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Low-dose chemotherapeutic drugs induce reactive oxygen species and initiate apoptosis-mediated genomic instability.

ABSTRACT: Prolonged cancer cell survival, acquiring drug resistance, and secondary cancer development despite chemotherapy are the major challenges during cancer treatment, whose underlying mechanism still remains elusive. In this study, low-doses of chemotherapeutic drugs (LDCD) - doxorubicin (DOX), etoposide (ETOP), and busulfan (BUS) were used to ascertain the effect of residual concentrations of drugs on breast cancer cells. Our results showed that exposure to LDCD caused significant induction of ROS, early signs of apoptosis and accumulation of cells in S and G₂-M phases of the cell cycle in MCF-7 and MDA-MB-231 cell lines. Under drug-free recovery conditions, a decrease in the number of apoptotic cells and an increase in the number of colonies formed were observed. Analysis of the molecular mechanism showed lower expression of cleaved products of caspase 3, 9, PARP and occurrence of DNA strand breaks in recovered cells compared to LDCD-treated cells, suggesting incomplete cell death activation and survival of cells with genomic damage after therapeutic insult. Thus, LDCD induces defective apoptosis in cancer cells allowing a small population of cells to escape from cell cycle check points and survive with accumulated genetic damage that could eventually result in secondary cancers that warrants further studies for better therapeutic strategies.

SUBMITTER: Arun R

PROVIDER: S-EPMC6062221 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Low-dose chemotherapeutic drugs induce reactive oxygen species and initiate apoptosis-mediated genomic instability.

Arun Renganathan R Dhivya Sridaran S Abraham Suresh K SK Premkumar Kumpati K

Toxicology research 20160107 2

Prolonged cancer cell survival, acquiring drug resistance, and secondary cancer development despite chemotherapy are the major challenges during cancer treatment, whose underlying mechanism still remains elusive. In this study, low-doses of chemotherapeutic drugs (LDCD) - doxorubicin (DOX), etoposide (ETOP), and busulfan (BUS) were used to ascertain the effect of residual concentrations of drugs on breast cancer cells. Our results showed that exposure to LDCD caused significant induction of ROS, ...[more]

PMID: 30090369

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Project description:Diesel exhaust particles (DEPs) are a main contributor to air pollution. Ultrafine DEPs can cause neurodegenerative diseases by increasing intracellular reactive oxygen species (ROS). Compared with other cells in the brain, oligodendrocytes responsible for myelination are more susceptible to oxidative stress. However, the mechanisms underlying ROS generation in oligodendrocytes and the susceptibility of oligodendrocytes to ROS by ultrafine DEPs remain unclear. Herein, we examined the effects of excessive ROS generated by NOX2, an isoform of the NADPH oxidase family, after exposure to ultrafine DEPs (200 μg/mL) on the survival of two types of oligodendrocytes-oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes (mOLs)--isolated from the brain of neonatal rats. In addition, mice were exposed to ultrafine DEP suspension (20 μL, 0.4 mg/mL) via the nasal route for 1 week, after which the expression of NOX2 and cleaved caspase-3 was examined in the white matter of the cerebellum. Exposure to DEPs significantly increased NOX2 expression and ROS generation in OPCs and mOLs. OPCs and mOLs clearly exhibited viability reduction, and a significant change in p53, Bax, Bcl-2, and cleaved caspase-3 expression, after DEP exposure. In contrast, treatment with berberine (BBR), an NOX2 inhibitor, significantly mitigated these effects. In mice exposed to DEP, the presence of NOX2-positive and cleaved caspase-3-positive oligodendrocytes was demonstrated in the cerebellar white matter; NOX2 and cleaved caspase-3 expression in the cerebellum lysates was significantly increased. BBR treatment returned expression of these proteins to control levels. These results demonstrate that the susceptibility of OPCs and mOLs to ultrafine DEPs is, at least in part, caused by excessive ROS produced by NOX2 and the sequential changes in the expression of p53, Bax, Bcl-2, and cleaved caspase-3. Overall, NOX2 inhibitor enhances the survival of two types of oligodendrocytes.

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Low-dose chemotherapeutic drugs induce reactive oxygen species and initiate apoptosis-mediated genomic instability.

Publications

Low-dose chemotherapeutic drugs induce reactive oxygen species and initiate apoptosis-mediated genomic instability.

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