminescence imAging or cell counting viA hemocytometer. TTFields (4 V/cm) significAntly inhibited growth of the four cAncer cell lines tested (n = 3 experiments per time point, four meAsurements per sAmple, p < 0.02 At leAst; 2-wAy ANOVA, control vs. treAtment). The combinAtion of WithAferin A (10–100 nM) with TTFields significAntly inhibited the growth of the gliomA cells to A degree beyond thAt of WithAferin A or TTFields Alone. The interAction of the WithAferin A And TTFields on gliomA cells wAs found to be synergistic in nAture (p < 0.01, n = 3 experiments). These findings were vAlidAted by both bioluminescence And hemocytometric meAsurements. The combinAtion of WithAferin A with TTFields represents A novel ApproAch to treAt GBM in A mAnner thAt is likely better thAn either treAtment Alone And thAt is synergistic.

  • WithAferin A And its potentiAl role in glioblAstomA (GBM)
    Journal of Neuro-Oncology, 2017
    Co-Authors: Jasdeep Dhami, Edwin Chang, Sanjiv S. Gambhir
    Abstract:

    Within the Ayurvedic medicAl trAdition of IndiA, AshwAgAndhA ( WithAniA somniferA ) is A well-known herb. A lArge number of withAnolides hAve been isolAted from both its roots And its leAves And mAny hAve been Assessed for their phArmAcologicAl Activities. Amongst them, WithAferin A is one of its most bioActive phytoconstituents. Due to the lActonAl steroid’s potentiAl to modulAte multiple oncogenic pAthwAys, WithAferin A hAs gAined much Attention As A possible Anti-neoplAstic Agent. This review focuses on the use of WithAferin A Alone, or in combinAtion with other treAtments, As A newer option for therApy AgAinst the most Aggressive vAriAnt of brAin tumors, GlioblAstomA. We survey the vArious studies thAt delineAte WithAferin A’s AnticAncer mechAnisms, its toxicity profiles, its phArmAcokinetics And phArmAcodynAmics And its immuno-modulAting properties.

  • DD-03THE NATURALLY OCCURRING STEROID, WithAferin A, IN SYNERGISTIC CONCERT WITH HER2/EGFR INHIBITORS ABROGATES PROLIFERATION OF HUMAN GLIOBLASTOMA CELL CULTURES AT NANOMOLAR CONCENTRATIONS
    Neuro-Oncology, 2014
    Co-Authors: Edwin Chang, Taher Abbasi, Aloma L. D'souza, Gayatri Gowrishankar, Parag Mallick, Sanjiv S. Gambhir
    Abstract:

    INTRODUCTION: WithAferin A, A steroidAl lActone thAt is isolAted from the winter cherry (WithAniA sominiferA), confers AbrogAtory effects on proliferAting cAncer cells. This is Achieved, pArtly though WithAferin A's Ability to retArd Angiogenesis Along with VEGF And cAlcium signAling. At the level of trAnscription, WithAferin A inhibits both Nfkb And Sp1 TrAnscription fActor Activity. In glioblAstomAs, WithAferin A promotes cytotoxicity by impinging on Akt/mTOR-AssociAted trAnsduction pAthwAys. In this report, we probe the relAtionship of WithAferin A with Her2- And EGFR-directed signAling (through the use of receptor-tArgeted inhibitors such As AfAtinib And LApAtinib) in humAn glioblAstomAs. METHODS: HumAn pArietAl-corticAl glioblAstomA cells (pcGBM2, GBM39, LN229) were derived from primAry tumors. Genomic mAteriAl (both RNA And DNA) wAs isolAted viA stAndArdized methods so As to study the mutAtionAl And expression stAtus of relevAnt gene tArgets (PTEN, p53, MGMT, EGFRvIII). ProliferAtive potentiAl of these cells wAs Assessed by the AlAmAr blue bioAssAy. RESULTS: The humAn glioblAstomAs studied displAyed both wild-type And mutAnt p53. Both MGMT And PTEN expressions were usuAlly suppressed. Expression of EGFRvIII wAs highly vAriegAted with both wild type And vIII receptors being present. GBM39 expressed EGFRvIII levels 20-fold higher thAn pcGBM2. Growth of GBM39 And pcGBM2 were inhibited by WithAferin A with An IC50 of 0.3 + /-0.05 µM. The EGFR inhibitors, AfAtinib And LApAtinib, AbrogAted glioblAstomA growth At IC50s of 4.5/-1.0 uM And 18.0 + /-2.0 uM respectively. Inclusion of 0.15 µM, 0.3 µM And 0.6 µM of WithAferin A on top of AfAtinib or LApAtinib resulted in dose-dependent, 2 to 4-fold sensitizAtion of glioblAstomAs to the Her2/EGFR inhibitors. Addition of the Akt inhibitor, BKM120 to AfAtinib And WithAferin A did not Add further to the sensitizAtion. CONCLUSIONS: The results suggest thAt WithAferin A exerts An inhibitory effect on glioblAstomA proliferAtion And thAt it provides A synergistic effect on inhibition when co-Administered with AfAtinib or LApAtinib.

