Format

Send to

Choose Destination
Oncol Rep. 2019 May;41(5):2636-2646. doi: 10.3892/or.2019.7080. Epub 2019 Mar 20.

The PI3K inhibitor buparlisib suppresses osteoclast formation and tumour cell growth in bone metastasis of lung cancer, as evidenced by multimodality molecular imaging.

Author information

1
Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China.
2
Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
3
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200433, P.R. China.
4
Department of Oncology, Yueyang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P.R. China.
5
Department of Orthopaedics and Traumatology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200000, P.R. China.

Abstract

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.

Supplemental Content

Full text links

Icon for Spandidos Publications Icon for PubMed Central
Loading ...
Support Center