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Em08red, a dual functional antiproliferative emodin analogue, is a downregulator of ErbB2 expression and inducer of intracellular oxidative stress.

Liang FP, Lien JC, Wu YH, Chen CS, Juang SH - Drug Des Devel Ther (2015)

Bottom Line: Among these analogues, em08red (1,8-dihydroxy-9(10H)-anthracenone) demonstrated potent antiproliferative activity against all three tested ErbB2-overexpressing cell lines, ie, FaDu, HSC3, and OECM1.Antiapoptosis protein (Bcl-xl and Bcl-2) expression levels were also downregulated, and active caspase-3 and caspase-9 was detected in cells after treatment with em08red.Moreover, treatment with em08red stimulated production of cytotoxic reactive oxygen species in treated cells, and this could be partially reversed by pretreatment with N-acetylcysteine.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University Hospital, Taichung, Taiwan.

ABSTRACT
Expression of ErbB2 protein is inversely correlated with the prognosis in cancer patients. Consequently, strategies targeting ErbB2 remain an attractive option in treating several types of malignancies, including oral cancer. In addition, many studies have shown that emodin and emodin derivatives are able to inhibit growth of ErbB2-overexpressing tumor cells. In this study, a series of computer modeling-generated emodin analogues were synthesized and tested for their antiproliferative activity against oral cancer cell lines overexpressing ErbB2. Among these analogues, em08red (1,8-dihydroxy-9(10H)-anthracenone) demonstrated potent antiproliferative activity against all three tested ErbB2-overexpressing cell lines, ie, FaDu, HSC3, and OECM1. Treatment with em08red significantly downregulated activation of ErbB2 as well as the ErbB2 protein expression level in the tested cell lines and induced G2 arrest. Antiapoptosis protein (Bcl-xl and Bcl-2) expression levels were also downregulated, and active caspase-3 and caspase-9 was detected in cells after treatment with em08red. Moreover, treatment with em08red stimulated production of cytotoxic reactive oxygen species in treated cells, and this could be partially reversed by pretreatment with N-acetylcysteine. Overall, we demonstrated inhibition of ErbB2 function and induction of reactive oxygen species in tumor cells by em08red, which prevented proliferation of tumor cells and induced apoptotic cell death.

No MeSH data available.


Related in: MedlinePlus

MG132, a proteasome inhibitor, abolished em08red-mediated ErbB2 protein downregulation.Notes: In the cotreatment group, HSC3 cells were preincubated with MG132 (10 μM) for one hour, and em08red (10 μM) was then added to each treatment group for a further 16 hours of incubation. Cells were harvested at the indicated times and the total cell lysates were subjected to Western blot analysis. Antibodies specific for total ErbB2 and actin were used to detect protein expression after treatment. Actin expression served as the loading control.
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f6-dddt-9-1499: MG132, a proteasome inhibitor, abolished em08red-mediated ErbB2 protein downregulation.Notes: In the cotreatment group, HSC3 cells were preincubated with MG132 (10 μM) for one hour, and em08red (10 μM) was then added to each treatment group for a further 16 hours of incubation. Cells were harvested at the indicated times and the total cell lysates were subjected to Western blot analysis. Antibodies specific for total ErbB2 and actin were used to detect protein expression after treatment. Actin expression served as the loading control.

Mentions: To clarify further whether em08red-induced ErbB2 downregulation may also occur via proteasomal regulation, MG132, a proteasome inhibitor, was used to hinder proteasome activity in the presence of em08red. As shown in Figure 6, treatment with MG132 could restore ErbB2 expression in em08red-treated cells, indicating that em08red-induced ErbB2 downregulation could occur in a proteasome-dependent manner.


Em08red, a dual functional antiproliferative emodin analogue, is a downregulator of ErbB2 expression and inducer of intracellular oxidative stress.

Liang FP, Lien JC, Wu YH, Chen CS, Juang SH - Drug Des Devel Ther (2015)

MG132, a proteasome inhibitor, abolished em08red-mediated ErbB2 protein downregulation.Notes: In the cotreatment group, HSC3 cells were preincubated with MG132 (10 μM) for one hour, and em08red (10 μM) was then added to each treatment group for a further 16 hours of incubation. Cells were harvested at the indicated times and the total cell lysates were subjected to Western blot analysis. Antibodies specific for total ErbB2 and actin were used to detect protein expression after treatment. Actin expression served as the loading control.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4362900&req=5

f6-dddt-9-1499: MG132, a proteasome inhibitor, abolished em08red-mediated ErbB2 protein downregulation.Notes: In the cotreatment group, HSC3 cells were preincubated with MG132 (10 μM) for one hour, and em08red (10 μM) was then added to each treatment group for a further 16 hours of incubation. Cells were harvested at the indicated times and the total cell lysates were subjected to Western blot analysis. Antibodies specific for total ErbB2 and actin were used to detect protein expression after treatment. Actin expression served as the loading control.
Mentions: To clarify further whether em08red-induced ErbB2 downregulation may also occur via proteasomal regulation, MG132, a proteasome inhibitor, was used to hinder proteasome activity in the presence of em08red. As shown in Figure 6, treatment with MG132 could restore ErbB2 expression in em08red-treated cells, indicating that em08red-induced ErbB2 downregulation could occur in a proteasome-dependent manner.

Bottom Line: Among these analogues, em08red (1,8-dihydroxy-9(10H)-anthracenone) demonstrated potent antiproliferative activity against all three tested ErbB2-overexpressing cell lines, ie, FaDu, HSC3, and OECM1.Antiapoptosis protein (Bcl-xl and Bcl-2) expression levels were also downregulated, and active caspase-3 and caspase-9 was detected in cells after treatment with em08red.Moreover, treatment with em08red stimulated production of cytotoxic reactive oxygen species in treated cells, and this could be partially reversed by pretreatment with N-acetylcysteine.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University Hospital, Taichung, Taiwan.

ABSTRACT
Expression of ErbB2 protein is inversely correlated with the prognosis in cancer patients. Consequently, strategies targeting ErbB2 remain an attractive option in treating several types of malignancies, including oral cancer. In addition, many studies have shown that emodin and emodin derivatives are able to inhibit growth of ErbB2-overexpressing tumor cells. In this study, a series of computer modeling-generated emodin analogues were synthesized and tested for their antiproliferative activity against oral cancer cell lines overexpressing ErbB2. Among these analogues, em08red (1,8-dihydroxy-9(10H)-anthracenone) demonstrated potent antiproliferative activity against all three tested ErbB2-overexpressing cell lines, ie, FaDu, HSC3, and OECM1. Treatment with em08red significantly downregulated activation of ErbB2 as well as the ErbB2 protein expression level in the tested cell lines and induced G2 arrest. Antiapoptosis protein (Bcl-xl and Bcl-2) expression levels were also downregulated, and active caspase-3 and caspase-9 was detected in cells after treatment with em08red. Moreover, treatment with em08red stimulated production of cytotoxic reactive oxygen species in treated cells, and this could be partially reversed by pretreatment with N-acetylcysteine. Overall, we demonstrated inhibition of ErbB2 function and induction of reactive oxygen species in tumor cells by em08red, which prevented proliferation of tumor cells and induced apoptotic cell death.

No MeSH data available.


Related in: MedlinePlus