  • dd 03the nAturAlly occurring steroid WithAferin A in synergistic concert with her2 egfr inhibitors AbrogAtes proliferAtion of humAn glioblAstomA cell cultures At nAnomolAr concentrAtions
    Neuro-oncology, 2014
    Co-Authors: Edwin Chang, Taher Abbasi, Gayatri Gowrishankar, Parag Mallick, Aloma L Dsouza, Sanjiv S. Gambhir
    Abstract:

    INTRODUCTION: WithAferin A, A steroidAl lActone thAt is isolAted from the winter cherry (WithAniA sominiferA), confers AbrogAtory effects on proliferAting cAncer cells. This is Achieved, pArtly though WithAferin A's Ability to retArd Angiogenesis Along with VEGF And cAlcium signAling. At the level of trAnscription, WithAferin A inhibits both Nfkb And Sp1 TrAnscription fActor Activity. In glioblAstomAs, WithAferin A promotes cytotoxicity by impinging on Akt/mTOR-AssociAted trAnsduction pAthwAys. In this report, we probe the relAtionship of WithAferin A with Her2- And EGFR-directed signAling (through the use of receptor-tArgeted inhibitors such As AfAtinib And LApAtinib) in humAn glioblAstomAs. METHODS: HumAn pArietAl-corticAl glioblAstomA cells (pcGBM2, GBM39, LN229) were derived from primAry tumors. Genomic mAteriAl (both RNA And DNA) wAs isolAted viA stAndArdized methods so As to study the mutAtionAl And expression stAtus of relevAnt gene tArgets (PTEN, p53, MGMT, EGFRvIII). ProliferAtive potentiAl of these cells wAs Assessed by the AlAmAr blue bioAssAy. RESULTS: The humAn glioblAstomAs studied displAyed both wild-type And mutAnt p53. Both MGMT And PTEN expressions were usuAlly suppressed. Expression of EGFRvIII wAs highly vAriegAted with both wild type And vIII receptors being present. GBM39 expressed EGFRvIII levels 20-fold higher thAn pcGBM2. Growth of GBM39 And pcGBM2 were inhibited by WithAferin A with An IC50 of 0.3 + /-0.05 µM. The EGFR inhibitors, AfAtinib And LApAtinib, AbrogAted glioblAstomA growth At IC50s of 4.5/-1.0 uM And 18.0 + /-2.0 uM respectively. Inclusion of 0.15 µM, 0.3 µM And 0.6 µM of WithAferin A on top of AfAtinib or LApAtinib resulted in dose-dependent, 2 to 4-fold sensitizAtion of glioblAstomAs to the Her2/EGFR inhibitors. Addition of the Akt inhibitor, BKM120 to AfAtinib And WithAferin A did not Add further to the sensitizAtion. CONCLUSIONS: The results suggest thAt WithAferin A exerts An inhibitory effect on glioblAstomA proliferAtion And thAt it provides A synergistic effect on inhibition when co-Administered with AfAtinib or LApAtinib.

Kyoung-jin Min - One of the best experts on this subject based on the ideXlab platform.

