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Emodin azide methyl anthraquinone derivative
induces proteasomal degradation of Her2/neu in
Her2/neu-overexpressing cancer cells
Li-sheng Zheng, Yan-yan Yan, Li-wu Fu Cancer
Center, Sun Yat-sen University 2010. 5
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Background

• ? Overexpression of HER2/neu is common in
  multiple malignancies,
• including breast, ovarian, lung and prostate
  cancer, etc.
• ? Clinical studies have demonstrated that
  elevated HER2/neu
• expression correlates with poor prognosis in
  multiple malignancies
• ? During the last decade, HER2/neu has been
  targeted in order to
• develop novel anticancer drugs
• Trastuzumab (Herceptin)
• Lapatinib (Tykerb)
• ------ efficacy and long-term use in patients
  are quite limited due to
• resistance to these inhibitors or
  severe side effects

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Background
Emodin

• ? Anthraquinone derivative
• ? Active ingredient of various
• Chinese herbs including rhubarb,
• Polygonum cuspidatum
• ? Anti-bacterial, anti-inflammatory,
• anti-tumor

Structure of emodin
? Block auto- or trans-phosphorylation of
HER2/neu ? Increases the susceptibility of
HER2/neu overexpressing cancer cells to standard
cytotoxic therapeutic agents
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Background
? anticancer activity not obvious ? side effects
such as cardiac toxicity ? We and Professor
Lian-quan Gu group (School of Chemistry and
Chemical Engineering, Sun Yat-sen University)
modified structure of emodin and synthesized a
series of emodin anthraquinone derivatives
Structure of emodin AMAD
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AMAD shows potent anticancer effect on breast
cancer and lung adenocarcinoma cell lines
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AMAD inhibits the growth of human non-small cell
lung carcinoma H460 cell xenografts in nude mice
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AMAD down-regulates Her2/neu protein expression
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AMAD inhibits Her2/neu downstream signaling
pathways
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AMAD increses Her2/neu protein instability
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AMAD induces polyubiquitination of HER2/neu
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AMAD depletes HER2/neu by proteasomal degradation
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AMAD inhibited Her2/neu binding to Hsp90
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Knockdown Her2/neu by siRNA induces growth
inhibition
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Combination of AMAD and siRNA against Her2
synergistically induces apoptosis
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Combination of AMAD and siRNA against Her2
further promotes HER2/neu degradation and
inhibites downstream signaling pathways
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Discussion
Apigenin and Geldanamycin can induce HER2 protein
degradation by ubiquitin-proteasome pathway
?Downregulation of HER2 by AMAD is dependent of
Her2 protein stability but not mRNA
level ?Dissociation of Her2/Hsp90 heterocomplex
by AMAD may be correlated with promoted
proteasomal degradation of Her2 protein ?HER2
specific AMAD does not decrease the expression
of Her1 protein
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Conclusions
? AMAD exerts potent cytotoxic effects on
MDA-MB-453 and Calu-3 cells. ? AMAD inhibits
the proliferation via MAPK and PI(3)K/Akt pathway
signaling. ?AMAD targets HER2/neu to
ubiquitinylation-dependent proteasomal
degradation. ?Combined AMAD with siRNA against
HER2/neu further promotes Her2/neu degradation,
induces apoptosis and inhibits the proliferation.
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