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
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Reem Karmali1,2,**, Vineela Chukkapalli3,**, Leo I. Gordon1,2, Jeffrey A. Borgia4, Andrey Ugolkov5,6,*, Andrew P. Mazar7 and Francis J. Giles8
1Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
2Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
3Department of Hematology, Oncology and Stem Cell Therapy, Rush University Medical Center, Chicago, IL, USA
4Departments of Pathology and Cell & Molecular Medicine, Rush University Medical Center, Chicago, IL, USA
5Center for Developmental Therapeutics Northwestern University, Evanston, IL, USA
6Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
7Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
8Developmental Therapeutics Consortium, Chicago, IL, USA
*Current/Present address: Tempus, Inc., Chicago, IL, USA
**These authors have contributed equally to this work
Reem Karmali, email: [email protected]
Keywords: GSK-3β inhibitor; DLBCL; Myc+ Lymphoma; Bcl-2 inhibitor; CDK9 inhibitor
Received: July 31, 2017 Accepted: September 16, 2017 Published: November 11, 2017
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.
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