Imatinib inhibits inactivation of the ATM/ATR signaling pathway and recovery from adriamycin/doxorubicin‐induced DNA damage checkpoint arrest

Abstract

The DNA damage checkpoint arrests cell cycle progression to allow time for DNA repair. After completion of DNA repair, checkpoint activation is terminated, and cell cycle progression is resumed in a process called checkpoint recovery. The activation of the checkpoint has been studied in depth, but little is known about recovery from the DNA damage checkpoint. Recently we showed that Src family kinases promote recovery from the G2 DNA damage checkpoint. Here we show that imatinib inhibits inactivation of ATM/ATR signaling pathway to suppress recovery from Adriamycin/doxorubicin-induced DNA damage checkpoint arrest. Imatinib and pazopanib, two distinct inhibitors of PDGFR/c-Kit family kinases, delayed recovery from checkpoint arrest and inhibited the subsequent S-G2-M transition after Adriamycin exposure. By contrast, imatinib and pazopanib did not delay the recovery from checkpoint arrest in the presence of an ATM/ATR inhibitor caffeine. Consistently, imatinib induced a persistent activation of ATR-Chk1 signaling. By the way, the maintenance of G2 checkpoint arrest is largely dependent on ATR-Chk1 signaling. However, unlike Src inhibition, imatinib did not delay the recovery from checkpoint arrest in the presence of an ATM inhibitor KU-55933. Furthermore, imatinib induced a persistent activation of ATM-KAP1 signaling, and a possible involvement of imatinib in an ATM-dependent DNA damage response is suggested. These results reveal that imatinib inhibits recovery from Adriamycin-induced DNA damage checkpoint arrest in an ATM/ATR-dependent manner and raise the possibility that imatinib may inhibit resumption of tumor proliferation after chemo- and radiotherapy.

Combinatorial high-throughput experimental and bioinformatic approach identifies molecular pathways linked with the sensitivity to anticancer target drugs

“…This observation is in line with previously reported fail of clinical trials of Pazopanib in castrate-sensitive (androgen signaling-negative) prostate cancer patients [ 18 ]. For positively-correlated pathways, we found a recent literature report that Pazopanib most likely suppresses cell cycle progression in cancer cells by preventing inactivation of ATM checkpoint signaling [ 19 ]. Thus, enhanced activity of Pazopanib may be linked with dynamic trans-activation of ATM, which is originally suppressed in a cancer cell, in good agreement with the positive correlation discovered here.…”

Tyrosine kinase inhibitors protect the salivary gland from radiation damage by increasing DNA double-strand break repair

“…Activation of c-Abl often results in increased DNA instability, either through inhibition of DNA repair, or by activation of SSA and alt-NHEJ mediated DNA repair (48)(49)(50). In contrast, inhibition of c-Abl with imatinib can decrease SSA (51), inhibit inactivation of ATM/ATR signaling (52), and increase NHEJ (53).…”

Arsenic trioxide inhibits glioma cell growth through induction of telomerase displacement and telomere dysfunction

“…Cell cycle arrest is another result of DNA damage [ 45 ]. ATM and ATR are major signals of G2-M phase arrest resulting from DNA damage [ 46 ]. The phosphorylation of PI3k and p53 by ATM induces the cell cycle block [ 47 , 48 ].…”