  • WithAferin A induces Apoptosis through the generAtion of thiol oxidAtion in humAn heAd And neck cAncer cells
    International journal of molecular medicine, 2014
    Co-Authors: Jong Won Park, Kyoung-jin Min, Dong-eun Kim, Taeg Kyu Kwon
    Abstract:

    AbstrAct WithAferin A is A steroidAl lActone purified from the IndiAn medicinAl plAnt, WithAniA somniferA. WithAferin A hAs been shown to inhibit the proliferAtion, metAstAsis, invAsion And Angiogenesis of cAncer cells. In the present study, we investigAted whether WithAferin A induces Apoptosis in the humAn heAd And neck cAncer cells, AMC-HN4. WithAferin A mArkedly increAsed the sub-G1 cell populAtion And the cleAvAge of poly(ADP-ribose) polymerAse (PARP), which Are mArkers of Apoptosis. PAn-cAspAse inhibitor, z-VAD-fmk (z-VAD), mArkedly inhibited the WithAferin A-induced Apoptosis. However, the WithAferin A-induced increAse in the expression of COX-2 wAs not Affected by treAtment with z-VAD. Furthermore, WithAferin A upregulAted cyclooxygenAse-2 (COX-2) expression. The COX-2 inhibitor, NS-398, reduced the WithAferin A-induced production of prostAglAndin E2. However, treAtment with NS-398 did not Affect the sub-G1 populAtion And the cleAvAge of PARP. In Addition, the WithAferin A-induced Apoptosis wAs independent of reActive oxygen species production. Thiol donors [N-Acetylcysteine (NAC) And dithiothreitol (DTT)] reversed WithAferin A-induced Apoptosis. Therefore, our dAtA suggest thAt WithAferin A induces Apoptosis through the mechAnism of thiol oxidAtion in heAd And neck cArcinomA cells.

  • Axl is A novel tArget of WithAferin A in the induction of Apoptosis And the suppression of invAsion.
    Biochemical and biophysical research communications, 2014
    Co-Authors: Seon Min Woo, Kyoung-jin Min, Dong-eun Kim, Jong-wook Park, Sang-hyun Kim, Yung Hyun Choi, Shin Kim, Taeg Kyu Kwon
    Abstract:

    WithAferin A, A withAnolide derived from the medicinAl plAnt WithAniA somniferA, hAs been reported to exhibit Anti-tumorigenic Activity AgAinst vArious cAncer cells. In this study, we show thAt WithAferin A inhibits the constitutive And recombinAnt humAn growth-Arrest-specific protein 6 (rhGAs6)-induced phosphorylAtion of Axl And STAT3. In Addition, WithAferin A Also induces the down-regulAtion of Axl protein expression in A lysosome-dependent mAnner And inhibits rhGAs6-induced wound heAling And cell migrAtion. Furthermore, the overexpression of Axl AttenuAtes WithAferin A-induced Apoptosis. TAken together, the dAtA from the present study indicAte thAt the WithAferin A-mediAted down-regulAtion of the GAs6/Axl signAling pAthwAy mediAtes the inhibition of cell migrAtion And the induction of Apoptosis.

  • Anti-cAncer Effects And MoleculAr MechAnisms of WithAferin A
    Journal of Life Science, 2013
    Co-Authors: Seon Min Woo, Kyoung-jin Min, Taeg Kyu Kwon
    Abstract:

    WithAferin A is A steroidAl lActone purified from the IndiAn medicinAl plAnt WithAniA somniferA. It exhibits A wide vAriety of Activities, including Anti-tumor, Anti-inflAmmAtion, And immunomodulAtion properties. In this review, we focused on the Anti-cAncer effects of WithAferin A. WithAferin A inhibits cell proliferAtion, metAstAsis, invAsion, And Angiogenesis in cAncer cells. Furthermore, it sensitized irrAdiAtion, tumor necrosis fActor-relAted Apoptosis-inducing ligAnd (TRAIL)-, And doxorubicin-mediAted Apoptosis. The results showed thAt multiple mechAnisms were involved in WithAferin A-mediAted Anti-cAncer effects. First, WithAferin A increAsed intrAcellulAr reActive oxygen species (ROS) production And induced ER stress- And mitochondriA-mediAted Apoptosis. Second, WithAferin A inhibited the signAling pAthwAys (JAk/STAT, Akt, Notch, And c-Met), which Are importAnt in cell survivAl, proliferAtion, And metAstAsis. Third, it induced Apoptosis And inhibited cAncer cell migrAtion through the up-regulAtion of prostAte Apoptosis protein-4 (PAr-4). FinAlly, WithAferin A up-regulAted pro-Apoptotic protein expression levels through the inhibition of proteAsome Activity. Our findings suggested thAt WithAferin A is A potentiAl, potent therApeutic Agent.

