TY - JOUR
T1 - Combination of pim kinase inhibitor SGI-1776 and bendamustine in B-cell lymphoma
AU - Yang, Qingshan
AU - Chen, Lisa S.
AU - Neelapu, Sattva S.
AU - Gandhi, Varsha
N1 - Funding Information:
This work was supported by a Lymphoma SPORE grant ( CA136411 ) to Varsha Gandhi and Sattva S. Neelapu, and a Leukemia and Lymphoma Society Translational Research Award to Varsha Gandhi. The primary tumor samples were provided by The University of Texas MD Anderson Cancer Center Lymphoma SPORE Biospecimens Core and Tissue Bank, which are supported by the Cancer Center Support Grant CA16672 .
PY - 2013/9
Y1 - 2013/9
N2 - 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.
AB - 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.
KW - Bendamustine
KW - Combination strategy
KW - Mantle cell lymphoma
KW - Pim kinase
KW - SGI-1776
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U2 - 10.1016/j.clml.2013.05.024
DO - 10.1016/j.clml.2013.05.024
M3 - Article
C2 - 24290221
AN - SCOPUS:84889066145
SN - 2152-2650
VL - 13
SP - S355-S362
JO - Clinical Lymphoma, Myeloma and Leukemia
JF - Clinical Lymphoma, Myeloma and Leukemia
IS - SUPPL. 2
ER -