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Oncotarget. 2017 Nov 11;8(70):114924-114934. doi: 10.18632/oncotarget.22414. eCollection 2017 Dec 29.

GSK-3β inhibitor, 9-ING-41, reduces cell viability and halts proliferation of B-cell lymphoma cell lines as a single agent and in combination with novel agents.

Author information

1
Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
2
Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.
3
Department of Hematology, Oncology and Stem Cell Therapy, Rush University Medical Center, Chicago, IL, USA.
4
Departments of Pathology and Cell & Molecular Medicine, Rush University Medical Center, Chicago, IL, USA.
5
Center for Developmental Therapeutics Northwestern University, Evanston, IL, USA.
6
Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
7
Developmental Therapeutics Consortium, Chicago, IL, USA.
#
Contributed equally

Abstract

The complexities of GSK-3β function and interactions with PI3K/AKT/mTOR signaling, cell cycling, and apoptotic pathways are poorly understood in the context of lymphomagenesis and cancer therapeutics. In this study, we explored the anti-tumor effects of the GSK-3β inhibitor, 9-ING-41, in lymphoma cell lines as a single agent and in combination with novel agents comprising BCL-2 inhibitor (Venetoclax), CDK-9 inhibitor (BAY-1143572) and p110δ-PI3K inhibitor (Idelalisib). Treatment of Daudi, SUDHL-4, Karpas 422, KPUM-UH1, and TMD8 lymphoma cell lines with 1 μM 9-ING-41 reduced cell viability by 40-70% (p<0.05) and halted proliferation. Luminex analysis of apoptotic pathways revealed a significant increase in active caspase 3 in all lymphoma cell lines (p<0.001) except TMD8 cells. Co-treating SUDHL-4 and KPUM-UH1 lymphoma cells with 0.5 μM 9-ING-41 showed 8-and 2-fold reduction in IC50 values of Venetoclax, respectively. No significant benefit for this combination was seen in other lymphoma cells tested. The combination of BAY-1143572 with 0.5 μM 9-ING-41 showed an 8-fold reduction in the IC50 value of the former in SUDHL-4 lymphoma cells alone. No significant changes in IC50 values of Idelalisib were measured across all cell lines for the combination of 9-ING-41 and Idelalisib. Further, signaling analysis via Western blot in the double-hit lymphoma cell line, KPUM-UH1, suggests that phospho-c-MYC is modified with 9-ING-41 treatment. Altogether, our data show that 9-ING-41 results in increased apoptosis and decreased proliferation in aggressive B-cell lymphoma cells and enhances the antitumor effects of BCL-2 and CDK-9 antagonists.

KEYWORDS:

Bcl-2 inhibitor; CDK9 inhibitor; DLBCL; GSK-3β inhibitor; Myc+ Lymphoma

Conflict of interest statement

CONFLICTS OF INTEREST 9-ING-41 has been licensed to Actuate Therapeutics, Inc. Andrew Mazar and Andrey Ugolkov hold an equity interest in Actuate Therapeutics, Inc., and Francis Giles is an advisor to this company.

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