RESUMEN
Cancers frequently have increased ROS levels due to disrupted redox balance, leading to oxidative DNA and protein damage, mutations, and apoptosis. The MTH1 protein plays a crucial role by sanitizing the oxidized dNTP pools. Hence, cancer cells rely on MTH1 to prevent the integration of oxidized dNTPs into DNA, preventing DNA damage and allowing cancer cell proliferation. We have discovered Thymoquinone (TQ) and Baicalin (BC) as inhibitors of MTH1 using combined docking and MD simulation approaches complemented by experimental validations via assessing binding affinity and enzyme inhibition. Docking and MD simulations studies revealed an efficient binding of TQ and BC to the active site pocket of the MTH1, and the resultant complexes are appreciably stable. Fluorescence measurements estimated a strong binding affinity of TQ and BC with Ka 3.4 ×106 and 1.0 ×105, respectively. Treating breast cancer cells with TQ and BC significantly inhibited the growth and proliferation (IC50 values 28.3⯵M and 34.8⯵M) and induced apoptosis. TQ and BC increased the ROS production in MCF7 cells, imposing substantial oxidative stress on cancer cells and leading to cell death. Finally, TQ and BC are proven strong MTH1 inhibitors, offering promising prospects for anti-cancer therapy.
Asunto(s)
Neoplasias de la Mama , Flavonoides , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Especies Reactivas de Oxígeno , Benzoquinonas/farmacología , Benzoquinonas/uso terapéutico , Apoptosis , Nucleótidos/metabolismo , ADN , Monoéster Fosfórico Hidrolasas/genética , Línea Celular TumoralRESUMEN
MTH1 enzyme belongs to the family of Nudix hydro-lases, which can prevent the oxidative damage of nucleic acid by cleaning up oxidized purine nucleotides .Close relationships were found between the activity of MTH 1 and neurodegenerative dis-eases, anti-aging et al.In recent years, MTH1 has been regar-ded as a new promising target for cancer treatment , because it plays an essential role in tumor growth , survival , invasion and metastasis.The transcription and translation , structure, catalyt-ic mechanism, detection and application of MTH1 were de-scribed, as well as various MTH1 inhibitors.