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Steroid Receptor Coactivator-3 (SRC-3/AIB1) as a Novel Therapeutic Target in Triple Negative Breast Cancer and Its Inhibition with a Phospho-Bufalin Prodrug.

Song X, Zhang C, Zhao M, Chen H, Liu X, Chen J, Lonard DM, Qin L, Xu J, Wang X, Li F, O'Malley BW, Wang J - PLoS ONE (2015)

Bottom Line: Furthermore, we demonstrated that bufalin, a SRC-3 small molecule inhibitor, when introduced even at nM concentrations, can significantly reduce TNBC cell viability and motility.Therefore, we developed a water soluble prodrug, 3-phospho-bufalin, to facilitate its in vivo administration.In addition, we demonstrated that 3-phospho-bufalin can effectively inhibit tumor growth in an orthotopic TNBC mouse model, suggesting its potential application as a targeted therapy for TNBC treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, Texas, United States of America.

ABSTRACT
Triple negative breast cancer (TNBC) has the poorest prognosis of all types of breast cancer and currently lacks efficient targeted therapy. Chemotherapy is the traditional standard-of-care for TNBC, but is frequently accompanied by severe side effects. Despite the fact that high expression of steroid receptor coactivator 3 (SRC-3) is correlated with poor survival in estrogen receptor positive breast cancer patients, its role in TNBC has not been extensively investigated. Here, we show that high expression of SRC-3 correlates with both poor overall survival and post progression survival in TNBC patients, suggesting that SRC-3 can serve as a prognostic marker for TNBC. Furthermore, we demonstrated that bufalin, a SRC-3 small molecule inhibitor, when introduced even at nM concentrations, can significantly reduce TNBC cell viability and motility. However, because bufalin has minimal water solubility, its in vivo application is limited. Therefore, we developed a water soluble prodrug, 3-phospho-bufalin, to facilitate its in vivo administration. In addition, we demonstrated that 3-phospho-bufalin can effectively inhibit tumor growth in an orthotopic TNBC mouse model, suggesting its potential application as a targeted therapy for TNBC treatment.

No MeSH data available.


Related in: MedlinePlus

H-E staining of bufalin or 3-phospho-bufalin treated mouse heart.H&E staining of heart tissues 24 h after drug administration. Neither of bufalin or 3-phospho-bufalin caused severe damage to the heart muscle, indicating that the acute toxicity of bufalin is reversible.
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pone.0140011.g006: H-E staining of bufalin or 3-phospho-bufalin treated mouse heart.H&E staining of heart tissues 24 h after drug administration. Neither of bufalin or 3-phospho-bufalin caused severe damage to the heart muscle, indicating that the acute toxicity of bufalin is reversible.

Mentions: In contrast, following 3-phospho-bufalin administration even at 7.5mg/kg and 11.25 mg/kg we did not observe significant changes in EKG parameters. We therefore assume that 3-phospho-bufalin has no acute cardiotoxicity at these higher doses, suggesting it may be a safer agent than its parent drug, bufalin. In addition, histological examinations found little damage to cardiomyocytes treated with bufalin and P-Buf (Fig 6).


Steroid Receptor Coactivator-3 (SRC-3/AIB1) as a Novel Therapeutic Target in Triple Negative Breast Cancer and Its Inhibition with a Phospho-Bufalin Prodrug.

Song X, Zhang C, Zhao M, Chen H, Liu X, Chen J, Lonard DM, Qin L, Xu J, Wang X, Li F, O'Malley BW, Wang J - PLoS ONE (2015)

H-E staining of bufalin or 3-phospho-bufalin treated mouse heart.H&E staining of heart tissues 24 h after drug administration. Neither of bufalin or 3-phospho-bufalin caused severe damage to the heart muscle, indicating that the acute toxicity of bufalin is reversible.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4592245&req=5

pone.0140011.g006: H-E staining of bufalin or 3-phospho-bufalin treated mouse heart.H&E staining of heart tissues 24 h after drug administration. Neither of bufalin or 3-phospho-bufalin caused severe damage to the heart muscle, indicating that the acute toxicity of bufalin is reversible.
Mentions: In contrast, following 3-phospho-bufalin administration even at 7.5mg/kg and 11.25 mg/kg we did not observe significant changes in EKG parameters. We therefore assume that 3-phospho-bufalin has no acute cardiotoxicity at these higher doses, suggesting it may be a safer agent than its parent drug, bufalin. In addition, histological examinations found little damage to cardiomyocytes treated with bufalin and P-Buf (Fig 6).

Bottom Line: Furthermore, we demonstrated that bufalin, a SRC-3 small molecule inhibitor, when introduced even at nM concentrations, can significantly reduce TNBC cell viability and motility.Therefore, we developed a water soluble prodrug, 3-phospho-bufalin, to facilitate its in vivo administration.In addition, we demonstrated that 3-phospho-bufalin can effectively inhibit tumor growth in an orthotopic TNBC mouse model, suggesting its potential application as a targeted therapy for TNBC treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, Texas, United States of America.

ABSTRACT
Triple negative breast cancer (TNBC) has the poorest prognosis of all types of breast cancer and currently lacks efficient targeted therapy. Chemotherapy is the traditional standard-of-care for TNBC, but is frequently accompanied by severe side effects. Despite the fact that high expression of steroid receptor coactivator 3 (SRC-3) is correlated with poor survival in estrogen receptor positive breast cancer patients, its role in TNBC has not been extensively investigated. Here, we show that high expression of SRC-3 correlates with both poor overall survival and post progression survival in TNBC patients, suggesting that SRC-3 can serve as a prognostic marker for TNBC. Furthermore, we demonstrated that bufalin, a SRC-3 small molecule inhibitor, when introduced even at nM concentrations, can significantly reduce TNBC cell viability and motility. However, because bufalin has minimal water solubility, its in vivo application is limited. Therefore, we developed a water soluble prodrug, 3-phospho-bufalin, to facilitate its in vivo administration. In addition, we demonstrated that 3-phospho-bufalin can effectively inhibit tumor growth in an orthotopic TNBC mouse model, suggesting its potential application as a targeted therapy for TNBC treatment.

No MeSH data available.


Related in: MedlinePlus