Targeting the phosphoinositide 3-kinase/AKT pathways by small molecules and natural compounds as a therapeutic approach for breast cancer cells

• Published in: Molecular biology reports 2019-10, Vol.46 (5), p.4809-4816
• Main Authors: Soltani, Amin, Torki, Samira, Ghahfarokhi, Milad Sabzevary, Jami, Mohammad Saied, Ghatrehsamani, Mahdi
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animal Anatomy; Animal Biochemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biological Products - pharmacology; Biomedical and Life Sciences; Breast cancer; Breast Neoplasms; Caffeic acid; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell viability; Chemotherapy; CXCR4 protein; Female; Flow cytometry; Gene expression; Histology; Humans; Kinases; Life Sciences; Metastases; Morphology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Original Article; Phosphatidylinositol 3-Kinase - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; Signal Transduction - drug effects; TOR protein; Transforming growth factor-b1; Twist-Related Protein 1 - genetics; Twist-Related Protein 1 - metabolism
• ISSN: 0301-4851; 1573-4978
• DOI: 10.1007/s11033-019-04929-x

The phosphoinositide 3-kinase/AKT/mTOR (PI3K/AkT/mTOR) pathway plays a pivotal role in the uncontrolled growth, migration and development of human breast cancer. The elevated expression of TGF-β1 increases the PI3K/AkT/mTOR activity in human breast cancer tissue and potentially motivates tumor metastasis and resistance to chemotherapy. Here, we investigated whether treatment with PI3K/AkT/mTOR dual inhibitor NVP-BEZ235 alone or in combination with caffeic acid phenyl ester (CAPE) could prevent TGF-β1 effects on breast cancer cells. MCF-7 human breast cancer cells were exposed to TGF-β1 for 14 days and then were treated with/without NVP-BEZ235 and/or CAPE. Cell viability, apoptosis, CXCR4 surface expression and mRNA levels of CXCR4 and TWIST-1 were analyzed in all treated groups. We found that treatment of human breast cancer cells with a combination of NVP-BEZ235 and CAPE increased induction of cellular death. Although flow cytometry analysis demonstrated that NVP-BEZ235 alone treatment reduced CXCR4 expression while increasing CXCR4 mRNA level; when NVP-BEZ235 was combined with CAPE, inhibition of CXCR4 surface expression and enhancement of CXCR4 mRNA expression was diminished. In addition, TWIST-1 mRNA expression was down regulated in samples treated with both NVP-BEZ235 and CAPE. These altogether signified that NVP-BEZ235 in combination with CAPE showed improved therapeutic efficacy in breast cancer cells by decreasing apoptotic resistance and reduction of CXCR4 and TWIST-1 expression at mRNA level could be one of mechanism of action.