{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T19:20:42Z","timestamp":1788895242356,"version":"build-2803163510"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,15]],"date-time":"2021-02-15T00:00:00Z","timestamp":1613347200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Despite advances in neoadjuvant chemotherapy, outcomes for patients with osteosarcoma resistant to first-line chemotherapy have been dismal for decades. There is thus an urgent need to develop novel targeted drugs to effectively treat refractory osteosarcoma. Dysregulation in the PI3K\/AKT pathway has been observed during the development of osteosarcoma. Herein, we first evaluated p-AKT (Ser473) expression levels in osteosarcoma tissue using high-throughput tissue microarrays. Then, we demonstrated the role of pictilisib, a novel potent PI3K inhibitor, in osteosarcoma and related osteolysis. Functional studies of pictilisib in osteosarcoma cell lines and bone marrow-derived macrophages were performed <jats:italic>in vitro<\/jats:italic>. Patient-derived xenografts and orthotopic mouse models were used to assess the effects of pictilisib <jats:italic>in vivo<\/jats:italic>. The results showed that positive p-AKT expression levels after neoadjuvant chemotherapy were significantly associated with tumor cell necrosis rate. Pictilisib effectively inhibited the proliferation of osteosarcoma through G0\/G1-S phase cell cycle arrest, and enhanced the sensitivity of osteosarcoma to doxorubicin, although it failed to induce cell apoptosis alone. In addition, pictilisib inhibited differentiation of osteoclasts and bone resorption <jats:italic>in vitro<\/jats:italic> and tumor-related osteolysis <jats:italic>in vivo via<\/jats:italic> inhibition of the PI3K\/AKT\/GSK3<jats:italic>\u03b2<\/jats:italic> and NF-<jats:italic>\u03ba<\/jats:italic>B pathways. Pictilisib combined with conventional chemotherapy drugs represents a potential treatment strategy to suppress tumor growth and bone destruction in p-AKT-positive patients.<\/jats:p>","DOI":"10.3389\/fonc.2020.615146","type":"journal-article","created":{"date-parts":[[2021,2,15]],"date-time":"2021-02-15T16:39:02Z","timestamp":1613407142000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Pictilisib Enhances the Antitumor Effect of Doxorubicin and Prevents Tumor-Mediated Bone Destruction by Blockade of PI3K\/AKT 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