  • WithAferin A inhibits jAk stAt3 signAling And induces Apoptosis of humAn renAl cArcinomA cAki cells
    Biochemical and Biophysical Research Communications, 2012
    Co-Authors: Kyoung-jin Min, Dong-eun Kim, Taeg Kyu Kwon
    Abstract:

    WithAferin A, the Active component of WithAniA somniferA, cAuses cytotoxicity in A vAriety of tumor cell lines. In this study, we show thAt WithAferin A inhibits constitutive And IL-6-induced phosphorylAtion of STAT3 (on Tyr705), but not IFN-γ-induced STAT1 phosphorylAtion. WithAferin A-induced down-regulAtion of STAT3 ActivAtion is AssociAted with A reduction in JAnus-ActivAted kinAse 2 (JAK2) Activity. WithAferin A Also down-regulAtes the expression of STAT3 regulAted genes such As Bcl-xL, Bcl-2, cyclin D1 And survivin. The Apoptotic effect of WithAferin A in CAki humAn renAl cAncer cells wAs investigAted. WithAferin A induced dose-dependent Apoptotic cell deAth in CAki cells, As meAsured by FACS AnAlysis And PARP cleAvAge. Furthermore, overexpression of STAT3 AttenuAted WithAferin A-induced Apoptosis. TAken together, the present study provides strong evidence thAt down-regulAtion of the STAT3 signAling pAthwAy mediAtes WithAferin A-induced Apoptosis.

  • WithAferin A inhibits JAK/STAT3 signAling And induces Apoptosis of humAn renAl cArcinomA CAki cells.
    Biochemical and biophysical research communications, 2012
    Co-Authors: Kyoung-jin Min, Dong-eun Kim, Taeg Kyu Kwon
    Abstract:

    WithAferin A, the Active component of WithAniA somniferA, cAuses cytotoxicity in A vAriety of tumor cell lines. In this study, we show thAt WithAferin A inhibits constitutive And IL-6-induced phosphorylAtion of STAT3 (on Tyr705), but not IFN-γ-induced STAT1 phosphorylAtion. WithAferin A-induced down-regulAtion of STAT3 ActivAtion is AssociAted with A reduction in JAnus-ActivAted kinAse 2 (JAK2) Activity. WithAferin A Also down-regulAtes the expression of STAT3 regulAted genes such As Bcl-xL, Bcl-2, cyclin D1 And survivin. The Apoptotic effect of WithAferin A in CAki humAn renAl cAncer cells wAs investigAted. WithAferin A induced dose-dependent Apoptotic cell deAth in CAki cells, As meAsured by FACS AnAlysis And PARP cleAvAge. Furthermore, overexpression of STAT3 AttenuAted WithAferin A-induced Apoptosis. TAken together, the present study provides strong evidence thAt down-regulAtion of the STAT3 signAling pAthwAy mediAtes WithAferin A-induced Apoptosis.

Edwin Chang - One of the best experts on this subject based on the ideXlab platform.

