Pictilisib Enhances the Antitumor Effect of Doxorubicin and Prevents Tumor-Mediated Bone Destruction by Blockade of PI3K/AKT Pathway
Copyright © 2021 Liang, Yu, Xiong, Zhang, Sun and Dong..
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 in vitro. Patient-derived xenografts and orthotopic mouse models were used to assess the effects of pictilisib in vivo. 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 in vitro and tumor-related osteolysis in vivo via inhibition of the PI3K/AKT/GSK3β and NF-κB pathways. Pictilisib combined with conventional chemotherapy drugs represents a potential treatment strategy to suppress tumor growth and bone destruction in p-AKT-positive patients.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
|---|---|
| Enthalten in: |
Frontiers in oncology - 10(2020) vom: 01., Seite 615146 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Liang, Chao [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Journal Article |
|---|
| Anmerkungen: |
Date Revised 05.03.2021 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.3389/fonc.2020.615146 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM322166667 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM322166667 | ||
| 003 | DE-627 | ||
| 005 | 20231226202655.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3389/fonc.2020.615146 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1073.xml |
| 035 | |a (DE-627)NLM322166667 | ||
| 035 | |a (NLM)33659212 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Liang, Chao |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Pictilisib Enhances the Antitumor Effect of Doxorubicin and Prevents Tumor-Mediated Bone Destruction by Blockade of PI3K/AKT Pathway |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 05.03.2021 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a Copyright © 2021 Liang, Yu, Xiong, Zhang, Sun and Dong. | ||
| 520 | |a 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 in vitro. Patient-derived xenografts and orthotopic mouse models were used to assess the effects of pictilisib in vivo. 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 in vitro and tumor-related osteolysis in vivo via inhibition of the PI3K/AKT/GSK3β and NF-κB pathways. Pictilisib combined with conventional chemotherapy drugs represents a potential treatment strategy to suppress tumor growth and bone destruction in p-AKT-positive patients | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a PI3K inhibitor | |
| 650 | 4 | |a osteoclasts | |
| 650 | 4 | |a osteosarcoma | |
| 650 | 4 | |a pictilisib | |
| 650 | 4 | |a targeted therapy | |
| 700 | 1 | |a Yu, Xijiao |e verfasserin |4 aut | |
| 700 | 1 | |a Xiong, Naping |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Zhichang |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Zhenyu |e verfasserin |4 aut | |
| 700 | 1 | |a Dong, Yang |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Frontiers in oncology |d 2011 |g 10(2020) vom: 01., Seite 615146 |w (DE-627)NLM218189583 |x 2234-943X |7 nnns |
| 773 | 1 | 8 | |g volume:10 |g year:2020 |g day:01 |g pages:615146 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.3389/fonc.2020.615146 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 10 |j 2020 |b 01 |h 615146 | ||