title: Multidrug resistance-associated protein-overexpressing teniposide-resistant human lymphomas undergo apoptosis by a tubulin-binding agent.
abstract: Several DNA- and microtubule-binding agents are used to manage hematologic malignancies in the clinic. However, drug resistance has been a challenge, perhaps due to a few surviving cancer stem cells. Toxicity is another major impediment to successful chemotherapy, leading to an impoverished quality of life. Here, we show that a semisynthetic nontoxic tubulin-binding agent, 9-bromonoscapine (EM011), effectively inhibits growth and regresses multidrug resistance-associated protein (MRP)-overexpressing teniposide-resistant T-cell lymphoma xenografts and prolongs longevity. As expected, teniposide treatment failed to regress teniposide-resistant xenografts, rather, treated mice suffered tremendous body weight loss. Mechanistically, EM011 displays significant antiproliferative activity, perturbs cell cycle progression by arresting mitosis, and induces apoptosis in teniposide-resistant lymphoblastoid T cells both in vitro and in vivo. EM011-induced apoptosis has a mitochondrially-mediated component, which was attenuated by pretreatment with cyclosporin A. We also observed alterations of apoptosis-regulatory molecules such as inactivation of Bcl2, translocation of BAX to the mitochondrial membrane, cytochrome c release, and activation of downstream apoptotic signaling. EM011 caused DNA degradation as evident by terminal deoxynucleotidyl transferase-mediated dUTP-biotin end labeling staining of the increased concentration of 3'-DNA ends. Furthermore, the apoptotic induction was caspase dependent as shown by cleavage of the caspase substrate, poly(ADP)ribose polymerase. In addition, EM011 treatment caused a suppression of natural survival pathways such as the phosphatidylinositol-3'-kinase/Akt signaling. These preclinical findings suggest that EM011 is an excellent candidate for clinical evaluation.
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. raneja@emory.edu
authors.forename: Ritu
authors.initials: R
authors.lastname: Aneja
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Clayton
authors.initials: C
authors.lastname: Yates
authors.forename: Jinmin
authors.initials: J
authors.lastname: Gao
authors.forename: Xin
authors.initials: X
authors.lastname: Dong
authors.forename: Binfei
authors.initials: B
authors.lastname: Zhou
authors.forename: Surya N
authors.initials: SN
authors.lastname: Vangapandu
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.forename: Harish C
authors.initials: HC
authors.lastname: Joshi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D004149:Dioxoles / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D007546:Isoquinolines / Q000494:pharmacology*; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding; D013713:Teniposide / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004149:Dioxoles; D007546:Isoquinolines; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019869:Phosphatidylinositol 3-Kinases; D011065:Poly(ADP-ribose) Polymerases; D013713:Teniposide; D014404:Tubulin; C510553:EM011 compound