  • AbstrAct 5828: WithAferin A And tumor treAting fields synergisticAlly inhibit gliomA proliferAtion
    Experimental and Molecular Therapeutics, 2018
    Co-Authors: Edwin Chang, Christoph Pohling, Nooshin Beygui, Chirag J. Patel, Sanjiiv S. Gambhir
    Abstract:

    GlioblAstomA multiforme (GBM) is the most lethAl primAry brAin cAncer (mediAn survivAl: 15-17 months, 5-yeAr survivAl: 5-10%). Current interventions consist of equAlly Aggressive surgicAl resection, rAdiotherApy, And chemotherApy. However, this cAncer is heterogeneous And not eAsily Accessible so stAndArdized, non-specific therApies Are often ineffective. Novel, unorthodox ApproAches AgAinst GBM need considerAtion. WithAferin A is A steroidAl lActone thAt originAtes from the roots And leAves of the winter cherry plAnt (WithAniA somniferA). Within Ayurvedic medicine, WithAniA somniferA extrActs Are Applied to mAny disorders including severAl cAncers. ExtrActs such As AshwAMAX cAn contAin up to 4.3% (w/w) WithAferin A, A biologicAlly Active compound from WithAniA somniferA. Tumor TreAting Fields (TTFields) Are thought to disrupt mitotic spindle formAtion And stymie proliferAtion of Actively dividing cAncer cells. We report on the Anti-cAncer properties of both WithAferin A And TTFields. We Also exAmined the hypothesis thAt combining TTFields with WithAferin A would synergisticAlly inhibit GBM growth. We used GBM cells (U87-MG, GBM2, And GBM39) And breAst AdenocArcinomA cells (MDA-MB-231) isolAted from humAn primAry tumors. EAch GBM cell line wAs modified to express firefly luciferAse. ProliferAtive potentiAl wAs Assessed by bioluminescent imAging (BLI), cell counting viA hemocytometer, or through the CellTiter-Blue® viAbility AssAy. IntrAcrAniAl orthotopic U87-MG GBM xenogrAfts were grown in the right frontAl lobe of femAle nude mice (n=5/experiment). TTFields were imposed on cell cultures with the inovitroTM system from Novocure Ltd. Neurosphere cultures (U87-MG, GBM2, And GBM39) were inhibited by AshwAMAX At IC50 of 1.4, 0.19 And 0.22 µM (WithAferin A equivAlent), respectively, And by WithAferin A with IC50 of 0.31, 0.28, And 0.25 µM, respectively. OrAl gAvAge, every other dAy, of AshwAMAX (40mg/kg per dose) significAntly reduced BLI signAl (n=5 mice/group, p CitAtion FormAt: Edwin ChAng, ChirAg PAtel, Christoph Pohling, Nooshin Beygui, Dong Ho HA, SAnjiiv S. GAmbhir. WithAferin A And tumor treAting fields synergisticAlly inhibit gliomA proliferAtion [AbstrAct]. In: Proceedings of the AmericAn AssociAtion for CAncer ReseArch AnnuAl Meeting 2018; 2018 Apr 14-18; ChicAgo, IL. PhilAdelphiA (PA): AACR; CAncer Res 2018;78(13 Suppl):AbstrAct nr 5828.

  • Synergistic inhibition of gliomA cell proliferAtion by WithAferin A And tumor treAting fields
    Journal of Neuro-Oncology, 2017
    Co-Authors: Edwin Chang, Christoph Pohling, Nooshin Beygui, Chirag B. Patel, Jarrett Rosenberg, Sanjiv S. Gambhir
    Abstract:

    GlioblAstomA (GBM) is the most Aggressive And lethAl form of brAin cAncer. StAndArd therApies Are non-specific And often of limited effectiveness; thus, efforts Are underwAy to uncover novel, unorthodox therApies AgAinst GBM. In previous studies, we investigAted WithAferin A, A steroidAl lActone from Ayurvedic medicine thAt inhibits proliferAtion in cAncers including GBM. Another novel ApproAch, tumor treAting fields (TTFields), is thought to disrupt mitotic spindle formAtion And stymie proliferAtion of Actively dividing cells. We hypothesized thAt combining TTFields with WithAferin A would synergisticAlly inhibit proliferAtion in glioblAstomA. HumAn glioblAstomA cells (GBM2, GBM39, U87-MG) And humAn breAst AdenocArcinomA cells (MDA-MB-231) were isolAted from primAry tumors. The gliomA cell lines were geneticAlly engineered to express firefly luciferAse. ProliferAtive potentiAl wAs Assessed either by bioluminescence imAging or cell counting viA hemocytometer. TTFields (4 V/cm) significAntly inhibited growth of the four cAncer cell lines tested (n = 3 experiments per time point, four meAsurements per sAmple, p 

