In vitro combinatorial therapeutics in breast cancer against the Notch and PI3K pathways

Research Abstract

Purpose: Several studies indicate that T- acute lymphoblastic leukemia (T-ALL) cell lines that exhibit activation of both Notch andphosphoinositidine 3-Kinase (PI3K)/AKT/ mammalian target of rapamycin (mTOR) are resistant to gamma secretase inhibitor (GSI) treatment. In this study, we investigated the sensitivity and /or resistance of breast cancer cell lines to the inhibition of Notch pathway by gamma secretase inhibitor (DBZ) and inhibition of PI3K/AKT/mTOR inhibitor ( rapamycin) both alone or in combination . Methods: Six breast cancer cell lines with down regulated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and overexpressed Notch homologs were identified and treated with DBZ and rapamycin alone or in combination for ten days. The inhibition of cell proliferation was evaluated by alamar blue assay and efficiency of pathway inhibition was assessed by Western blot of Notch 1, Notch 3 and phospho-p70 S6K target proteins. Results: Our breast cancer cell lines showed variable sensitivity to rapamycin treatment and generally were resistant to DBZ treatment. However, the combinatorial treatment was highly effective for all but one cell line and could significantly reduce cell proliferation and growth compared to each drug alone (p< 0.001). Conclusion: The combinatorial treatment of DBZ and rapamycin provides a promising therapeutic option for GSI-resistant breast cancers.

Research Keywords

In vitro combinatorial therapeutics in breast cancer against the Notch and PI3K pathways