title: Targeting p53-deficient chronic lymphocytic leukemia cells in vitro and in vivo by ROS-mediated mechanism.
abstract: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries. Loss of p53 function in CLL cells due to chromosome 17p deletion or p53 mutations often leads to a more malignant disease phenotype and is associated with drug resistance and poor clinical outcome. Thus, development of novel therapeutic strategies to effectively target CLL cells with p53 deficiency is clinically important. Here we showed that p53-null CLL cells were highly sensitive to ROS-mediated cell killing due to their intrinsic ROS stress. We further demonstrated that a natural compound phenethyl isothiocyanate (PEITC) was able to effectively kill CLL cells with loss of p53, even under the protection of stromal cells. In p53-defficient CLL cells, PEITC induced a rapid depletion of glutathione and a severe accumulation of ROS, leading to massive leukemia cell death in the stromal microenvironment. The drug-induced cell death was associated with a significant decrease of in MCL-1 survival molecule. We further showed that ROS-mediated cell death was the key mechanism by which PEITC induced cytotoxicity, since such cell death could be prevented by addition of antioxidant NAC. Importantly, in vivo study showed that PEITC was able to induce substantial leukemia cell death in mice. Treatment of CLL mice harboring TCL1-Tg:p53-/- genotype with PEITC significantly prolonged the median survival time of the animals. Our study identifies a vulnerability of p53-null CLL cells with high sensitivity to ROS-generating agents, and suggests that PEITC may potentially be useful for clinical treatment of CLL with 17p deletion and p53 mutations.
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jinyun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Helene
authors.initials: H
authors.lastname: Pelicano
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Liao
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Feng
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.|Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
mesh_terms: D000818:Animals; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D017879:Isothiocyanates / Q000627:therapeutic use*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D051379:Mice; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D017879:Isothiocyanates; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C058305:phenethyl isothiocyanate; D005978:Glutathione
keywords: CLL; PEITC; oxidative stress; p53