DNA damage response and repair in osteosarcoma: Defects, regulation and therapeutic implications
DNA damage response and repair in osteosarcoma: Defects, regulation and therapeutic implications
Fatemeh Sadoughi,1,*Parisa Maleki Dana,2Zatollah Asemi,3Bahman Yousefi ,4
1. Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, I.R. Iran 2. Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, I.R. Iran 3. Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, I.R. Iran 4. Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
Introduction: Osteosarcoma (OS) is the most common primary malignancy developing bones. This disease which predominantly is developed in the metaphysis of long bones is able to show invasion and systemic metastases. In the late 70s, the 5-year survival rate of patients with OS has been estimated to be approximately 20%. In recent years, by the aid of new therapeutic methods the 5-year survival rate of OS has been improved to 78% in patients with localized disease; However, metastatic or recurrent forms of the disease have kept their 20% survival rate. DNA damage response (DDR) is a sophisticated multistep process containing a diversity of proteins which are necessary for the survival of any cell and organism. DDR machinery is able to detect abundant DNA lesions and afterwards, inhibiting the cell cycle progression when these lesions are not repairable. DDR is involved in a line of diseases including cancer. In recent years, DDR inhibitors have gained great attention due to their potentials in offering novel therapeutic targets and improving the response of many cancers to either chemo- or radio-therapy.
Methods: Surveying different articles related to our subject by using several search engines like google scholar, PubMed, and Scopus. We have tried to gather the most recent studies about the roles of DDR ingredients in OS pathogenesis and how these ingredients can be targeted for therapeutic purposes.
Results: According to evidence, a diversity of DDR ingredients are involved in the pathogenesis of OS. For instance, MRN complex (including MRE11, NBS1, and RAD50), PARP1, γH2AX, ATR/CHK1, MDC1, ATM/CHK2, BRCA1, EXO1, RAD51, and RAD52 are some of these ingredients with significant roles in OS initiation, progression, and resistance to therapies. Furthermore, a majority of these proteins can be used as therapeutic targets in order to increase the response of OS cells to either chemo or radiotherapy. For instance, different PARP1 inhibitors like Olaparib and 3-aminobenzamide, H2AX inhibitors like miR 328 3p and miR-138, CHK1 inhibitors like Prexasertib, ATR inhibitors like Berzosertib, and CHK2 inhibitors like miR-191 are approved to be effective on OS cells.
Conclusion: Taken together, a majority of DDR-related proteins and genes are involved in OS initiation and/or progression and thus, DDR ingredients are considered proper options for treating OS patients. the least advantages of utilizing DDR inhibitors for osteosarcoma treatment is chemo- and radio-sensitization and thus, DDR inhibition is a promising procedure for enhancing the survival rate and prognosis of this cancer in the coming years.