# DNA Damage Response and Redox Status in the Resistance of Multiple Myeloma Cells to Genotoxic Treatment

## TL;DR

This study explores how DNA repair and cell stress levels affect how well multiple myeloma cells resist DNA-damaging treatments.

## Contribution

The study identifies new correlations between DNA damage response, redox status, and treatment resistance in multiple myeloma cells.

## Key findings

- MM cell lines with higher apoptosis had increased baseline DNA damage and reduced GSH/GSSG ratio.
- Cells with higher DNA damage and poor repair capacity showed greater sensitivity to melphalan.
- Chromatin structure and repair capacities correlated with treatment response in MM cells.

## Abstract

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 defense, can significantly impact cell viability, leading to cell death or survival. Herein, we tested the hypothesis that DDR-related signals and redox status measured in multiple myeloma (MM) cell lines correlate with the sensitivity to genotoxic insults. At baseline and following irradiation with Ultraviolet C (UVC; 50 J/m2) or treatment with melphalan (100 μg/mL for 5 min) DDR-related parameters, redox status expressed as GSH/GSSG ratio and apurinic/apyrimidinic sites were evaluated in a panel of eleven human MM cell lines and one healthy B lymphoblastoid cell line. We found that MM cell lines with increased apoptosis rates displayed significantly higher levels of endogenous/baseline DNA damage, reduced GSH/GSSG ratio, augmented 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, specifically melphalan, and, if further validated, may be exploited as novel sensitive/effective biomarkers.