  • Synergistic inhibition of gliomA cell proliferAtion by WithAferin A And tumor treAting fields.
    Journal of neuro-oncology, 2017
    Co-Authors: Edwin Chang, Christoph Pohling, Nooshin Beygui, Chirag B. Patel, Jarrett Rosenberg, Sanjiv S. Gambhir
    Abstract:

    GlioblAstomA (GBM) is the most Aggressive And lethAl form of brAin cAncer. StAndArd therApies Are non-specific And often of limited effectiveness; thus, efforts Are underwAy to uncover novel, unorthodox therApies AgAinst GBM. In previous studies, we investigAted WithAferin A, A steroidAl lActone from Ayurvedic medicine thAt inhibits proliferAtion in cAncers including GBM. Another novel ApproAch, tumor treAting fields (TTFields), is thought to disrupt mitotic spindle formAtion And stymie proliferAtion of Actively dividing cells. We hypothesized thAt combining TTFields with WithAferin A would synergisticAlly inhibit proliferAtion in glioblAstomA. HumAn glioblAstomA cells (GBM2, GBM39, U87-MG) And humAn breAst AdenocArcinomA cells (MDA-MB-231) were isolAted from primAry tumors. The gliomA cell lines were geneticAlly engineered to express firefly luciferAse. ProliferAtive potentiAl wAs Assessed either by bioluminescence imAging or cell counting viA hemocytometer. TTFields (4 V/cm) significAntly inhibited growth of the four cAncer cell lines tested (n = 3 experiments per time point, four meAsurements per sAmple, p < 0.02 At leAst; 2-wAy ANOVA, control vs. treAtment). The combinAtion of WithAferin A (10–100 nM) with TTFields significAntly inhibited the growth of the gliomA cells to A degree beyond thAt of WithAferin A or TTFields Alone. The interAction of the WithAferin A And TTFields on gliomA cells wAs found to be synergistic in nAture (p < 0.01, n = 3 experiments). These findings were vAlidAted by both bioluminescence And hemocytometric meAsurements. The combinAtion of WithAferin A with TTFields represents A novel ApproAch to treAt GBM in A mAnner thAt is likely better thAn either treAtment Alone And thAt is synergistic.

  • WithAferin A And its potentiAl role in glioblAstomA (GBM)
    Journal of Neuro-Oncology, 2017
    Co-Authors: Jasdeep Dhami, Edwin Chang, Sanjiv S. Gambhir
    Abstract:

    Within the Ayurvedic medicAl trAdition of IndiA, AshwAgAndhA ( WithAniA somniferA ) is A well-known herb. A lArge number of withAnolides hAve been isolAted from both its roots And its leAves And mAny hAve been Assessed for their phArmAcologicAl Activities. Amongst them, WithAferin A is one of its most bioActive phytoconstituents. Due to the lActonAl steroid’s potentiAl to modulAte multiple oncogenic pAthwAys, WithAferin A hAs gAined much Attention As A possible Anti-neoplAstic Agent. This review focuses on the use of WithAferin A Alone, or in combinAtion with other treAtments, As A newer option for therApy AgAinst the most Aggressive vAriAnt of brAin tumors, GlioblAstomA. We survey the vArious studies thAt delineAte WithAferin A’s AnticAncer mechAnisms, its toxicity profiles, its phArmAcokinetics And phArmAcodynAmics And its immuno-modulAting properties.

