Abstract
Aurora A kinase (Aurora A) is a serine/threonine kinase regulating control of multiple events during cell-cycle progression. Playing roles in promoting proliferation and inhibiting cell death in cancer cells leads Aurora A to become a target for cancer therapy. It is overexpressed and associated with a poor prognosis in ovarian cancer. Improving cisplatin therapy outcomes remains an important issue for advanced-stage ovarian cancer treatment, and Aurora A inhibitors may improve it. In the present study, we identified natural compounds with higher docking scores than the known Aurora A ligand through structure-based virtual screening, including the natural compound fangchinoline, which has been associated with anticancer activities but not yet investigated in ovarian cancer. The binding and inhibition of Aurora A by fangchinoline were verified using cellular thermal shift and enzyme activity assays. Fangchinoline reduced viability and proliferation in ovarian cancer cell lines. Combination fangchinoline and cisplatin treatment enhanced cisplatin–DNA adduct levels, and the combination index revealed synergistic effects on cell viability. An in vivo study showed that fangchinoline significantly enhanced cisplatin therapeutic effects in OVCAR-3 ovarian cancer-bearing mice. Fangchinoline may inhibit tumor growth and enhance cisplatin therapy in ovarian cancer. This study reveals a novel Aurora A inhibitor, fangchinoline, as a potentially viable adjuvant for ovarian cancer therapy.
Highlights
Licensee MDPI, Basel, Switzerland.Ovarian cancer, the fifth cause of cancer-related deaths among women in the UnitedStates [1], leads to 152,000 deaths annually in the world [2]
Structure-based virtual screening (VS) using the molecular docking methodology has been broadly apStructure-based VS using the molecular docking methodology has been broadly applied for the purposes of drug discovery for over a decade [29,30]
To identify potential small molecules able to bind the active site of a target protein, many useful VS docking tools small molecules able to bind the active site of a target protein, many useful VS docking have been developed, such as DOCK, AutoDock Vina, and GOLD [30]
Summary
The fifth cause of cancer-related deaths among women in the United. States [1], leads to 152,000 deaths annually in the world [2]. Because the symptoms are not obvious during early stages, approximately 70% of patients are diagnosed with ovarian cancer at advanced stages, with poor prognosis [3]. The five-year relative survival rate is approximately 45%. The standard treatment for ovarian cancer consists of cytoreductive surgery, followed by cisplatin-based chemotherapy [4].
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