A Boronic-Chalcone Derivative Exhibits Potent Anticancer Activity through Inhibition of the Proteasome

Achanta, Geetha; Modzelewska, Aneta; Li, Feng; Khan, Saeed R.; Huang, Peng

doi:10.1124/mol.105.021311

Cited by 121 publications

(97 citation statements)

References 24 publications

(32 reference statements)

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“…In the reported natural proteasome inhibitors, several flavonoids from plants or foods have been discovered in our lab and other labs. In flavones, chrysin, apigenin and luteolin have been reported to inhibit proteasome function (25,26); in flavonols, quercetin, myricetin and kaempferol were reported as proteasome inhibitors (3); other flavonoids were also reported as proteasome inhibitors including chalcones and derivatives (27), catechin and derivatives (28), naringenin in flavonones (25) and genistein in isoflavones (29). It has been reported that there are different biological activities between prenylated and non-prenylated flavonoids (30).…”

Section: Discussionmentioning

confidence: 99%

Sanggenon C decreases tumor cell viability associated with proteasome inhibition

Huang¹

2009

Front Biosci

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Several flavonoids have been reported to be proteasome inhibitors, but whether prenylated flavonoids are able to inhibit proteasome function remains unknown. We report for the first time that Sanggenon C, a natural prenylated flavonoid, inhibits tumor cellular proteasomal activity and cell viability. We found that (1) Sanggenon C inhibited tumor cell viability and induced cell cycle arrest at G0/G1 phase; (2) Sanggenon C inhibited the chymotrypsin-like activity of purified human 20S proteasome and 26S proteasome in H22 cell lysate, and Sanggenon C was able to dosedependently accumulate ubiquitinated proteins and proteasome substrate protein p27; (3) Sanggenon C-induced proteasome inhibition occurred prior to cell death in murine H22 and P388 cell lines; (4) Sanggenon C induced death of human K562 cancer cells and primary cells isolated from leukemic patients. We conclude that Sanggenon C inhibits tumor cell viability via induction of cell cycle arrest and cell death, which is associated with its ability to inhibit the proteasome function and that proteasome inhibition by Sanggenon C at least partially contributes to the observed tumor cell growth-inhibitory activity. Proteasome inhibition has been demonstrated as a novel therapeutic strategy in multiple disease models, including fibrosis (4), inflammation (5), ischemia-reperefusion injury (6), myocardial hypertrophy (7) and cancer (8). Proteasome inhibitor bortezomib (Valcade or PS-341) has been approved by the United States FDA to treat multiple myeloma. Other proteasome inhibitors are now under clinical trials for cancer therapy (8). However, there were some associated toxicity observed in the clinical trials using bortezomib (8). Therefore, there is a need to search for novel proteasome inhibitors with decreased side effect. It is an attractive idea to identify and isolate novel natural proteasome inhibitors from medicinal plants. Many of the reported natural proteasome inhibitors belong to the flavonoid family (3). Among all these reported natural flavonoid proteasome inhibitors, an aromatic ketone structure plays a very important role for binding to the threonine residue at the N terminus (Thr 1) of the proteasome subunits and inhibiting the proteasomal activities (3, 9, 10). KeywordsSeveral flavonoids have been isolated from the stem bark of Morus cathayana (SANGPAIPI), including Sanggenon C. Sanggenon C is a flavanone Diel-Alder adduct compound. Up to now, there are only a few reports on the biological and pharmacological effects of Sanggenon C. It has been reported that Sanggenon C has anti-oxidant and antiinflammation activities (2) and could inhibit TNF-alpha-stimulated cell adhesion and expression of VCAM-1 by suppressing the activation of NF-kappa B. It has also been proposed that Sanggenon C decreases ICAM-1 protein expression at a post-translational level (11). In addition, it was reported that Sanggenon C inhibited protein tyrosine phosphatase 1B (12) and possessed the function to decrease blood pressure. Since Sanggenon C possesses the mo...

