title: Combination of Pim kinase inhibitor SGI-1776 and bendamustine in B-cell lymphoma.
abstract: BACKGROUND
  SGI-1776 is a small-molecule Pim kinase inhibitor that primarily targets c-MYC-driven transcription and cap-dependent translation in mantle cell lymphoma (MCL) cells. Bendamustine is an alkylating chemotherapeutic agent approved for use in B-cell lymphoma that is known to induce DNA damage and initiate response to repair.
  
  
  METHODS
  Our studies were conducted in MCL cell lines JeKo-1 and Mino, as well as primary B-cell lymphoma samples of MCL and splenic marginal zone lymphoma (SMZL), where we treated cells with SGI-1776 and bendamustine. We measured levels of cellular apoptosis, macromolecule synthesis inhibition, and DNA damage induced by drug treatments.
  
  
  RESULTS
  Both SGI-1776 and bendamustine effectively induced apoptosis as single agents, and when used in combination, an additive effect in cell killing was observed in MCL cell lines JeKo-1 and Mino, as well as in MCL and SMZL primary cells. As expected, SGI-1776 was effective in inducing a decrease of global RNA and protein synthesis, and bendamustine significantly inhibited DNA synthesis and generated a DNA damage response. When used in combination, the effects were intensified in DNA, RNA, and protein synthesis inhibition compared with single-agent treatments.
  
  
  CONCLUSIONS
  These data provide a foundation and suggest the feasibility of using Pim kinase inhibitors in combination with chemotherapeutic agents such as bendamustine in B-cell lymphoma.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX.
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Yang
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Chen
authors.forename: Sattva S
authors.initials: SS
authors.lastname: Neelapu
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000069461:Bendamustine Hydrochloride; D045744:Cell Line, Tumor; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000201:enzymology; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000008:administration & dosage
chemical_list: D007093:Imidazoles; D009588:Nitrogen Mustard Compounds; D011724:Pyridazines; C545188:SGI 1776; D000069461:Bendamustine Hydrochloride; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim
keywords: Bendamustine; Combination strategy; Mantle cell lymphoma; Pim kinase; SGI-1776