Doxorubicin (Dox) is one of the most commonly used anthracyclines for the treatment of solid and hematological tumors such as B-/T cell acute lymphoblastic leukemia (ALL). Dox compromises topoisomerase II enzyme functionality, thus inducing structural damages during DNA replication and causes direct damages intercalating into DNA double helix. Eukaryotic cells respond to DNA damages by activating the ATM-CHK2 and/or ATR-CHK1 pathway, whose function is to regulate cell cycle progression, to promote damage repair, and to control apoptosis. We evaluated the efficacy of a new drug schedule combining Dox and specific ATR (VE-821) or CHK1 (prexasertib, PX) inhibitors in the treatment of human B-/T cell precursor ALL cell lines and primary ALL leukemic cells. We found that ALL cell lines respond to Dox activating the G2/M cell cycle checkpoint. Exposure of Dox-pretreated ALL cell lines to VE-821 or PX enhanced Dox cytotoxic effect. This phenomenon was associated with the abrogation of the G2/M cell cycle checkpoint with changes in the expression pCDK1 and cyclin B1, and cell entry in mitosis, followed by the induction of apoptosis. Indeed, the inhibition of the G2/M checkpoint led to a significant increment of normal and aberrant mito...Continue Reading
Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity
The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia
Doxorubicin activates ATM-dependent phosphorylation of multiple downstream targets in part through the generation of reactive oxygen species.
Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents
Defining the ATM-mediated barrier to tumorigenesis in somatic mammary cells following ErbB2 activation.
Dose- and time-dependent effects of doxorubicin on cytotoxicity, cell cycle and apoptotic cell death in human colon cancer cells
A randomized study of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in elderly patients with acute lymphoblastic leukemia: the GRAALL-SA1 study
Outcome of treatment of adult acute lymphoblastic leukemia with hyperfractionated cyclophosphamide, doxorubicin, vincristine, dexamethasone/methotrexate, cytarabine: results from an Australian population
MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts
Effects of the novel DNA dependent protein kinase inhibitor, IC486241, on the DNA damage response to doxorubicin and cisplatin in breast cancer cells.
Thr-1989 phosphorylation is a marker of active ataxia telangiectasia-mutated and Rad3-related (ATR) kinase.
FLAG-liposomal doxorubicin (Myocet) regimen for refractory or relapsed acute leukemia pediatric patients
Elevated cyclin G2 expression intersects with DNA damage checkpoint signaling and is required for a potent G2/M checkpoint arrest response to doxorubicin.
Synergistic cytotoxic effects of inorganic phosphate and chemotherapeutic drugs on human osteosarcoma cells
Preclinical evaluation of a novel ATM inhibitor, KU59403, in vitro and in vivo in p53 functional and dysfunctional models of human cancer
Improved ataxia telangiectasia mutated kinase inhibitor KU60019 provides a promising treatment strategy for non-invasive breast cancer
Aven-mediated checkpoint kinase control regulates proliferation and resistance to chemotherapy in conventional osteosarcoma
Imatinib inhibits inactivation of the ATM/ATR signaling pathway and recovery from adriamycin/doxorubicin-induced DNA damage checkpoint arrest
Doxorubicin-induced necrosis is mediated by poly-(ADP-ribose) polymerase 1 (PARP1) but is independent of p53
CHK1 and replicative stress in T-cell leukemia: Can an irreverent tumor suppressor end up playing the oncogene?
Prexasertib, a Chk1/Chk2 inhibitor, increases the effectiveness of conventional therapy in B-/T- cell progenitor acute lymphoblastic leukemia
Inhibition of DNA-PK enhances chemosensitivity of B-cell precursor acute lymphoblastic leukemia cells to doxorubicin
Chemotherapy-induced differential cell cycle arrest in B-cell lymphomas affects their sensitivity to Wee1 inhibition
The PARP inhibitor olaparib potentiates the effect of the DNA damaging agent doxorubicin in osteosarcoma
Metronomic oral doxorubicin in combination of Chk1 inhibitor MK-8776 for p53-deficient breast cancer treatment
Beta1 integrin blockade overcomes doxorubicin resistance in human T-cell acute lymphoblastic leukemia
An ATR and CHK1 kinase signaling mechanism that limits origin firing during unperturbed DNA replication
Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis