Toosendanin demonstrates promising antitumor efficacy in osteosarcoma by targeting STAT3

Zhang, T; Li, J; Yin, Fei; Lin, Binhui; Wang, Z; Xu, Jing; Wang, H; Zuo, Dongqing; Wang, G; Hua, Yingqi; Cai, Zhengdong

doi:10.1038/onc.2017.270

Cited by 103 publications

(94 citation statements)

References 43 publications

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“…Our team previously reported that STAT3 is a critical regulator of osteosarcoma development and progression . The effect of RA on the JNK and STAT3 signaling pathways was assessed to investigate the molecular mechanism of the antitumor activity of RA using pharmacological inhibitors and shRNA.…”

Section: Resultsmentioning

confidence: 99%

“…Compared with the transient activation of STAT3 in normal cells, STAT3 remains abnormally active in tumors and promotes the induction and survival of cancer . Our previous results showed that selective inactivation of STAT3 blocks tumorigenesis in human osteosarcoma . Our most recent studies have shown that a natural compound, alternol, suppresses cell proliferation and migration and induces apoptosis and cell cycle arrest by modulating ROS‐dependent MAPK and STAT3 signaling pathways in human osteosarcoma cells .…”

Section: Introductionmentioning

confidence: 98%

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Antitumor activity of Raddeanin A is mediated by Jun amino‐terminal kinase activation and signal transducer and activator of transcription 3 inhibition in human osteosarcoma

et al. 2019

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Osteosarcoma is the most common primary malignant bone tumor. Raddeanin A ( RA ) is an active oleanane‐type triterpenoid saponin extracted from the traditional Chinese herb Anemone raddeana Regel that exerts antitumor activity against several cancer types. However, the effect of RA on osteosarcoma remains unclear. In the present study, we showed that RA inhibited proliferation and induced apoptosis of osteosarcoma cells in a dose‐ and time‐dependent way in vitro and in vivo. RA treatment resulted in excessive reactive oxygen species ( ROS ) generation and JNK and ERK 1/2 activation. Apoptosis induction was evaluated by the activation of caspase‐3, caspase‐8, and caspase‐9 and poly‐ADP ribose polymerase ( PARP ) cleavage. RA ‐induced cell death was significantly restored by the ROS scavenger glutathione ( GSH ), the pharmacological inhibitor of JNK SP 600125, or specific JNK knockdown by sh RNA . Additionally, signal transducer and activator of transcription 3 ( STAT 3) activation was suppressed by RA in human osteosarcoma, and this suppression was restored by GSH , SP 600125, and JNK ‐sh RNA . Further investigation showed that STAT 3 phosphorylation was increased after JNK knockdown. In a tibial xenograft tumor model, RA induced osteosarcoma apoptosis and notably inhibited tumor growth. Taken together, our results show that RA suppresses proliferation and induces apoptosis by modulating the JNK /c‐Jun and STAT 3 signaling pathways in human osteosarcoma. Therefore, RA may be a promising candidate antitumor drug for osteosarcoma intervention.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Antitumor activity of Raddeanin A is mediated by Jun amino‐terminal kinase activation and signal transducer and activator of transcription 3 inhibition in human osteosarcoma

et al. 2019

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“…The downstream signaling targets of c‐Met, including Akt, ERK and stat3, were also inhibited. The stat3 pathway was postulated to be important in OS formation because the selective inactivation of phospho‐stat3 blocks tumorigenesis in OS . In addition, Akt and ERK represent 2 of the most important intracellular pathways that drive tumor cell survival, transformation and proliferation .…”

