Phosphatidyl inositol 3-kinase (PI3K)-mTOR inhibitor PKI-402 inhibits breast cancer induced osteolysis

• Published in: Cancer letters 2019-02, Vol.443, p.135-144
• Main Authors: Yuan, Guixin, Lian, Zhen, Liu, Qian, Lin, Xixi, Xie, Dantao, Song, Fangming, Wang, Xinjia, Shao, Siyuan, Zhou, Bo, Li, Chen, Li, Muyan, Yao, Guanfeng
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Apoptosis; Bone cancer; Bone destruction; Bone growth; Bone marrow; Bone metastasis; Bone resorption; Bones; Breast cancer; Cell growth; Cell proliferation; Clinical trials; Enzyme inhibitors; Gene expression; Hydroxyapatite; Immunoglobulins; Inositol; Kinases; Leukocyte migration; Macrophages; MDA-MB-231 cells; Metastases; Metastasis; Osteoclast; Osteoclastogenesis; Osteolysis; Pain; Penicillin; Phosphatase; PI3K-mTOR-AKT-Signaling pathway; Signal transduction; Software; Three dimensional imaging; TOR protein; TRANCE protein
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2018.11.038

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. •PKI-402 inhibits osteoclast differentiation and function, and expression of osteoclastic-specific genes.•PKI-402 reduces the abilities of MDA-MB-231 cells to proliferate, migrate and invade the extracellular matrix.•PKI-402 greatly reverses bone damage caused by breast cancer in vivo.•PKI-402 prevents breast cancer induced osteolysis via inhibiting both osteoclast function and breast cancer cell function.