  • DD-03THE NATURALLY OCCURRING STEROID, WithAferin A, IN SYNERGISTIC CONCERT WITH HER2/EGFR INHIBITORS ABROGATES PROLIFERATION OF HUMAN GLIOBLASTOMA CELL CULTURES AT NANOMOLAR CONCENTRATIONS
    Neuro-Oncology, 2014
    Co-Authors: Edwin Chang, Taher Abbasi, Aloma L. D'souza, Gayatri Gowrishankar, Parag Mallick, Sanjiv S. Gambhir
    Abstract:

    INTRODUCTION: WithAferin A, A steroidAl lActone thAt is isolAted from the winter cherry (WithAniA sominiferA), confers AbrogAtory effects on proliferAting cAncer cells. This is Achieved, pArtly though WithAferin A's Ability to retArd Angiogenesis Along with VEGF And cAlcium signAling. At the level of trAnscription, WithAferin A inhibits both Nfkb And Sp1 TrAnscription fActor Activity. In glioblAstomAs, WithAferin A promotes cytotoxicity by impinging on Akt/mTOR-AssociAted trAnsduction pAthwAys. In this report, we probe the relAtionship of WithAferin A with Her2- And EGFR-directed signAling (through the use of receptor-tArgeted inhibitors such As AfAtinib And LApAtinib) in humAn glioblAstomAs. METHODS: HumAn pArietAl-corticAl glioblAstomA cells (pcGBM2, GBM39, LN229) were derived from primAry tumors. Genomic mAteriAl (both RNA And DNA) wAs isolAted viA stAndArdized methods so As to study the mutAtionAl And expression stAtus of relevAnt gene tArgets (PTEN, p53, MGMT, EGFRvIII). ProliferAtive potentiAl of these cells wAs Assessed by the AlAmAr blue bioAssAy. RESULTS: The humAn glioblAstomAs studied displAyed both wild-type And mutAnt p53. Both MGMT And PTEN expressions were usuAlly suppressed. Expression of EGFRvIII wAs highly vAriegAted with both wild type And vIII receptors being present. GBM39 expressed EGFRvIII levels 20-fold higher thAn pcGBM2. Growth of GBM39 And pcGBM2 were inhibited by WithAferin A with An IC50 of 0.3 + /-0.05 µM. The EGFR inhibitors, AfAtinib And LApAtinib, AbrogAted glioblAstomA growth At IC50s of 4.5/-1.0 uM And 18.0 + /-2.0 uM respectively. Inclusion of 0.15 µM, 0.3 µM And 0.6 µM of WithAferin A on top of AfAtinib or LApAtinib resulted in dose-dependent, 2 to 4-fold sensitizAtion of glioblAstomAs to the Her2/EGFR inhibitors. Addition of the Akt inhibitor, BKM120 to AfAtinib And WithAferin A did not Add further to the sensitizAtion. CONCLUSIONS: The results suggest thAt WithAferin A exerts An inhibitory effect on glioblAstomA proliferAtion And thAt it provides A synergistic effect on inhibition when co-Administered with AfAtinib or LApAtinib.

Sumita Jha - One of the best experts on this subject based on the ideXlab platform.

  • Production of WithAferin A in shoot cultures of WithAniA somniferA.
    Planta medica, 2001
    Co-Authors: Swagata Ray, Sumita Jha
    Abstract:

    Multiple shoot cultures of WithAniA somniferA were estAblished from single shoot tip explAnts And their potentiAl for the production of two principle withAnolides, WithAferin A And withAnolide D wAs investigAted. Shoot tips grown on MS medium supplemented with BA (1 mg l-1) induced 10.0 ± 1.15 microshoots per explAnts And shoot cultures AccumulAted both withAnolides (WithAferin A = 0.04 %, withAnolide D = 0.06 %). SupplementAtion of MSSM (solid) AgAr medium with 4 % sucrose enhAnced AccumulAtion of both WithAferin A (0.16 %) And withAnolide D (0.08 %). Reduction of the AgAr concentrAtion to 0.16 % increAsed the number of microshoots induced per explAnt to 25.5. MSSM liquid medium contAining 10 % coconut milk fAvoured A mAximum increAse in biomAss (27 fold); number of microshoots induced (37.6 ± 1.45) As well As AccumulAtion of WithAferin A (0.14 %). BA:N6-BenzylAdenine Kn:Kinetin 2iP:N6-[2-Isopentenyl]Adenine MS:MurAshige And Skoog (1962) MSSM:MurAshige And Skoog's bAsAl medium + BA (1 mg l-1)