Francesco Gentile, Jack A. Tuszynski and Khaled H. Barakat Pages 3527 - 3546 ( 20 )
Background: A major class of chemotherapy drugs targets the genome of cancer cells. These DNA damaging agents induce damage to the DNA helix, resulting in the programmed death of cancer cells. An overactivated DNA repair mechanism in cancer cells can reduce the efficacy of these drugs, thereby eliminating their therapeutic benefit and developing an acquired resistance to these otherwise effective drugs. A promising approach to enhance the therapeutic window of DNA damaging agents is to target the DNA repair pathways causing this type of resistance. Methods: Computational approaches have been applied successfully to study many of these DNA repair mechanisms at different scales and focusing on various aspects. The ultimate goal of these studies has been to identify the key players in developing resistance to DNA damaging agents and to design regulators for their activities. This review covers the most important and recent computational efforts toward this goal. This includes modelling the mechanisms involved in DNA repair and identifying novel pharmacological inhibitors for their activities. Results: We focus here mainly on the pathways associated with an acquired drug resistance to DNA damaging agents, concentrating on the recent advances in modelling the key mechanisms and foreseeing the future directions in this field. Conclusion: We hope that this short, yet comprehensive review can help in discovering novel strategies to overcome the resistance effects inherent in various cancer treatments.
DNA repair, molecular modelling, drug resistance, small molecule inhibitors, cancer chemotherapy.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.