Rac1 Protein Signaling Is Required for DNA Damage Response Stimulated by Topoisomerase II Poisons

Abstract

Background: Topoisomerase inhibitors are potent anticancer drugs triggering cell death via induction of DNA damage. Results: DNA damage response stimulated by topoisomerase type I and II inhibitors is affected differently by Rac1 inhibition. Conclusion: Rac1 signaling is required for the formation of the DNA topoisomerase II cleavable complex. Significance: Membrane-bound Rac1 GTPase is essential for a full DNA damage response.

Synthesis and biological activity of 2,4-di-p-phenolyl-6-2-furanyl-pyridine as a potent topoisomerase II poison

“…We subsequently examined whether compounds 54, 56 and etoposide generated the accumulation of DNA strand breaks in HCT15 cells using comet assay. The more percentage of DNA in the tail implies more DNA strand breaks [42,43]. Figure 8B and C show that compound 56 (18.7 ± 5.2% at 10 µM and 46.7 ± 5.5% at 20 µM) induced significant tail at 20 µM treatment which is comparable to the extent induced by etoposide (43.0 ± 8.4% at 10 µM and 60.7 ± 8.4% at 20 µM).…”

Rac1 GTPase-deficient HeLa cells present reduced DNA repair, proliferation, and survival under UV or gamma irradiation

“…Recently, Rac1 was shown to be an essential GTPase involved in the DNA damage response and repair in cells lesioned by doxorubicin and etoposide topoisomerase II inhibitors, as well as in human breast cancer cells subjected to ionizing radiation treatment [9,43,44]. Additionally, in human liver injured by doxorubicin and other genotoxic stresses, Rac1 activity was demonstrated to be necessary to protect oncogene-transformed acute myeloid leukemia (AML) cells against apoptosis in the presence of DNA double-strand breaks (DSBs) induced by lipidlowering drugs that inhibit cholesterol synthesis [45].…”

Lovastatin protects keratinocytes from DNA damage-related pro-apoptotic stress responses stimulated by anticancer therapeutics

“…Taken together, lovastatin renders keratinocytes resistant to the genotoxic insult of doxorubicin, which is independent from mechanisms of drug transport, and IR. We assume that protection of keratinocytes from Doxo injury is related to an interference of lovastatin with topoisomerase II (topo II) function, as already reported for cardiomyocytes and liver cells [43,55,56]. It is hypothesized that lovastatin inhibits the activity of the Ras-homologous GTPase Rac1, which is required for topo II cleavable complex formation following treatment of cells with topo II poisons [43,55,56].…”