ROS as a novel indicator to predict anticancer drug efficacy.


Zaidieh, Tarek; Smith, James R; Ball, Karen E; An, Qian

Publication Year 2019
Journal BMC Cancer
Pages 1224
Volume 19
Issue 1
PMID 31842863.0
PMCID PMC6916036
DOI 10.1186/s12885-019-6438-y

BACKGROUND: Mitochondria are considered a primary intracellular site of reactive oxygen species (ROS) generation. Generally, cancer cells with mitochondrial genetic abnormalities (copy number change and mutations) have escalated ROS levels compared to normal cells. Since high levels of ROS can trigger apoptosis, treating cancer cells with low doses of mitochondria-targeting / ROS-stimulating agents may offer cancer-specific therapy. This study aimed to investigate how baseline ROS levels might influence cancer cells' response to ROS-stimulating therapy. METHODS: Four cancer and one normal cell lines were treated with a conventional drug (cisplatin) and a mitochondria-targeting agent (dequalinium chloride hydrate) separately and jointly. Cell viability was assessed and drug combination synergisms were indicated by the combination index (CI). Mitochondrial DNA copy number (mtDNAcn), ROS and mitochondrial membrane potential (MMP) were measured, and the relative expression levels of the genes and proteins involved in ROS-mediated apoptosis pathways were also investigated. RESULTS: Our data showed a correlation between the baseline ROS level, mtDNAcn and drug sensitivity in the tested cells. Synergistic effect of both drugs was also observed with ROS being the key contributor in cell death. CONCLUSIONS: Our findings suggest that mitochondria-targeting therapy could be more effective compared to conventional treatments. In addition, cancer cells with low levels of ROS may be more sensitive to the treatment, while cells with high levels of ROS may be more resistant. Doubtlessly, further studies employing a wider range of cell lines and in vivo experiments are needed to validate our results. However, this study provides an insight into understanding the influence of intracellular ROS on drug sensitivity, and may lead to the development of new therapeutic strategies to improve efficacy of anticancer therapy.