The treatment of skin carcinoma, induced by UV B radiation, using 1-oxo-5β, 6β-epoxy-witha-2-enolide, isolated from the roots of Withania somnifera, in a rat model

Mathur, Sheenu; Kaur, Parvinder; Sharma, Meenakshi; Katyal, Anju; Singh, Bharat; Tiwari, Manisha; Chandra, Ramesh

doi:10.1016/j.phymed.2003.05.004

Cited by 31 publications

(18 citation statements)

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“…It has the potential to increase tumor sensitization to radiation and chemotherapy while reducing some of the most common side effects of these conventional therapies [42]. Most recently, WA has been shown to potentiate apoptosis of tumor cells by inhibiting Hsp90 in human pancreatic cancer cells [43], protect against UV-induced skin cancer [44] and enhance neurite regeneration and memory [45,46]. Thus, many studies have been reported depicting the effect of WA on putting a check on human cancers, but the mechanism behind this effect is still eluding the researchers.…”

Section: Introductionmentioning

confidence: 99%

Hsp90/Cdc37 Chaperone/co-chaperone complex, a novel junction anticancer target elucidated by the mode of action of herbal drug Withaferin A

et al. 2011

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BackgroundHSPs (Heat shock proteins) are highly conserved ubiquitous proteins among species which are involved in maintaining appropriate folding and conformation of other proteins and are thus referred to as molecular chaperones. Hsp90 (Heat-shock protein 90 kDa) is one of a group of molecular chaperones responsible for managing protein folding and quality control in cell environment. However it is also involved in the maturation and stabilization of a wide range of oncogenic client proteins which are crucial for oncogenesis and malignant progression. Hsp90 requires a series of co-chaperones to assemble into a super-chaperone complex for its function. These co-chaperones bind and leave the complex at various stages to regulate the chaperoning process. Arresting the chaperone cycle at these stages by targeting different co-chaperone/Hsp90 interactions seems to be quite a viable alternative and is likely to achieve similar consequences as that of Hsp90 direct inhibition with added favors of high specificity and reduced side effect profile. The study conducted here is an attempt to explore the potential of Withania somnifera’s major constituent WA (Withaferin A) in attenuating the Hsp90/Cdc37 chaperone/co-chaperone interactions for enhanced tumor arresting activity and to elucidate the underlying mode of action using computational approaches.ResultsFormation of active Hsp90/Cdc37 complex is one of the essential steps for facilitation of chaperone client interaction, non-assembly of which can lead to prevention of the chaperone-client association resulting in apoptosis of tumor cells. From our flexible docking analysis of WA into active Hsp90/Cdc37 complex in which key interfacing residues of the complex were kept flexible, disruption of the active association complex can be discerned. While docking of WA into segregated Hsp90 leaves the interface residues untouched. Thus the molecular docking analysis of WA into Hsp90 and active Hsp90/Cdc37 complex conducted in this study provides significant evidence in support of the proposed mechanism of chaperone assembly suppression by inhibition or disruption of active Hsp90/Cdc37 complex formation being accounted by non-assembly of the catalytically active Hsp90/Cdc37 complex. Results from the molecular dynamics simulations in water show that the trajectories of the protein complexed with ligand WA are stable over a considerably long time period of 4 ns, with the energies of the complex being lowered in comparison to the un-docked association complex, suggesting the thermodynamic stability of WA complexed Hsp90/Cdc37.ConclusionsThe molecular chaperone Hsp90 has been a promising target for cancer therapy. Cancer is a disease marked by genetic instability. Thus specific inhibition of individual proteins or signalling pathways holds a great potential for subversion of this genetic plasticity of cancers. This study is a step forward in this direction. Our computational analysis provided a rationalization to the ability of naturally occurring WA to alter the chaperone signalling ...

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Section: Introductionmentioning

confidence: 99%

Hsp90/Cdc37 Chaperone/co-chaperone complex, a novel junction anticancer target elucidated by the mode of action of herbal drug Withaferin A

et al. 2011

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“…Long-term effects of W. somnifera on adjuvant-induced arthritis in rats have also been reported [18]. Most recently, these were shown to potentiate apoptosis of tumor cells by suppression of NF-κB activation [19-21], protect against UV-induced skin cancer [22] and enhance neurite regeneration and memory [23,24]. Thus, many studies have been reported depicting the effect of WA on suppression of NF-κB activation, but the mechanism behind this effect is still eluding the researchers.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the NEMO/IKKβ association complex formation, a novel mechanism associated with the NF-κB activation suppression by Withania somnifera’s key metabolite withaferin A

