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

摘要

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 G(2)-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.