buparlisib and Bone-Neoplasms

Osteosarcoma (OS) is the most common pediatric malignant neoplasia of the skeletal system. It is characterized by a high degree of malignancy and a severe tendency to metastasize. In the past decade, many studies have provided evidence that the phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most frequently altered pathways in human cancer, and has a critical role in driving tumor initiation and progression. Here, we have analyzed the therapeutic potential of the pan-PI3K inhibitor NVP-BKM120, which has recently entered clinical Phase II for treatment of PI3K-dependent cancers on three OS cell lines. We observed a concentration- and time-dependent decrease of Ser473 p-Akt as well as reduced levels of Thr37/46 p-4E-BP1, an indicator of the mammalian target of rapamycin complex 1 activity. All OS cell lines used in this study responded to BKM120 treatment with an arrest of cell proliferation, an increase in cell mortality, and an increase in caspase-3 activity. MG-63 cells were the most responsive cell line, demonstrating a significant increase in sub-G1 cells, and a rapid induction of cell death. Furthermore, we demonstrate that BKM120 is more effective when used in combination with other standard chemotherapeutic drugs. Combining BKM120 with vincristine demonstrated a more synergistic effect than BKM120 with doxorubicin in all the lines. Hence, we suggest that BKM120 may be a novel therapy for the treatment of OS presenting with anomalous upregulation of the PI3K signaling pathway.

Topics: Aminopyridines; Antineoplastic Agents; Apoptosis; Bone Neoplasms; Caspase 3; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Humans; Morpholines; Osteosarcoma; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction

Non‑small cell lung cancer (NSCLC) metastasis commonly occurs in bone, which often results in pathological fractures. Sustained phosphoinositide‑3‑kinase (PI3K) signalling promotes the growth of PI3K‑dependent NSCLC and elevates osteoclastogenic potential. The present study investigated the effects of a PI3K inhibitor on NSCLC growth in bone and osteoclast formation, and aimed to determine whether it could control symptoms associated with bone metastasis. A bone metastasis xenograft model was established by implanting NCI‑H460‑luc2 lung cancer cells, which contain a phosphatidylinositol‑​4,5‑bisphosphate 3‑kinase catalytic subunit α mutation, into the right tibiae of mice. After 1 week, the tumours were challenged with a PI3K inhibitor (buparlisib) or blank control for 3 weeks. Tumour growth and burden were longitudinally assessed in vivo via reporter gene bioluminescence imaging (BLI), small animal positron emission tomography/computed tomography (CT) [18F‑fluorodeoxyglucose (18F‑FDG)] and single‑photon emission computed tomography/CT [99mTc‑methylene diphosphonate (99mTc‑MDP)] imaging. Tibia sections of intraosseous NCI‑H460 tumours were analysed by immunohistochemistry (IHC), western blotting and flow cytometry. Dynamic weight bearing (DWB) tests were further performed to examine the improvement of symptoms associated with bone metastasis during the entire study. Administration of buparlisib significantly inhibited the progression of bone metastasis of NSCLC, as evidenced by significantly reduced uptake of 18F‑FDG, 99mTc‑MDP and BLI signals in the treated lesions. In addition, buparlisib appeared to inhibit the expression of tartrate‑resistant acid phosphatase and receptor activator of nuclear factor‑κB ligand, as determined by IHC. Buparlisib also resulted in increased cell apoptosis, as determined by a higher percentage of Annexin V staining and increased caspase 3 expression. Furthermore, buparlisib significantly increased weight‑bearing capacity, as revealed by DWB tests. The PI3K inhibitor, buparlisib, suppressed osteoclast formation in vivo, and exhibited antitumour activity, thus leading to increased weight‑bearing ability in mice with bone metastasis of lung cancer. Therefore, targeting the PI3K pathway may be a potential therapeutic strategy that prevents the structural skeletal damage associated with bone metastasis of lung cancer.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Apoptosis; Bone and Bones; Bone Neoplasms; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Female; Fluorodeoxyglucose F18; Humans; Lung Neoplasms; Male; Mice; Mice, Nude; Molecular Imaging; Morpholines; Osteoclasts; Positron Emission Tomography Computed Tomography; Single Photon Emission Computed Tomography Computed Tomography; Treatment Outcome; X-Ray Microtomography