The Checkpoint Kinase Inhibitor AZD7762 Potentiates Chemotherapy Induced Apoptosis of p53 Mutated Multiple Myeloma Cells
Menée sur des lignées cellulaires de myélome multiple présentant une mutation de p53, cette étude montre qu'un composé appelé AZD7762, un inhibiteur de Chk1/2, augmente l'efficacité de divers agents de chimiothérapie
DNA cross-linking agents are frequently used in the treatment of multiple myeloma (MM) generating lesions which activate checkpoint kinase 1 (Chk1), a critical transducer of the DNA damage response. Chk1 activation promotes cell survival by regulating cell cycle arrest and DNA repair following genotoxic stress. The ability of AZD7762, an ATP-competitive Chk1/2 inhibitor to increase the efficacy of the DNA damaging agents bendamustine, melphalan and doxorubicin was examined using four human myeloma cell lines, KMS-12-BM, KMS-12-PE, RPMI-8226, and U266B1. The in vitro activity of AZD7762 as monotherapy and combined with alkylating agents and the "novel" drug bortezomib was evaluated by studying its effects on cytotoxicity, signaling and apoptotic pathways. The Chk1/2 inhibitor AZD7762 potentiated the anti-proliferative effects of bendamustine, melphalan and doxorubicin but not bortezomib in MM cell lines that were p53-deficient. Increased γH2AX staining in cells treated with bendamustine or melphalan plus AZD7762 indicates a greater degree of DNA damage with combined therapy. Abrogation of the G2/M checkpoint by AZD7762 resulted in mitotic catastrophe with ensuing apoptosis evidenced by PARP and caspase 3 cleavage. In summary, the cytotoxic effects of bendamustine, melphalan and doxorubicin on p53-deficient MM cell lines were enhanced by the co-administration of AZD7762. These data provide a rationale for testing these combinations in patients with relapsed and/or refractory MM.
http://mct.aacrjournals.org/content/early/2012/05/30/1535-7163.MCT-11-0949.abstract