Sensitizing estrogen receptor–negative breast cancer cells to tamoxifen with OSU-03012, a novel celecoxib-derived phosphoinositide-dependent protein kinase-1/Akt signaling inhibitor

Abstract

Tamoxifen is a mainstay in the treatment of estrogen receptor (ER) -positive breast cancer patients. Although the efficacy of tamoxifen has been attributed to induction of tumor cell growth arrest and apoptosis by inhibition of ER signaling, recent evidence indicates that tamoxifen possesses ER-independent antitumor activities. Here, we use OSU-03012, a small-molecule inhibitor of phosphoinositide-dependent protein kinase-1 (PDK-1) to address the hypothesis that PDK-1/Akt signaling represents a therapeutically relevant target to sensitize ER-negative breast cancer to tamoxifen. OSU-03012 sensitized both ER-positive MCF-7 and ER-negative MDA-MB-231 cells to the antiproliferative effects of tamoxifen in an ER-independent manner. Flow cytometric analysis of phosphatidylserine externalization revealed that this augmented suppression of cell viability was attributable to a marked enhancement of tamoxifen-induced apoptosis by OSU-03012. Mechanistically, this OSU-03012-mediated sensitization was associated with suppression of a transient tamoxifen-induced elevation of Akt phosphorylation and enhanced modulation of the functional status of multiple Akt downstream effectors, including FOXO3a, GSK3A/B, and p27. The growth of established MDA-MB-231 tumor xenografts was suppressed by 50% after oral treatment with the combination of tamoxifen (60 mg/kg) and OSU-03012 (100 mg/kg), whereas OSU-03012 and tamoxifen alone suppressed growth by 30% and 0%, respectively. These findings indicate that the inhibition of PDK-1/Akt signaling to sensitize ER-negative breast cancer cells to the ER-independent antitumor activities of tamoxifen represents a feasible approach to extending the use of tamoxifen to a broader population of breast cancer patients. Considering the urgent need for novel therapeutic strategies for ER-negative breast cancer patients, this combinatorial approach is worthy of continued investigation.

A new role for tamoxifen in oestrogen receptor-negative breast cancer when it is combined with epigallocatechin gallate

“…However, the overall tumour volume was only decreased by 49% as compared with control after EGCG þ curcumin treatment, indicating that EGCG þ tamoxifen is a more effective combination therapy as tumour volume was decreased by 71% as compared with control. Another recent study has shown that ER-negative breast cancer cells can be sensitised to the effects of tamoxifen by using a PDK-1/ Akt inhibitor (Weng et al, 2008). In this study, tamoxifen (60 mg kg À1 ) was unable to suppress the growth of MDA-MB-231 xenografts, but the addition of OUS-03012 (100 mg kg À1 ) showed significant tumour suppression (decreased 50% in control).…”

“…This concept has been shown by combining docetaxel, genistein, black cohosh, and palm oil tocotrienols (Ferlini et al, 1997;Guthrie et al, 1997;Tanos et al, 2002;Bollig et al, 2005;Al-Akoum et al, 2007) with tamoxifen, which elicited cytotoxicity, apoptosis, and G1 arrest in various ERnegative breast cancer cell lines. Recently, this has been shown in both MDA-MB-231 cells and a xenograft model by combining tamoxifen with OSU-03012, a phosphoinositide-dependent protein kinase-1/Akt inhibitor (Weng et al, 2008). Our laboratory has also used ER-negative breast cancer cells to demonstrate that a combination of epigallocatechin gallate (EGCG) and tamoxifen elicits synergistic cytotoxicity (Chisholm et al, 2004).…”

OSU-03012, a Novel Celecoxib Derivative, Induces Reactive Oxygen Species–Related Autophagy in Hepatocellular Carcinoma

“…OSU-03012 has been shown to induce apoptosis in non-small cell lung cancer (26) and breast cancer cells (27,28) through inhibition of PDK/AKT signaling pathway. However, only very limited PDK1 and AKT inhibition were detected in OSU-03012-treated Huh7 cells in this study, suggesting that OSU-03012 suppresses the growth of Huh7 cells through a mechanism different from PDK1 and AKT inhibition.…”

A ferrocenyl derivative of hydroxytamoxifen elicits an estrogen receptor-independent mechanism of action in breast cancer cell lines

“…Binding of OH-TAM to ERa leads to a decrease in tumor cell growth [6]. OH-TAM is also effective in the absence of ER expression in breast cancer, melanoma, glioma and pancreatic carcinoma [7][8][9]. However this non-genomic effect (i.e.…”