Multidrug resistance-associated protein-overexpressing teniposide-resistant human lymphomas undergo apoptosis by a tubulin-binding agent

Cancer Res. 2008 Mar 1;68(5):1495-503. doi: 10.1158/0008-5472.CAN-07-1874.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis*
  • Cell Line, Tumor
  • Dioxoles / pharmacology*
  • Gene Expression Regulation, Neoplastic*
  • Isoquinolines / pharmacology*
  • Lymphoma / drug therapy*
  • Lymphoma / metabolism*
  • Lymphoma / pathology
  • Mice
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Neoplasm Transplantation
  • Phosphatidylinositol 3-Kinases / metabolism
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein Binding
  • Teniposide / pharmacology*
  • Tubulin / metabolism*


  • Antineoplastic Agents
  • Dioxoles
  • EM011 compound
  • Isoquinolines
  • Multidrug Resistance-Associated Proteins
  • Tubulin
  • Teniposide
  • Poly(ADP-ribose) Polymerases
  • Phosphatidylinositol 3-Kinases