Natural bioactive compounds-doxorubicin combinations targeting topoisomerase II-alpha: Anticancer efficacy and safety

Cancer is one of the leading causes of death worldwide, so pursuing effective and safe therapeutics for cancer is a key research objective nowadays. Doxorubicin (DOX) is one of the commonly prescribed chemotherapeutic agents that has been used to treat cancer with its antimitotic properties via inhibition of topoisomerase II (TOP2) activity. However, many problems hinder the broad use of DOX in clinical practice, including cardiotoxicity and drug resistance. Research in drug discovery has confirmed that natural bioactive compounds (NBACs) display a wide range of biological activities correlating to anticancer outcomes. The combination of NBACs has been seen to be an ideal candidate that might increase the effectiveness of DOX therapy and decreases its unfavorable adverse consequences. The current review discusses the chemo-modulatory mechanism and the protective effects of combined DOX with NBACs with a binding affinity (pKi) toward TOP2A more than pKi of DOX. This review will also discuss and emphasize the molecular mechanisms to provide a pathway for further studies to reveal other signaling pathways. Taken together, understanding the fundamental mechanisms and implications of combined therapy may provide a practical approach to battling cancer diseases.