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.

MATERIALS AND 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.

CONCLUSION:

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: Qingshan Yang, Lisa S Chen, Sattva S Neelapu, Varsha Gandhi
• Journal: Clinical lymphoma, myeloma & leukemia (Clin Lymphoma Myeloma Leuk) Vol. 13 Suppl 2 Pg. S355-62 (Sep 2013) ISSN: 2152-2669 [Electronic] United States
• PMID: 24290221 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Imidazoles
• Nitrogen Mustard Compounds
• Pyridazines
• SGI 1776
• Bendamustine Hydrochloride
• Proto-Oncogene Proteins c-pim-1
• proto-oncogene proteins pim

Topics

• Aged
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Bendamustine Hydrochloride
• Cell Line, Tumor
• Humans
• Imidazoles (administration & dosage)
• Lymphoma, B-Cell (drug therapy, enzymology)
• Lymphoma, Mantle-Cell (drug therapy, enzymology)
• Male
• Middle Aged
• Nitrogen Mustard Compounds (administration & dosage)
• Proto-Oncogene Proteins c-pim-1 (antagonists & inhibitors)
• Pyridazines (administration & dosage)