Abstract
Topotecan is a clinically active anticancer agent for the management of various human tumors. While the principal mechanism of tumor cell killing by topotecan is due to its interactions with topoisomerase I and formation of DNA double-strand breaks, recent studies suggest that mechanisms involving generation of reactive free radicals and induction of oxidative stress may play a significant role in topotecan-dependent tumor cell death. We have shown that topotecan generates a topotecan radical following one-electron oxidation by a peroxidase-hydrogen peroxide system which reacts with reduced glutathione and cysteine, forming the glutathiyl and cysteinyl radicals, respectively. While little is known how these events are involved in topotecan-induced tumor cell death, we have now examined the effects of topotecan short (1 h) and long (24 h) exposure on global gene expression patterns using gene expression microarray analysis in human breast MCF-7 cancer cells, a wild-type p53 containing cell line. We show here that topotecan treatment significantly down-regulated estrogen receptor alpha (ERα/ESR1) and antiapoptotic BCL2 genes in addition to many other p53-regulated genes. Furthermore, 8-oxoguanine DNA glycosylase (OGG1), ferredoxin reductase (FDXR), methionine sulfoxide reductase (MSR), glutathione peroxidases (GPx), and glutathione reductase (GSR) genes were also differentially expressed by topotecan treatment. The differential expression of these genes was observed in a wild-type p53-containing breast ZR-75-1 tumor cell line following topotecan treatment. The involvement of reactive oxygen free radical sensor genes, the oxidative DNA damage (OGG1) repair gene and induction of pro-apoptotic genes suggest that reactive free radical species play a role in topotecan-induced tumor cell death.
Highlights
Gene expression profiling is an important tool to understand pharmacological effects of drugs in complex biological systems (Kannan et al, 2001; Daoud et al, 2003; L’Esperance et al, 2008; Januchowski et al, 2017; Qin et al, 2017; Monks et al, 2018)
We used MCF-7 breast cancer cells to show that TPT is readily oxidized to a free radical intermediate (TPT) and we found that ascorbic acid, a cellular generator of hydrogen peroxide, was extremely synergistic with TPT in inducing cell death (Sinha et al, 2017)
One of the main reasons for utilizing MCF-7 tumor cells to identify free radical based pathways for TPT-induced tumor cell death was that we have shown that MCF-7 breast tumor cells are extremely efficient in activating adriamycin to its free radical species and these cells contain significant numbers of free radical-based detoxification enzymes e.g., SOD, catalase and Glutathione peroxidases (GPx) (Sinha et al, 1987, 1989)
Summary
Gene expression profiling is an important tool to understand pharmacological effects of drugs in complex biological systems (Kannan et al, 2001; Daoud et al, 2003; L’Esperance et al, 2008; Januchowski et al, 2017; Qin et al, 2017; Monks et al, 2018). These observations, taken together, suggest that TPT-dependent ROS formation could contribute to topo I-induced DNA damage and cytotoxicity
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