Responses in Mantle Cell Lymphoma Cells to SNS-032 Depend on the Biological Context of Each Cell Line

Abstract

SNS-032 is a potent inhibitor of cyclin-dependent kinases (Cdk) 2, 7, and 9 that regulate the cell cycle and transcription. Our studies in indolent primary chronic lymphocytic leukemia cells showed that SNS-032 inhibited transcription, diminished the antiapoptotic protein Mcl-1, and induced apoptosis. The present study focuses on evaluating this compound in four proliferating mantle cell lymphoma lines (Jeko-1, Granta 519, Mino, and SP-53). Consistent with its action against Cdk9 and Cdk7, SNS-032 inhibited the phosphorylation of RNA pol II in all four lines and blocked RNA synthesis. The transcripts and protein levels of short-lived proteins decreased, including cyclin D1 and Mcl-1. Cell growth was inhibited in a concentration-dependent manner in all lines. Apoptosis was induced in JeKo-1, Mino, and SP-53 cells without disrupting cell cycle distribution. However, apoptosis was limited in Granta cells; rather, there was a significant reduction of clonogenic survival. Small interfering RNA was used to specifically knock down Mcl-1 and cyclin D1 in JeKo-1 and Granta cells. Knocking down Mcl-1 induced significant apoptosis in Jeko-1 cells but not Granta cells. Reducing cyclin D1, rather than Mcl-1, was associated with loss of clonogenic survival in Granta cells. Thus, these results indicated that mantle cell lymphoma cell lines have distinct mechanisms sustaining their survival, and the mechanism of action of SNS-032 is dependent on the biological context of an individual line.

A small-molecule inhibitor of D-cyclin transactivation displays preclinical efficacy in myeloma and leukemia via phosphoinositide 3-kinase pathway

“…17,18 To examine whether cyclin D was decreased by S14161 via the CDK9 signaling pathway, we checked expression of CDK9 in the myeloma cell lines LP1 and OPM2. CDK9 was decreased by S14161 in both LP1 and OPM2 cells within 24 hours in a concentration-dependent manner ( Figure 1H), which further demonstrated that S14161 regulates cyclin D on the transcriptional level.…”

New Strategies in the Treatment of Mantle Cell Lymphoma

“…SCH727965 (dinaciclib), a novel inhibitor of CDK1, -2, -5, and -9, showed superior activity and an improved therapeutic index compared with flavopiridol in laboratory models of solid and hematologic malignancies (61,62) and was the subject of intense investigation in numerous clinical trials (63)(64)(65). However, preliminary data did not show a dramatic response to these CDK inhibitors, suggesting that other deregulated pathways are contributing to the growth and survival advantages of aggressive MCL cells compared with normal cells (8,33,34).…”

“…On the other hand, high-level p27 expression is associated with better survival (26,32), again supporting the notion that MCL is a disease characterized by gross cell-cycle dysregulation at a variety of levels, and that the level of dysregulation correlates with prognosis. Finally, direct inhibition of the expression of cyclin D1 can be achieved in the laboratory by short-hairpin RNA targeting cyclin D1, and has been shown to reduce proliferation and clonogenic survival of MCL cells (8,33,34).…”

Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma

“…19 The dysregulation of the cell-cycle machinery suggests that inhibition of CDK4 should have antiproliferative effects in MCL, and has prompted the preclinical and clinical evaluation of CDK inhibitors in this disease. The agents tested to date, including flavopiridol, 20,21 seliciclib, 22 and SNS-032, 23 have greater potency against other CDK family members, including the transcriptional CDK9, and may be of interest for their ability to deplete antiapoptotic proteins from malignant hematopoietic cells. 14 PD0332991, a potent, selective CDK 4/6 inhibitor, causes G 1 arrest in MCL and other cell lines by blocking phosphorylation of Rb at CDK4/6-specific sites, including Ser 807/811 and Ser 780 .…”