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Section: Discussionmentioning

confidence: 99%

Sanggenon C decreases tumor cell viability associated with proteasome inhibition

Huang¹

2009

Front Biosci

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“…The diaryldienone 67 inhibits the activity of the 20S proteasome in vitro with an IC 50 value of approximately 1 μM [97]. Thus the cytotoxicity of 67 towards cancer cells may be via inhibition of the proteasome leading to the accumulation of p53 and ubiquitinated proteins.…”

Section: Modes Of Actionmentioning

confidence: 99%

1,5-Diaryl-3-oxo-1,4-pentadienes: A Case for Antineoplastics with Multiple Targets

Das

Sharma²,

Dimmock³

2009

CMC

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A number of organic molecules which contain the 1,5-diaryl-3-oxo-1,4-pentadienyl group, referred to hereafter as the dienone moiety, have antineoplastic properties. Emphasis is made on the attachment of this structural moiety to several molecular scaffolds, namely piperidines, Nacylpiperidines, cycloalkanes and 3,4-dihydro-1H-napthalenes. Many of these compounds are potent cytotoxins having micromolar and nanomolar IC 50 values towards a wide range of neoplastic and transformed cells. On occasions, greater toxicity towards neoplasms than normal cells has been demonstrated. A number of these compounds have in vivo anticancer properties and in general excellent tolerability in rodents is demonstrated. The way in which a number of physicochemical properties such as redox potentials, torsion angles, atomic charges and logP values govern cytotoxic potencies are presented. The importance of the shapes of different compounds as determined by molecular modeling in contributing to antineoplastic properties is outlined. Arguments are presented in favour of designing antineoplastics which have multiple sites of action in contrast to those bioactive molecules which have only one molecular target. A number of compounds which possess the dienone group have different modes of action some of which are chronicled in this review, such as inducing apoptosis, affecting respiration in mitochondria, inhibiting macro-molecular biosynthesis and both inhibiting and stimulating certain enzymes. Other important properties of these compounds are discussed including their anti-angiogenic, MDR-revertant and antioxidant properties. It is hoped that this eulogy of the importance of the dienone group will encourage researchers to consider incorporating this structural unit into candidate cytotoxins in the future.

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“…In addition, among several newly synthesized chalcone derivatives tested for their anticancer activities is a boronic-chalcone derivative, 3,5-bis-(4-boronic acid-benzylidene)-1-methyl-piperidin-4-one (AM114, 18), that has the most potent inhibitory activity [208]. AM114 treatment leads to p53 and p21 accumulation and apoptosis, but does not significantly disrupt the MDM2-p53 interaction [209].…”

Section: Chalcone Derivativesmentioning

confidence: 99%

Natural Product MDM2 Inhibitors: Anticancer Activity and Mechanisms of Action

Qin

Nag²,

Voruganti³

et al. 2012

CMC

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The mdm2 oncogene has recently been suggested to be a valuable target for cancer therapy and prevention. Overexpression of mdm2 is often seen in various human cancers and correlates with high-grade, late-stage, and more treatment-resistant tumors. The MDM2-p53 auto-regulatory loop has been extensively investigated and is an attractive cancer target, which indeed has been the main focus of anti-MDM2 drug discovery. Much effort has been expended in the development of small molecule MDM2 antagonists targeting the MDM2-p53 interaction, and a few of these have advanced into clinical trials. However, MDM2 exerts its oncogenic activity through both p53-dependent and -independent mechanisms. Recently, there is an increasing interest in identifying natural MDM2 inhibitors; some of them have been shown to decrease MDM2 expression and activity in vitro and in vivo. These identified natural MDM2 inhibitors include a plethora of diverse chemical frameworks, ranging from flavonoids, steroids, and sesquiterpenes to alkaloids. In addition to a brief review of synthetic MDM2 inhibitors, this review focuses on natural product MDM2 inhibitors, summarizing their biological activities in vitro and in vivo and the underlying molecular mechanisms of action, targeting MDM2 itself, regulators of MDM2, and/or the MDM2-p53 interaction. These MDM2 inhibitors can be used alone or in combination with conventional treatments, improving the prospects for cancer therapy and prevention. Their complex and unique molecular architectures may provide a stimulus for developing synthetic analogs in the future.

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A Boronic-Chalcone Derivative Exhibits Potent Anticancer Activity through Inhibition of the Proteasome

Cited by 121 publications

References 24 publications

Sanggenon C decreases tumor cell viability associated with proteasome inhibition

Sanggenon C decreases tumor cell viability associated with proteasome inhibition

1,5-Diaryl-3-oxo-1,4-pentadienes: A Case for Antineoplastics with Multiple Targets

Natural Product MDM2 Inhibitors: Anticancer Activity and Mechanisms of Action

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