In vitro and in vivo characterization of a benzofuran derivative, a potential anticancer agent, as a novel Aurora B kinase inhibitor

AbstractAurora B kinase is aberrantly overexpressed in various tumors and shown to be a promising target for anti-cancer therapy. In human oral squamous cell carcinoma (OSCC), the high protein level of Aurora B is required for maintaining of malignant phenotypes, including in vitro cell growth, colony formation, and in vivo tumor development. By molecular modeling screening of 74 commercially available natural products, we identified that Tanshinone IIA (Tan IIA), as a potential Aurora B kinase inhibitor. The in silico docking study indicates that Tan IIA docks into the ATP-binding pocket of Aurora B, which is further confirmed by in vitro kinase assay, ex vivo pull-down, and ATP competitive binding assay. Tan IIA exhibited a significant anti-tumor effect on OSCC cells both in vitro and in vivo, including reduction of Aurora B and histone H3 phosphorylation, induction of G2/M cell cycle arrest, increase the population of polyploid cells, and promotion of apoptosis. The in vivo mouse model revealed that Tan IIA delayed tumor growth of OSCC cells. Tan IIA alone or in combination with radiation overcame radioresistance in OSCC xenograft tumors. Taken together, our data indicate that Tan IIA is an Aurora B kinase inhibitor with therapeutic potentials for cancer treatment.

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Targeting Aurora B kinase with Tanshinone IIA Suppresses Tumor Growth and Overcomes Radioresistance

10.21203/rs.3.rs-113416/v1 ◽

2020 ◽

Author(s):

Ming Li ◽

Feng Gao ◽

haidan liu ◽

Qin Zhao ◽

Shuangze Han ◽

...

Keyword(s):

Molecular Modeling ◽

Tumor Growth ◽

Kinase Inhibitor ◽

Inhibitory Effect ◽

Tanshinone Iia ◽

Aurora B ◽

Aurora B Kinase ◽

M Cell

Abstract Background Aurora B kinase is aberrantly overexpressed in various tumors and shown to be a promising target for anti-cancer therapy. Methods A customized natural product library was used for natural compound screening through Molecular modeling. The expression of Aurora B in oral squamous cell carcinoma (OSCC) and the inhibitory effect of Tanshinone IIA (Tan IIA) on OSCC were examined by MTS and colony formation assays, immunoblot, immunofluorescence, immunohistochemical staining, and in vivo xenograft experiment. Results Aurora B is overexpressed in OSCC tumor tissues and cell lines. Knockdown of Aurora B inhibited the malignant phenotypes of OSCC cells in vitro and in vivo. With a molecular modeling screening of 74 commercially available natural products, we identified that Tan IIA, as a potential Aurora B kinase inhibitor. Tan IIA exhibited a significant anti-tumor effect on OSCC cells both in vitro and in vivo, including reduction of Aurora B and histone H3 phosphorylation, induction of G2/M cell cycle arrest, increase the population of polyploid cells, and promotion of apoptosis. The in vivo mouse model revealed that Tan IIA delayed tumor growth of OSCC cells. Tan IIA alone or in combination with radiation overcame radioresistance in OSCC xenograft tumors. Conclusion Our data indicates that targeting Aurora B kinase signaling is a promising anti-tumor strategy for OSCC treatment.

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