Induction of apoptosis and down regulation of cell cycle proteins in mantle cell lymphoma by flavopiridol treatment

Venkataraman, Girish; Maududi, Tazeen; Puyan, Fulya Öz; Bahar, Hakki I.; Izban, Keith F.; Qin, Jiang-Zon; Alkan, Serhan

doi:10.1016/j.leukres.2006.03.004

Cited by 21 publications

(17 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There was no apparent change in the expression of Cdk inhibitor p21, consistent with a previous report in JeKo-1 cells after flavopiridol treatment (18). Both Rb and p27 are tumor suppressor proteins that inhibit cell cycle progression.…”

Section: Resultssupporting

confidence: 92%

“…Thus, the combined actions of transcriptional inhibition, decreasing cyclin D1 protein, and inhibition of proliferation through Cdk2, may cause the loss of clonogenic survival in Granta 519 cells following SNS-032 exposure. Consistent with this, Cdk antagonists with inhibitory activity against both transcription and cell cycle, such as flavopiridol (27) and roscovitine (28), have shown induction of cell death in MCL cells lines (18, 29). Compared to flavopiridol and roscovitine, SNS-032 is more selective (4) and demonstrated greater potency in the inhibition of transcription and induction of apoptosis in primary CLL cells (5).…”

Section: Discussionmentioning

confidence: 56%

See 1 more Smart Citation

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

Chen¹,

Chubb

Cheng³

et al. 2010

Cancer Research

View full text Add to dashboard Cite

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.

show abstract

Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 56%

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

Chen¹,

Chubb

Cheng³

et al. 2010

Cancer Research

View full text Add to dashboard Cite

show abstract

“…Flavopiridol is known to effectively inhibit Mcl-1 transcription in CLL and MM (21,22). In MCL, flavopiridol was reported to induce apoptosis (31). Therefore, flavopiridol is currently under investigation for treatment of several hematologic malignancies including both CLL and MCL (32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

ABT-737 Induces Apoptosis in Mantle Cell Lymphoma Cells with a Bcl-2high/Mcl-1low Profile and Synergizes with Other Antineoplastic Agents

Touzeau

Dousset

Bodet

et al. 2011

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Mantle cell lymphoma (MCL) is considered to be incurable. ABT-737 is a BH3 mimetic that targets Bcl-2, which is overexpressed in MCL and implicated in drug resistance. The present work investigated the antitumor effect of ABT-737. Experimental Design: Six MCL cell lines and primary MCL cells (n = 13) were used. Sensitivity to ABT-737 was assessed, and expression levels of Bcl-2 and Mcl-1 were analyzed. Finally, ABT-737 was combined with other cytotoxic agents to promote tailored therapy. Results: MINO and GRANTA-519 cell lines were highly sensitive to ABT-737 [the median lethal dose (LD50) = 20 and 80 nmol/L, respectively], whereas other cell lines were resistant. In primary MCL cells, 46% of patients' samples were sensitive to ABT-737. The analysis of protein expression levels revealed that both sensitive cell lines and primary MCL cells could be characterized by a Bcl-2high/Mcl-1low profile, whereas resistant MCL cells contained high levels of Mcl-1. ABT-737 induced a rapid disruption of both Bcl-2/Bax and Bcl-2/Bik complexes. In addition, silencing of Mcl-1 by siRNA sensitized MCL cell lines to ABT-737. Similarly, flavopiridol, which induces Mcl-1 downregulation, in combination with ABT-737 led to a synergistic anti-MCL effect in ABT-737–resistant cell lines. This synergy was also observed when ABT-737 was combined with either bortezomib or cytarabine. Conclusions: The present work shows that ABT-737 induces strong apoptosis in MCL cells expressing a Bcl-2high/Mcl-1low profile. In ABT-737–resistant MCL cells, downregulation of Mcl-1 overcomes Mcl-1–induced resistance and synergizes ABT-737 effects. Our results strongly support the use of ABT-737 according to the Bcl-2/Mcl-1 tumor cell profiles in the treatment of MCL. Clin Cancer Res; 17(18); 5973–81. ©2011 AACR.

show abstract

“…MCL is usually resistant to standard-dose chemotherapeutic reagents, and even with high-dose chemotherapy with or without stem cell transplantation, the prognosis of patients with MCL remains poor. 31 Therefore, the paradigm of cell cycle dysregulation has been used as the starting point for new therapies for MCL, aimed at cyclin D1 synthesis or function, such as mTOR inhibitors, which block mRNA translation of cell cycle proteins including cyclin D1, or inhibitors of CDK such as flavopiridol 32 and others. The reasoning behind these approaches is that if cyclin D1 is the main force inducing proliferation, the inhibition of cyclin D1 directly or indirectly could induce biological changes capable of inhibiting cell growth and/or promoting cell death.…”

Section: Discussionmentioning

confidence: 99%

Specific lentiviral shRNA-mediated knockdown of cyclin D1 in mantle cell lymphoma has minimal effects on cell survival and reveals a regulatory circuit with cyclin D2

et al. 2008

View full text Add to dashboard Cite

Cyclin D1 overexpression is the hallmark of mantle cell lymphoma (MCL). However, the importance of cyclin D1 in the maintenance and progression of the disease remains to be defined. The aim of this study was to elucidate the role of cyclin D1 overexpression using an efficient cyclin D1-shRNA and a lentiviral system in well-characterized MCL cell lines. Surprisingly, the knockdown of cyclin D1 led to a moderate retardation in growth, without induction of apoptosis. The cyclin D1-shRNA-transduced MCL cells showed a 15% shift from S phase to G 1 phase of the cell cycle, a weak induction of p27 Kip1 , decreased Rb (Ser807/811) phosphorylation, and a consistent upregulation of cyclin D2 mRNA and protein expression. However, double knockdown of cyclins D1 and D2 did not intensify the effects observed with cyclin D1 knockdown alone. These data suggest that the moderate effects of cyclin D1 downregulation on survival and proliferation are likely the result of compensatory cyclin-independent mechanisms governing proliferation or alternatively, secondary genetic events that make cyclin D1 dispensable. These findings have important implications for MCL therapy, as strategies targeting only cyclin D1 function might be hampered by compensatory regulatory mechanisms, resulting in a low probability of treatment response.

show abstract

Induction of apoptosis and down regulation of cell cycle proteins in mantle cell lymphoma by flavopiridol treatment

Cited by 21 publications

References 32 publications

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

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

ABT-737 Induces Apoptosis in Mantle Cell Lymphoma Cells with a Bcl-2high/Mcl-1low Profile and Synergizes with Other Antineoplastic Agents

Specific lentiviral shRNA-mediated knockdown of cyclin D1 in mantle cell lymphoma has minimal effects on cell survival and reveals a regulatory circuit with cyclin D2

Contact Info

Product

Resources

About