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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: 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.

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

Treatment with em08red downregulates phosphorylation and expression of ErbB2.Notes: Treated FaDu (A) and HSC3 (B) cells were harvested at the indicated times and total cell lysates were subjected to Western blot analysis. Antibodies specifically against total ErbB2 and phosphorylation sites of ErbB2 at tyrosine 1221/1222 or tyrosine 1248 were applied to detect protein expression after treatment. Actin expression served as the loading control.
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f2-dddt-9-1499: Treatment with em08red downregulates phosphorylation and expression of ErbB2.Notes: Treated FaDu (A) and HSC3 (B) cells were harvested at the indicated times and total cell lysates were subjected to Western blot analysis. Antibodies specifically against total ErbB2 and phosphorylation sites of ErbB2 at tyrosine 1221/1222 or tyrosine 1248 were applied to detect protein expression after treatment. Actin expression served as the loading control.

Mentions: Overactivation of the ErbB2 signaling pathway has a critical role in the development of oral cancer and survival. Previous reports indicate that emodin may serve as an adjuvant treatment for ErbB2-overexpressing cancer cells.9,19 Therefore, all compounds with antiproliferative activity were tested for their influence on ErbB2 activity. Phosphor-ErbB2 protein levels and total-ErbB2 expression were determined by Western blot analysis (data not shown). Among the analogues synthesized, only em08red showed significant inhibition of ErbB2 activity. As shown in Figure 2A and B, after 36 hours of treatment, ErbB2 expression levels were dramatically reduced and the level of ErbB2 phosphorylation at tyrosine 1221/1222 and 1248, which both account for activation of ErbB2 receptors,20 was below the level of detection in FaDu and HSC3 cells. The downregulatory effect of em08red on ErbB2 protein was also observed in the treated OECM1 cells (data not shown). Our results demonstrated effective inhibition of ErbB2 activity by em08red, warranting further investigation.


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)

Treatment with em08red downregulates phosphorylation and expression of ErbB2.Notes: Treated FaDu (A) and HSC3 (B) cells were harvested at the indicated times and total cell lysates were subjected to Western blot analysis. Antibodies specifically against total ErbB2 and phosphorylation sites of ErbB2 at tyrosine 1221/1222 or tyrosine 1248 were applied 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

f2-dddt-9-1499: Treatment with em08red downregulates phosphorylation and expression of ErbB2.Notes: Treated FaDu (A) and HSC3 (B) cells were harvested at the indicated times and total cell lysates were subjected to Western blot analysis. Antibodies specifically against total ErbB2 and phosphorylation sites of ErbB2 at tyrosine 1221/1222 or tyrosine 1248 were applied to detect protein expression after treatment. Actin expression served as the loading control.
Mentions: Overactivation of the ErbB2 signaling pathway has a critical role in the development of oral cancer and survival. Previous reports indicate that emodin may serve as an adjuvant treatment for ErbB2-overexpressing cancer cells.9,19 Therefore, all compounds with antiproliferative activity were tested for their influence on ErbB2 activity. Phosphor-ErbB2 protein levels and total-ErbB2 expression were determined by Western blot analysis (data not shown). Among the analogues synthesized, only em08red showed significant inhibition of ErbB2 activity. As shown in Figure 2A and B, after 36 hours of treatment, ErbB2 expression levels were dramatically reduced and the level of ErbB2 phosphorylation at tyrosine 1221/1222 and 1248, which both account for activation of ErbB2 receptors,20 was below the level of detection in FaDu and HSC3 cells. The downregulatory effect of em08red on ErbB2 protein was also observed in the treated OECM1 cells (data not shown). Our results demonstrated effective inhibition of ErbB2 activity by em08red, warranting further investigation.

Bottom Line: 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.

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