ROS as a Novel Indicator to Predict Anticancer Drug Efficacy

Abstract

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.

Mitochondrial DNA abnormalities provide mechanistic insight and predict reactive oxygen species-stimulating drug efficacy

“…Baseline intracellular ROS levels were positively correlated with the resistance levels to both drugs in the cell lines ( Fig. 3a & b), con rming our previous observations [36]. Positive correlations between mtDNAcn and intracellular ROS, mitochondrial superoxide ( Fig.…”

“…However, how speci c mtDNA variations in uence the e cacy of mitochondria-targeting/ROS-stimulating therapy remains unclear. Our previous data have shown that elevated baseline intracellular ROS levels among different cancer cell lines correlate positively with increased resistance towards cisplatin and dequalinium, both being ROS-stimulating drugs [36]. We hypothesised that certain mitochondrial genetic abnormalities, including variations and copy number (mtDNAcn) changes, could in uence intracellular ROS levels, and therefore be utilised as biomarkers to predict cancer cells' response to ROS-stimulating agents.…”

“…Our previous study showed a positive correlation between baseline intracellular ROS levels and drug response in human cancer cell lines. Therefore, baseline ROS levels were proposed as a novel biomarker to predict drug sensitivity [36]. However, since measuring ROS in tissues is technically challenging, a more straightforward, e.g.…”

The potential value of dequalinium chloride in the treatment of cancer: Focus on malignant glioma

“…Mitochondria are involved in many cellular processes, such as cellular energy metabolism, cellular communication, differentiation and apoptosis 14 . Changes in mitochondrial structure lead to disruption of mitochondrial membrane potential, unstable electron transport reaction, resulting in excessive production of reactive oxygen species, activation of caspase cascade reaction, and initiation of apoptosis pathway 15,16 . Abnormal mitochondrial function is closely associated with the characteristics of cancer cells, such as enhanced anabolism, unlimited proliferation potential, insensitivity to anti‐growth signals, impaired apoptosis, and reduced autophagy 16 .…”

“…The use of mitochondria‐targeted cations in anti‐cancer therapy has two advantages. One is that they have a synergistic killing effect and the other is that because of their higher membrane potential compared to those of mitochondria in normal cells, they preferentially enter mitochondrial cancer cells, which allows cations to selectively target cancer cells and accumulate faster in mitochondria 15,17,18 . Mitochondria mediate the apoptosis cascade and the dormancy of the apoptosis mechanism has been emphasized as a key factor for therapeutic resistance, recurrence, and poor prognosis in patients with malignant tumours such as GBM 19 .…”