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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

Synthesis of anthraquinone derivatives.Notes: (A) (i) AlCl3/NaCl, 165°C; (ii)10% HCl; (B) (i) SnCl2, HCl, HOAc/reflux.
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f1-dddt-9-1499: Synthesis of anthraquinone derivatives.Notes: (A) (i) AlCl3/NaCl, 165°C; (ii)10% HCl; (B) (i) SnCl2, HCl, HOAc/reflux.

Mentions: Anthraquinones 1–9 was synthesized by reaction of selected phthalic anhydrides with substituted phenols in the presence of AlCl3/NaCl (Figure 1A). Compound 7 and emodin were then treated with SnCl2 in the presence of HCl to generate compounds 10 and 11, respectively (Figure 1B).


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)

Synthesis of anthraquinone derivatives.Notes: (A) (i) AlCl3/NaCl, 165°C; (ii)10% HCl; (B) (i) SnCl2, HCl, HOAc/reflux.
© Copyright Policy
Related In: Results  -  Collection

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

f1-dddt-9-1499: Synthesis of anthraquinone derivatives.Notes: (A) (i) AlCl3/NaCl, 165°C; (ii)10% HCl; (B) (i) SnCl2, HCl, HOAc/reflux.
Mentions: Anthraquinones 1–9 was synthesized by reaction of selected phthalic anhydrides with substituted phenols in the presence of AlCl3/NaCl (Figure 1A). Compound 7 and emodin were then treated with SnCl2 in the presence of HCl to generate compounds 10 and 11, respectively (Figure 1B).

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