Section: Discussionmentioning

confidence: 99%

Norcantharidin inhibits proliferation and promotes apoptosis via c‐Met/Akt/mTOR pathway in human osteosarcoma cells

et al. 2019

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Osteosarcoma (OS) is the most common malignant bone tumor and frequently affects adolescents. Norcantharidin (NCTD), a demethylated derivative of cantharidin, has been reported to exhibit anticancer activity against various types of tumors but not human OS. The aim of the present study was to evaluate the effects of NCTD on OS cell lines (MG63 and HOS) and to explore the underlying mechanisms. In the present study, the proliferation of OS cells decreased significantly, while the apoptosis was accelerated significantly after exposure to NCTD. Meanwhile, our results also indicated that NCTD could suppress the migration and invasion, decrease the colony‐forming ability and induce S phase cell cycle arrest of OS cells in a dose‐dependent manner. Moreover, our results revealed that the anticancer effects induced by NCTD on OS cells involved autophagy, mitophagy, endoplasmic reticulum stress and c‐Met pathway. Furthermore, the results of animal experiments showed that NCTD inhibited tumor growth in a xenograft model of human OS. These results provide important new insight into the possible molecular mechanisms of NCTD and highlight its potential use as an antitumor drug for human OS.

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“…Three‐dimensional (3D) on‐top assay was performed as previously described . Briefly, 80 μL of Matrigel solution was added to a 48‐well plate, which was subsequently incubated at 37 °C to allowed the Matrigel to solidify.…”

Section: Methodsmentioning

confidence: 99%

Anlotinib, a novel small molecular tyrosine kinase inhibitor, suppresses growth and metastasis via dual blockade of VEGFR2 and MET in osteosarcoma

Wang

Sun

Jiang

et al. 2019

Intl Journal of Cancer

106

108

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Osteosarcoma is the most common primary malignant bone tumor in children and adolescents, with highly aggressive behavior and early systemic metastasis. The survival rates for osteosarcoma remain unchanged over the past two decades. Studies aiming to find new or alternative therapies for patients with refractory osteosarcoma are urgently needed. Anlotinib, a novel multi‐targeted tyrosine kinase inhibitor (TKI), has exhibited encouraging clinical activity in NSLCC and soft tissue sarcoma, whereas its effect on osteosarcoma has not been studied. In our study, we investigated the anti‐tumor activity and underlying mechanism of anlotinib in osteosarcoma. Various in vitro and in vivo models of human osteosarcoma were used to determine the anti‐proliferative, anti‐angiogenesis and anti‐metastasis efficacy of anlotinib. Our results showed that anlotinib suppressed tumor growth and increased the chemo‐sensitivity of osteosarcoma. In addition, anlotinib inhibited migration and invasion in osteosarcoma cells. Furthermore, in order to explore the anti‐tumor mechanism of anlotinib, phospho‐RTK antibody arrays were performed. These analyses confirmed that anlotinib suppressed the phosphorylation of MET, VEGFR2 and the downstream signaling pathway activation. Moreover, we demonstrated that anlotinib blocked hepatocyte growth factor (HGF)‐induced cell migration, invasion and VEGF‐induced angiogenesis. Notably, a 143B‐Luc orthotopic osteosarcoma model further showed that anlotinib significantly inhibited growth and lung metastasis of implanted tumor cells. Our preclinical work indicates that anlotinib acts as a novel inhibitor of VEGFR2 and MET that blocks tumorigenesis in osteosarcoma, which could be translated into future clinical trials.

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Toosendanin demonstrates promising antitumor efficacy in osteosarcoma by targeting STAT3

Cited by 103 publications

References 43 publications

Antitumor activity of Raddeanin A is mediated by Jun amino‐terminal kinase activation and signal transducer and activator of transcription 3 inhibition in human osteosarcoma

Antitumor activity of Raddeanin A is mediated by Jun amino‐terminal kinase activation and signal transducer and activator of transcription 3 inhibition in human osteosarcoma

Norcantharidin inhibits proliferation and promotes apoptosis via c‐Met/Akt/mTOR pathway in human osteosarcoma cells

Anlotinib, a novel small molecular tyrosine kinase inhibitor, suppresses growth and metastasis via dual blockade of VEGFR2 and MET in osteosarcoma

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