Kava, a Tonic for Relieving the Irrational Development of Natural Preventive Agents

Agarwal, Rajesh; Deep, Gagan

doi:10.1158/1940-6207.capr-08-0172

Cited by 8 publications

(7 citation statements)

References 27 publications

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“…Interestingly, epidemiological studies illustrated that populations that consume the kava beverage have low incidences of cancer, compared to non-kava-drinking populations (Steiner 2000;Agarwal and Deep 2008). Extracts of kava are classified into two main classes of compounds kavalactone and chalcone, and flavokawain B belongs to chalcone compounds (Warmka et al 2012;Zhao et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Discovery of 2′,4′-dimethoxychalcone as a Hsp90 inhibitor and its effect on iressa-resistant non-small cell lung cancer (NSCLC)

Seo

2015

Arch. Pharm. Res.

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Heat shock protein 90 (Hsp90) is a ATP dependent molecular chaperone and has emerged as an attractive therapeutic target in the war on cancer due to its role in regulating maturation and stabilization of numerous oncogenic proteins. In this study, we discovered that 2',4'-dimethoxychalcone (1b) disrupted Hsp90 chaperoning function and inhibited the growth of iressa-resistant non-small cell lung cancer (NSCLC, H1975). The result suggested that 2',4'-dimethoxychalcone (1b) could serve as a potential therapeutic lead to circumvent the drug resistance acquired by EGFR mutation and Met amplification.

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Section: Introductionmentioning

confidence: 99%

Discovery of 2′,4′-dimethoxychalcone as a Hsp90 inhibitor and its effect on iressa-resistant non-small cell lung cancer (NSCLC)

Seo

2015

Arch. Pharm. Res.

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“…Additionally, deguelin has been shown to induce a Parkinson’s disease-like syndrome in rats when administered in high doses, which is also potentially related to activity at complex I (Caboni et al, 2004). These undesired side effects related to complex I inhibition have hindered deguelin’s use as a chemotherapeutic agent (Agarwal and Deep, 2008; Fang and Casida, 1998). …”

Section: Introductionmentioning

confidence: 99%

Amelioration of an undesired action of deguelin

Vrana

Boggs

Currie

et al. 2013

Toxicon

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The pharmaceutical world has greatly benefited from the well-characterized structure-function relationships of toxins with endogenous biomolecules, such as ion-channels, receptors, and signaling molecules. Thus, therapeutics derived from toxins have been aggressively pursued. However, the multifunctional role of various toxins may lead to undesirable off-target effects, hindering their use as therapeutic agents. In this paper, we suggest that previously unsuccessful toxins (due to off-target effects) may be revisited with mixtures by utilizing the pharmacodynamic response to the potential primary therapeutic as a starting point for finding new targets to ameliorate the unintended responses. In this proof of principle study, the pharmacodynamic response of HepG2 cells to a potential primary therapeutic (deguelin, a plant-derived chemopreventive agent) was monitored, and a possible secondary target (p38MAPK) was identified. As a single agent, deguelin decreased cellular viability at higher doses (> 10 μM), but inhibited oxygen consumption over a wide dosing range (1.0 – 100 μM). Our results demonstrate that inhibition of oxygen consumption is related to an increase in p38MAPK phosphorylation, and may only be an undesired side effect of deguelin (i.e., one that does not contribute to the decrease in HepG2 viability). We further show that deguelin’s negative effect on oxygen consumption can be diminished while maintaining efficacy when used as a therapeutic mixture with the judiciously selected secondary inhibitor (SB202190, p38MAPK inhibitor). These preliminary findings suggest that an endogenous response-directed mixtures approach, which uses a pharmacodynamic response to a primary therapeutic to determine a secondary target, allows previously unsuccessful toxins to be revisited as therapeutic mixtures.

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“…In particular, chalcones are a major class of compounds found in a beverage made from the roots of the kava plant ( Piper methysticum ); intriguingly, epidemiological studies suggest that populations in the South Pacific Islands that consume the kava beverage, including smokers, have relatively low incidences of cancer [3]. Kava also reduced lung tumor formation in A/J mice treated with the tobacco smoke carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene [4].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of mitogen activated protein kinases increases the sensitivity of A549 lung cancer cells to the cytotoxicity induced by a kava chalcone analog

Warmka

Solberg

Zeliadt

et al. 2012

Biochemical and Biophysical Research Communications

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We are interested in investigating the biological activity of chalcones, a major class of compounds found in the beverage kava, in order to develop potent and selective chemopreventive candidates. Consumption of kava in the South Pacific Islands is inversely correlated with cancer incidence, even among smokers. Accordingly, chalcones have anti-cancer activities in animal and cell culture models. To investigate signaling pathways that affect chalcone action we studied a potent analog, (E)-3-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (chalcone-24). Chalcone-24 was selected from a series of chalcone analogs that were synthesized based on the structures derived from flavokawain compounds found in kava, and screened in A549 lung cancer cells for induction of cytotoxicity and inhibition of NF-κB, a transcription factor associated with cell survival. Incubation of A549 cells with chalcone-24 resulted in a dose-dependent inhibition of cell viability, inhibition of NF-κB, activation of caspases, and activation of extracellular signal regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK); ERK1/2 and JNK are mitogen activated protein kinases that play central roles in regulating cell fate. Pharmacological inhibitors of ERK1/2 or JNK increased the sensitivity of A549 cells to chalcone-24-induced cytotoxicity, without affecting NF-κB or caspase activity. These results will help refine the synthesis of chalcone analogs to maximize the combination of actions required to prevent and treat cancer.

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Kava, a Tonic for Relieving the Irrational Development of Natural Preventive Agents

Cited by 8 publications

References 27 publications

Discovery of 2′,4′-dimethoxychalcone as a Hsp90 inhibitor and its effect on iressa-resistant non-small cell lung cancer (NSCLC)

Discovery of 2′,4′-dimethoxychalcone as a Hsp90 inhibitor and its effect on iressa-resistant non-small cell lung cancer (NSCLC)

Amelioration of an undesired action of deguelin

Inhibition of mitogen activated protein kinases increases the sensitivity of A549 lung cancer cells to the cytotoxicity induced by a kava chalcone analog

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