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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.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.

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

Synthetic scheme of 3-phospho-bufalin.
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pone.0140011.g005: Synthetic scheme of 3-phospho-bufalin.

Mentions: Bufalin has low solubility in aqueous solutions, which limits its use as a therapeutic agent. Introducing a phosphate group is a common strategy to increase a compound’s aqueous solubility, and has been used before in prodrug development [48]. As shown in Fig 5, bufalin was converted to 3-(di-t-butyl-phospho)-bufalin through reaction with di-t-butyl diethylphosphoramidite and subsequent oxidation with m-chloroperoxybenzoic acid (mCPBA). The t-butyl groups were carefully de-protected in an acidic environment to supply the final p-Buf. The phosphate group now can be cleaved by endogenous phosphatases to regenerate free bufalin (see below). Similar to free bufalin, p-Buf can also inhibit SRC–3 expression levels in LM3-3 cells (Fig 2B). It should be noted that p-Buf is a prodrug and requires phosphatases to re-generate bufalin. Phospho-bufalin appeared to be less potent than bufalin to inhibit SRC–3 levels (Fig 2B), which may be due to incomplete conversion of p-Buf to bufalin under the culture conditions.


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)

Synthetic scheme of 3-phospho-bufalin.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0140011.g005: Synthetic scheme of 3-phospho-bufalin.
Mentions: Bufalin has low solubility in aqueous solutions, which limits its use as a therapeutic agent. Introducing a phosphate group is a common strategy to increase a compound’s aqueous solubility, and has been used before in prodrug development [48]. As shown in Fig 5, bufalin was converted to 3-(di-t-butyl-phospho)-bufalin through reaction with di-t-butyl diethylphosphoramidite and subsequent oxidation with m-chloroperoxybenzoic acid (mCPBA). The t-butyl groups were carefully de-protected in an acidic environment to supply the final p-Buf. The phosphate group now can be cleaved by endogenous phosphatases to regenerate free bufalin (see below). Similar to free bufalin, p-Buf can also inhibit SRC–3 expression levels in LM3-3 cells (Fig 2B). It should be noted that p-Buf is a prodrug and requires phosphatases to re-generate bufalin. Phospho-bufalin appeared to be less potent than bufalin to inhibit SRC–3 levels (Fig 2B), which may be due to incomplete conversion of p-Buf to bufalin under the culture conditions.

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.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.

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