LCS-1 inhibition of superoxide dismutase 1 induces ROS-dependent death of glioma cells and degradates PARP and BRCA1

Abstract

Gliomas are characterized by high morbidity and mortality, and have only slightly increased survival with recent considerable improvements for treatment. An innovative therapeutic strategy had been developed via inducing ROS-dependent cell death by targeting antioxidant proteins. In this study, we found that glioma tissues expressed high levels of superoxide dismutase 1 (SOD1). The expression of SOD1 was upregulated in glioma grade III and V tissues compared with that in normal brain tissues or glioma grade I tissues. U251 and U87 glioma cells expressed high levels of SOD1, low levels of SOD2 and very low levels of SOD3. LCS-1, an inhibitor of SOD1, increased the expression SOD1 at both mRNA and protein levels slightly but significantly. As expected, LCS-1 caused ROS production in a dose- and time-dependent manner. SOD1 inhibition also induced the gene expression of HO-1, GCLC, GCLM and NQO1 which are targeting genes of nuclear factor erythroid 2-related factor 2, suggesting the activation of ROS signal pathway. Importantly, LCS-1 induced death of U251 and U87 cells dose- and time-dependently. The cell death was reversed by the pretreatment of cells with ROS scavenges NAC or GSH. Furthermore, LCS-1 decreased the growth of xenograft tumors formed by U87 glioma cells in nude mice. Mechanistically, the inhibition of P53, caspases did not reverse LCS-1-induced cell death, indicating the failure of these molecules involving in cell death. Moreover, we found that LCS-1 treatment induced the degradation of both PARP and BRCA1 simultaneously, suggesting that LCS-1-induced cell death may be associated with the failure of DNA damage repair. Taking together, these results suggest that the degradation of both PARP and BRCA1 may contribute to cell death induced by SOD1 inhibition, and SOD1 may be a target for glioma therapy.

SOD1is a synthetic lethal target inPPM1D-mutant leukemia cells

“…In the context of PPM1D mutations, we showed that SOD1 inhibition amplifies oxidative stress and DNA damage, ultimately culminating in mutant cell death. These findings align with previous studies demonstrating that the inhibition of SOD1 by LCS-1 leads to the degradation of key DNA repair proteins, PARP1 and BRCA1, resulting in ROS-dependent death of glioma cells (Ling et al, 2022). Similar observations were made in colorectal cancer models, where LCS-1 treatment enhanced the effectiveness of PARP1 inhibition.…”

“…This sensitivity could be rescued upon supplementation with the antioxidant, NAC, consistent with a role in reducing the impact of reactive oxygen species. However, given potential off-target effects of LCS-1 (Ling et al, 2022; Steverding and Barcelos, 2020) we cannot verify that the cytotoxic effects are via its activity toward SOD1. Similarly, we cannot rule out that effects of ATN-224 are not due to other effects caused by copper chelation (Chidambaram et al, 1984; Lee et al, 2013; Lowndes et al, 2008; Lowndes et al, 2009).…”

Evolutionary conserved and divergent responses to copper zinc superoxide dismutase inhibition in plants

“…3). This inhibition of cell growth was also observed for tumor cells (Somwar et al, 2011;Ling et al, 2022), whereby cell death is triggered by higher concentrations (20 µM). Thus, LCS-1 is able to inhibit cell growth in both eukaryotic systems, humans and plants.…”

Oxidative Stress Inducers in Cancer Therapy: Preclinical and Clinical Evidence

“…Downstream of ROS generation, oxidative DNA damage-induced apoptosis [ 105 ], ER stress [ 107 ], loss of mitochondrial integrity [ 104 ], and loss of proteosome function [ 107 ] have been reported as anticancer effects of LCS-1. Recently, Ling et al reported that the anticancer activity of LCS-1 was independent of p53 function and that LCS-1 induced degradation of PARP and BRCA1 [ 108 ], suggesting that it inhibited DNA repair pathways. In contrast with numerous in vitro studies, only two studies [ 107 , 108 ] have assessed the in vivo activity of LCS-1 owing to its poor aqueous solubility and, hence, bioavailability.…”

“…Recently, Ling et al reported that the anticancer activity of LCS-1 was independent of p53 function and that LCS-1 induced degradation of PARP and BRCA1 [ 108 ], suggesting that it inhibited DNA repair pathways. In contrast with numerous in vitro studies, only two studies [ 107 , 108 ] have assessed the in vivo activity of LCS-1 owing to its poor aqueous solubility and, hence, bioavailability. However, LCS-1-loaded triple-polymer-coated magnetite nanocarrier exhibit enhanced efficacy, which could overcome this limitation [ 109 ].…”