et al. 2010

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BackgroundNuclear Factor kappa B (NF-κB) is a transcription factor involved in the regulation of cell signaling responses and is a key regulator of cellular processes involved in the immune response, differentiation, cell proliferation, and apoptosis. The constitutive activation of NF-κB contributes to multiple cellular outcomes and pathophysiological conditions such as rheumatoid arthritis, asthma, inflammatory bowel disease, AIDS and cancer. Thus there lies a huge therapeutic potential beneath inhibition of NF-κB signalling pathway for reducing these chronic ailments. Withania somnifera, a reputed herb in ayurvedic medicine, comprises a large number of steroidal lactones known as withanolides which show plethora of pharmacological activities like anti- inflammatory, antitumor, antibacterial, antioxidant, anticonvulsive, and immunosuppressive. Though a few studies have been reported depicting the effect of WA (withaferin A) on suppression of NF-κB activation, the mechanism behind this is still eluding the researchers. The study conducted here is an attempt to explore NF-κB signalling pathway modulating capability of Withania somnifera’s major constituent WA and to elucidate its possible mode of action using molecular docking and molecular dynamics simulations studies.ResultsFormation of active IKK (IκB kinase) complex comprising NEMO (NF-κB Essential Modulator) and IKKβ subunits is one of the essential steps for NF-κB signalling pathway, non-assembly of which can lead to prevention of the above mentioned vulnerable disorders. As observed from our semi-flexible docking analysis, WA forms strong intermolecular interactions with the NEMO chains thus building steric as well as thermodynamic barriers to the incoming IKKβ subunits, which in turn pave way to naive complex formation capability of NEMO with IKKβ. Docking of WA into active NEMO/IKKβ complex using flexible docking in which key residues of the complex were kept flexible also suggest the disruption of the active complex. Thus the molecular docking analysis of WA into NEMO and active NEMO/IKKβ complex conducted in this study provides significant evidence in support of the proposed mechanism of NF-κB activation suppression by inhibition or disruption of active NEMO/IKKβ complex formation being accounted by non-assembly of the catalytically active NEMO/IKKβ complex. Results from the molecular dynamics simulations in water show that the trajectories of the native protein and the protein complexed with WA are stable over a considerably long time period of 2.6 ns.ConclusionsNF-κB is one of the most attractive topics in current biological, biochemical, and pharmacological research, and in the recent years the number of studies focusing on its inhibition/regulation has increased manifolds. Small ligands (both natural and synthetic) are gaining particular attention in this context. Our computational analysis provided a rationalization of the ability of naturally occurring withaferin A to alter the NF-κB signalling pathway along with its proposed mode of inhibition of...

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“…The compound active for anti-cancerous property in this plant is withaferin A ((4β,5β,6β,22R)-4,27-dihydroxy-5,6:22,26-diepoxyergosta-2,24-diene-1,26-dione) [11], [12], [13], [14]. Its property to inhibit angiogenesis and furthermore to act as adjunct to chemotherapy treatment by protecting the gradual deterioration in white blood cells called neutrophils without any contrast, enlighten its performance as key step in fighting cancer [15], [16], [17], [18]. Animal toxicity studies designate this astonishing plant safe and well tolerated [19].…”

Section: Ashwagandhamentioning

confidence: 99%

Nature curing cancer – review on structural modification studies with natural active compounds having anti-tumor efficiency

Kaur

Verma

2015

Biotechnology Reports

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Cancer treatment has raised many drugs and radiation therapies whose side-effects are visible. Ongoing research throughout the world for effective treatment mainly concentrates on methods either in the form of drugs or therapies against this lethal disease. However returning to ayurvedic roots enlightens the fact that nature has many efficient components with anti-cancerous, anti-proliferating and anti-angiogenesis effects. Evidences confirm the participation of plants extracts in synthesizing many medicines against already existing and even emerging diseases. Structure activity relationship (SAR) studies and structural modifications are helping in observing the basis of compounds characteristics to exhibit inhibitor’s nature against carcinogenic agents by modifying parent compounds for creating an improved and potent compound. Many components are under clinical trials but most of them still need attention. In this review an attempt has been made to focus on the natural components gifted by nature and even included in our diet with their structures and sources that could be supportive in designing drug either by computational methods or by experimental methods.

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The treatment of skin carcinoma, induced by UV B radiation, using 1-oxo-5β, 6β-epoxy-witha-2-enolide, isolated from the roots of Withania somnifera, in a rat model

Cited by 31 publications

References 13 publications

Hsp90/Cdc37 Chaperone/co-chaperone complex, a novel junction anticancer target elucidated by the mode of action of herbal drug Withaferin A

Hsp90/Cdc37 Chaperone/co-chaperone complex, a novel junction anticancer target elucidated by the mode of action of herbal drug Withaferin A

Inhibition of the NEMO/IKKβ association complex formation, a novel mechanism associated with the NF-κB activation suppression by Withania somnifera’s key metabolite withaferin A

Nature curing cancer – review on structural modification studies with natural active compounds having anti-tumor efficiency

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