Identification of early gene expression changes in primary cultured neurons treated with topoisomerase I poisons

Abstract

Topoisomerase 1 (TOP1) poisons like camptothecin (CPT) are currently used in cancer chemotherapy but these compounds can have damaging, off-target effects on neurons leading to cognitive, sensory and motor deficits. To understand the molecular basis for the enhanced sensitivity of neurons to CPT, we examined the effects of compounds that inhibit TOP1—CPT, actinomycin D (ActD) and β-lapachone (β-Lap)—on primary cultured rat motor (MN) and cortical (CN) neurons as well as fibroblasts. Neuronal cells expressed higher levels of Top1 mRNA than fibroblasts but transcript levels are reduced in all cell types after treatment with CPT. Microarray analysis was performed to identify differentially regulated transcripts in MNs in response to a brief exposure to CPT. Pathway analysis of the differentially expressed transcripts revealed activation of ERK and JNK signaling cascades in CPT-treated MNs. Immediate-early genes like Fos, Egr-1 and Gadd45b were upregulated in CPT-treated MNs. Fos mRNA levels were elevated in all cell types treated with CPT; Egr-1, Gadd45b and Dyrk3 transcript levels, however, increased in CPT-treated MNs and CNs but decreased in CPT-treated fibroblasts. These transcripts may represent new targets for the development of therapeutic agents that mitigate the off-target effects of chemotherapy on the nervous system.

Peroxisomes contribute to oxidative stress in neurons during doxorubicin-based chemotherapy

“…Some other drugs damage mitochondria (e.g., paclitaxel and vincristine), leading to energy dyshomeostasis, production of reactive oxygen species (ROS), and oxidative stress (Broyl et al, 2010;Flatters and Bennett, 2006;Rzeski et al, 2004;Vijayanathan et al, 2011). Chemotherapy regimens based on the topoisomerase I poisons alter transcription in neurons (Mabb et al, 2016;Rossi et al, 2016). Overall, some or even all anti-cancer drugs may accelerate neuronal aging, leading to cognitive impairments and to increasing the risk for neurodegenerative diseases (Kesler, 2014;Kesler and Blayney, 2016;Kesler et al, 2015).…”