title: Antihelminthic benzimidazoles potentiate navitoclax (ABT-263) activity by inducing Noxa-dependent apoptosis in non-small cell lung cancer (NSCLC) cell lines.
abstract: BACKGROUND
  Evasion of apoptosis is a hallmark of cancer cells. One mechanism to deregulate the apoptotic pathway is by upregulation of the anti-apoptotic Bcl-2 family members. Navitoclax (ABT-263) is a Bcl-2/Bcl-xL inhibitor that restores the ability of cancer cells to undergo apoptosis.
  
  
  METHODS
  In this study we performed a high-throughput screen with 640 FDA-approved drugs to identify potential therapeutic combinations with navitoclax in a non-small cell lung cancer (NSCLC) cell line.
  
  
  RESULTS
  Other than a panel of cancer compounds such as doxorubicin, camptothecin, and docetaxel, four antihelminthic compounds (benzimidazoles) potentiated navitoclax activity. Treatment with benzimidazoles led to induction of the pro-apoptotic protein Noxa at the mRNA and protein level. Noxa binds and antagonizes antiapoptotic protein Mcl-1. siRNA-mediated knock-down of Noxa completely rescued benzimidazole-potentiated navitoclax activity. In addition, inhibiting caspase 3 and 9 partially rescued benzimidazole-potentiated navitoclax activity.
  
  
  CONCLUSIONS
  We have identified compounds and mechanisms which potentiate navitoclax activity in lung cancer cell lines. Further validation of the benzimidazole-potentiated navitoclax effect in vivo is required to evaluate the potential for translating this observation into clinical benefit.
authors: Oncology Research, Abbvie, 1 North Waukegan Road, North Chicago, IL 60064-6098 USA ; AbbVie, Tumor Genomics, bldg AP-10, dept R4CD, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064-6098 USA.
authors: Lloyd T
authors: LT
authors: Lam
authors: Oncology Research, Abbvie, 1 North Waukegan Road, North Chicago, IL 60064-6098 USA.
authors: Haichao
authors: H
authors: Zhang
authors: Oncology Research, Abbvie, 1 North Waukegan Road, North Chicago, IL 60064-6098 USA.
authors: John
authors: J
authors: Xue
authors: Oncology Research, Abbvie, 1 North Waukegan Road, North Chicago, IL 60064-6098 USA.
authors: Joel D
authors: JD
authors: Leverson
authors: Oncology Research, Abbvie, 1 North Waukegan Road, North Chicago, IL 60064-6098 USA.
authors: Anahita
authors: A
authors: Bhathena
keywords: Apoptosis; Benzimidazoles; Caspase; Navitoclax