A005, a novel inhibitor of phosphatidylinositol 3-kinase/mammalian target of rapamycin, prevents osteosarcoma-induced osteolysis

Zhen Lian, Jinsong Han, Lin Huang, Chengming Wei, Yongyong Fan, Jiake Xu, Mengyu Zhou, Haotian Feng, Qian Liu, Lingzi Chen, Zhaoning Li, Haichun Cheng, Guixin Yuan, Xixi Lin, Fangming Song, Yiji Su, Chao Wang, Guopeng Huang, An Qin, Yunlong Song & 1 others Guanfeng Yao

Research output: Contribution to journalArticle

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Abstract

Osteosarcoma is the most frequent primary bone tumor in children and adolescents. The phosphatidylinositol 3-kinase (PI3K)/ mammalian target of rapamycin (mTOR) signaling pathway is an attractive anticancer target because it plays key roles in the regulation of cell growth, division and differentiation. In this study, we demonstrated high expression of PI3K/mTOR signaling pathway-related genes in patients with osteosarcoma. We thus investigated the effects of A005, a newly synthesized dual PI3K/mTOR inhibitor, on osteosarcoma cells and in a mouse xenograft tumor model. The results confirmed that A005 inhibited the proliferation, migration and invasion of human osteosarcoma cells. In addition, A005 also inhibited receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation and bone resorption in vitro. Therefore, A005 was further applied to a SaOS-2 osteosarcoma-induced mouse osteolysis model. A005 inhibited tumor growth and prevented osteosarcoma-associated osteolysis via modulation of the PI3K/AKT/mTOR pathway. Overall, our results showed that A005 inhibited osteoclastogenesis and prevented osteosarcoma-induced bone osteolysis by suppressing PI3K/AKT/mTOR signaling. These findings indicated that A005 may be a promising candidate drug for the treatment of human osteosarcoma.

Original languageEnglish
Pages (from-to)E1-E13
JournalCarcinogenesis
Volume40
Issue number2
DOIs
Publication statusPublished - 1 Jan 2019

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Phosphatidylinositol 3-Kinase
Osteolysis
Osteosarcoma
Sirolimus
RANK Ligand
Bone and Bones
Neoplasms
Osteoclasts
Bone Resorption
Growth
Heterografts
Osteogenesis
Cell Division
Cell Differentiation

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Lian, Zhen ; Han, Jinsong ; Huang, Lin ; Wei, Chengming ; Fan, Yongyong ; Xu, Jiake ; Zhou, Mengyu ; Feng, Haotian ; Liu, Qian ; Chen, Lingzi ; Li, Zhaoning ; Cheng, Haichun ; Yuan, Guixin ; Lin, Xixi ; Song, Fangming ; Su, Yiji ; Wang, Chao ; Huang, Guopeng ; Qin, An ; Song, Yunlong ; Yao, Guanfeng. / A005, a novel inhibitor of phosphatidylinositol 3-kinase/mammalian target of rapamycin, prevents osteosarcoma-induced osteolysis. In: Carcinogenesis. 2019 ; Vol. 40, No. 2. pp. E1-E13.
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title = "A005, a novel inhibitor of phosphatidylinositol 3-kinase/mammalian target of rapamycin, prevents osteosarcoma-induced osteolysis",
abstract = "Osteosarcoma is the most frequent primary bone tumor in children and adolescents. The phosphatidylinositol 3-kinase (PI3K)/ mammalian target of rapamycin (mTOR) signaling pathway is an attractive anticancer target because it plays key roles in the regulation of cell growth, division and differentiation. In this study, we demonstrated high expression of PI3K/mTOR signaling pathway-related genes in patients with osteosarcoma. We thus investigated the effects of A005, a newly synthesized dual PI3K/mTOR inhibitor, on osteosarcoma cells and in a mouse xenograft tumor model. The results confirmed that A005 inhibited the proliferation, migration and invasion of human osteosarcoma cells. In addition, A005 also inhibited receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation and bone resorption in vitro. Therefore, A005 was further applied to a SaOS-2 osteosarcoma-induced mouse osteolysis model. A005 inhibited tumor growth and prevented osteosarcoma-associated osteolysis via modulation of the PI3K/AKT/mTOR pathway. Overall, our results showed that A005 inhibited osteoclastogenesis and prevented osteosarcoma-induced bone osteolysis by suppressing PI3K/AKT/mTOR signaling. These findings indicated that A005 may be a promising candidate drug for the treatment of human osteosarcoma.",
author = "Zhen Lian and Jinsong Han and Lin Huang and Chengming Wei and Yongyong Fan and Jiake Xu and Mengyu Zhou and Haotian Feng and Qian Liu and Lingzi Chen and Zhaoning Li and Haichun Cheng and Guixin Yuan and Xixi Lin and Fangming Song and Yiji Su and Chao Wang and Guopeng Huang and An Qin and Yunlong Song and Guanfeng Yao",
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pages = "E1--E13",
journal = "Carcinogenesis",
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Lian, Z, Han, J, Huang, L, Wei, C, Fan, Y, Xu, J, Zhou, M, Feng, H, Liu, Q, Chen, L, Li, Z, Cheng, H, Yuan, G, Lin, X, Song, F, Su, Y, Wang, C, Huang, G, Qin, A, Song, Y & Yao, G 2019, 'A005, a novel inhibitor of phosphatidylinositol 3-kinase/mammalian target of rapamycin, prevents osteosarcoma-induced osteolysis' Carcinogenesis, vol. 40, no. 2, pp. E1-E13. https://doi.org/10.1093/carcin/bgy036

