pki-402 and Breast-Neoplasms

PI3K/Akt/mTOR pathway activation causes relapse and resistance after radiotherapy in breast cancer (BC). We aimed to radiosensitize BC cell lines to irradiation (IR) by PKI-402, a dual PI3K/mTOR inhibitor.. We performed cytotoxicity, clonogenicity, hanging drop, apoptosis and double-strand break detection, and phosphorylation of 16 essential proteins involved in the PI3K/mTOR pathway.. Our findings showed that PKI-402 has cytotoxic efficiency in all cell lines. Clonogenic assay results showed that PKI-402 plus IR inhibited the colony formation ability of MCF-7 and breast cancer stem cell lines. Results showed that PKI-402 plus IR causes more apoptotic cell death than IR alone in the MCF-7 cells but did not cause significant changes in the MDA-MB-231. γ-H2AX levels were increased in MDA-MB-231 in PKI-402 plus IR groups, whereas we did not observe any apoptotic and γ-H2AX induction in BCSCs and MCF-10A cells in all treatment groups. Some pivotal phosphorylated proteins of the PI3K/AKT pathway decreased, several proteins increased and others did not change.. In conclusion, if the combined use of PKI-402 with radiation is supported by in vivo studies, it can contribute to the treatment options and the course of the disease.

Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Humans; Neoplasm Recurrence, Local; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Radiation Tolerance; TOR Serine-Threonine Kinases

Bone metastasis causes bone pain and pathological bone fracture in breast cancer patients with a serious complication. Previous studies have demonstrated that a novel phosphatidyl inositol 3-kinase (PI3K)-mTOR inhibitor PKI-402 suppressed the growth of breast cancer cells. However, the role of PKI-402 involved in osteolysis induced by breast cancer remains unclear. In this study, we showed that treatment of PKI-402 led to significant decreases in RANKL-induced osteoclastogenesis and osteoclast-specific gene expression in mouse bone marrow-derived macrophages and reduced proliferation, migration and invasion of MDA-MB-231 breast cancer cells by blocking the PI3K-AKT-mTOR signaling pathway. Importantly, as evidenced by the observation that the administration of PKI-402 inhibited MDA-MB-231-induced osteolysis in vivo, PKI-402 exerted an inhibitory effect on osteoclast formation and bone resorption, critical for cancer cells-induced bone destruction. These results strongly suggest that PKI-402 might have a therapeutic potential to inhibit breast cancer induced osteolysis.

Topics: Animals; Breast Neoplasms; Cell Movement; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; MAP Kinase Signaling System; Mice; Osteogenesis; Osteolysis; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; RANK Ligand; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays