Notoginsenoside R1 counteracts mesenchymal stem cell-evoked oncogenesis and doxorubicin resistance in osteosarcoma cells by blocking IL-6 secretion-induced JAK2/STAT3 signaling

• Published in: Investigational new drugs 2021-04, Vol.39 (2), p.416-425
• Main Authors: Lu, Minan, Xie, Kegong, Lu, Xianzhe, Lu, Lu, Shi, Yu, Tang, Yujin
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - drug effects; Biomedical materials; Bone cancer; Bone marrow; Cancer; Carcinogenesis - drug effects; Carcinoma; Caspase-3; Cell growth; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell viability; Dose-Response Relationship, Drug; Doxorubicin; Doxorubicin - pharmacology; Drug resistance; Drug Resistance, Neoplasm - drug effects; Gelatinase A; Gelatinase B; Ginsenosides - pharmacology; Herbal medicine; Humans; Interleukin 6; Janus kinase 2; Janus Kinase 2 - drug effects; Malignancy; Medicine; Medicine & Public Health; Mesenchymal stem cells; Mesenchymal Stem Cells - drug effects; Oncology; Osteosarcoma; Osteosarcoma - pathology; Osteosarcoma cells; Pharmacology/Toxicology; Preclinical Studies; Sarcoma; Signal transduction; Signal Transduction - drug effects; Signaling; Stat3 protein; STAT3 Transcription Factor - drug effects; Stem cells; Supplements; Traditional Chinese medicine; Tumor cells; Tumor microenvironment; Tumorigenesis; Tumors
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-020-01027-9

Summary Tumor microenvironment is a critical participant in the initiation, progression and drug resistance of carcinomas, including osteosarcoma. Notoginsenoside R1 (NGR1) is a proverbial active ingredient of the traditional Chinese medicine Panax notoginseng (PN) and possess undeniable roles in several cancers. Nevertheless, its function in osteosarcoma and tumor microenvironment remains elusive. In the current study, exposure to NGR1 dose-dependently inhibited osteosarcoma cell viability and migration, and induced apoptosis. Furthermore, osteosarcoma cells that were incubated with conditioned medium (CM) from bone marrow mesenchymal stem cells (BMSCs) exhibited greater proliferation, migration capacity and MMP-2 and MMP-9 expression relative to control cells, which was reversed when BMSCs were treated with NGR1. Notably, administration with NGR1 antagonized CM-evoked doxorubicin resistance in osteosarcoma cells by decreasing cell viability and increasing cell apoptosis and caspase-3/9 activity. Mechanically, NGR1 suppressed IL-6 secretion from BMSCs, as well as the subsequent activation of the JAK2/STAT3 signaling in osteosarcoma cells. In addition, blocking the JAK2 pathway by its antagonist AG490 reversed CM-induced osteosarcoma cell proliferation, migration and doxorubicin resistance. Moreover, exogenous supplementation with IL-6 engendered not only the reactivation of the JAK2/STAT3 signaling but also muted NGR1-mediated efficacy against osteosarcoma cell malignancy and doxorubicin resistance. Collectively, NGR1 may directly restrain osteosarcoma cell growth and migration, or indirectly antagonize MSC-evoked malignancy and drug resistance by interdicting IL-6 secretion-evoked activation of the JAK2/STAT3 pathway. Consequently, the current study may highlight a promising therapeutic strategy against osteosarcoma by regulating tumor cells and the tumor microenvironment.