A005, a novel inhibitor of phosphatidylinositol 3-kinase/mammalian target of rapamycin, prevents osteosarcoma-induced osteolysis. / Lian, Zhen; Han, Jinsong; Huang, Lin; Wei, Chengming; Fan, Yongyong; Xu, Jiake; Zhou, Mengyu; Feng, Haotian; Liu, Qian; Chen, Lingzi; Li, Zhaoning; Cheng, Haichun; Yuan, Guixin; Lin, Xixi; Song, Fangming; Su, Yiji; Wang, Chao; Huang, Guopeng; Qin, An; Song, Yunlong; Yao, Guanfeng.

In: Carcinogenesis, Vol. 40, No. 2, 01.01.2019, p. E1-E13.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A005, a novel inhibitor of phosphatidylinositol 3-kinase/mammalian target of rapamycin, prevents osteosarcoma-induced osteolysis

AU - Lian, Zhen

AU - Han, Jinsong

AU - Huang, Lin

AU - Wei, Chengming

AU - Fan, Yongyong

AU - Xu, Jiake

AU - Zhou, Mengyu

AU - Feng, Haotian

AU - Liu, Qian

AU - Chen, Lingzi

AU - Li, Zhaoning

AU - Cheng, Haichun

AU - Yuan, Guixin

AU - Lin, Xixi

AU - Song, Fangming

AU - Su, Yiji

AU - Wang, Chao

AU - Huang, Guopeng

AU - Qin, An

AU - Song, Yunlong

AU - Yao, Guanfeng

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Osteosarcoma is the most frequent primary bone tumor in children and adolescents. The phosphatidylinositol 3-kinase (PI3K)/ mammalian target of rapamycin (mTOR) signaling pathway is an attractive anticancer target because it plays key roles in the regulation of cell growth, division and differentiation. In this study, we demonstrated high expression of PI3K/mTOR signaling pathway-related genes in patients with osteosarcoma. We thus investigated the effects of A005, a newly synthesized dual PI3K/mTOR inhibitor, on osteosarcoma cells and in a mouse xenograft tumor model. The results confirmed that A005 inhibited the proliferation, migration and invasion of human osteosarcoma cells. In addition, A005 also inhibited receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation and bone resorption in vitro. Therefore, A005 was further applied to a SaOS-2 osteosarcoma-induced mouse osteolysis model. A005 inhibited tumor growth and prevented osteosarcoma-associated osteolysis via modulation of the PI3K/AKT/mTOR pathway. Overall, our results showed that A005 inhibited osteoclastogenesis and prevented osteosarcoma-induced bone osteolysis by suppressing PI3K/AKT/mTOR signaling. These findings indicated that A005 may be a promising candidate drug for the treatment of human osteosarcoma.

AB - Osteosarcoma is the most frequent primary bone tumor in children and adolescents. The phosphatidylinositol 3-kinase (PI3K)/ mammalian target of rapamycin (mTOR) signaling pathway is an attractive anticancer target because it plays key roles in the regulation of cell growth, division and differentiation. In this study, we demonstrated high expression of PI3K/mTOR signaling pathway-related genes in patients with osteosarcoma. We thus investigated the effects of A005, a newly synthesized dual PI3K/mTOR inhibitor, on osteosarcoma cells and in a mouse xenograft tumor model. The results confirmed that A005 inhibited the proliferation, migration and invasion of human osteosarcoma cells. In addition, A005 also inhibited receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation and bone resorption in vitro. Therefore, A005 was further applied to a SaOS-2 osteosarcoma-induced mouse osteolysis model. A005 inhibited tumor growth and prevented osteosarcoma-associated osteolysis via modulation of the PI3K/AKT/mTOR pathway. Overall, our results showed that A005 inhibited osteoclastogenesis and prevented osteosarcoma-induced bone osteolysis by suppressing PI3K/AKT/mTOR signaling. These findings indicated that A005 may be a promising candidate drug for the treatment of human osteosarcoma.

UR - http://www.scopus.com/inward/record.url?scp=85065509801&partnerID=8YFLogxK

U2 - 10.1093/carcin/bgy036

DO - 10.1093/carcin/bgy036

M3 - Article

VL - 40

SP - E1-E13

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 2

ER -