DNA Damage Response and Oxidative Stress in the Resistance of Multiple Myeloma Cells to Genotoxic Treatment

The DNA Damage Response (DDR) network is an essential machinery for maintaining genomic integrity, with DDR defects being implicated in cancer initiation, progression and treatment resistance. Moreover, oxidative stress, an imbalance between reactive oxygen species production and antioxidant defence, can significantly impact cell viability, leading to cell death or survival. Herein, we tested the hypothesis that DDR-related signals and oxidative stress status measured in multiple myeloma (MM) cell lines correlate with the sensitivity to genotoxic insults. In a panel of eleven human MM cell lines and one healthy B lymphoblastoid cell line, oxidative stress, apurinic/apyrimidinic sites and DDR-related parameters, including endogenous/baseline DNA damage, critical DNA repair mechanisms, chromatin condensation and apoptosis rates were evaluated. We found that MM cell lines with increased apoptosis rates displayed significantly higher levels of endogenous/baseline DNA damage, increased oxidative stress and apurinic/apyrimidinic lesions, decreased nucleotide excision repair and interstrand crosslinks repair capacities and highly condensed chromatin structure. Taken together, these findings demonstrate that DDR-related parameters and redox status correlate with the sensitivity of MM cells to DNA damaging agents and, if further validated, may be exploited as novel therapeutic targets and sensitive/effective biomarkers.