Cyclin-dependent kinase inhibitor dinaciclib potently synergizes with cisplatin in preclinical models of ovarian cancer

Chen, Xiuxiu; Xie, Fengfeng; Zhu, Xuejie; Lin, Feng; Pan, Shi-Shi; Gong, Lihua; Qiu, Jian-Ge; Zhang, Wenji; Jiang, Qiwei; Mei, Xiao-Long; Xue, Youqiu; Qin, Wu-Ming; Shi, Zhi; Yan, Xiaojian

doi:10.18632/oncotarget.3717

Cited by 49 publications

(38 citation statements)

References 52 publications

(46 reference statements)

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“…We also observed that the levels of MCL1, an anti-apoptotic protein of the BCL2 family, quickly decreased in MEC-1 after treatment with dinaciclib in a time and concentration dependent manner, which correlated to PARP cleavage and induction of apoptosis (see Fig 3A and Fig S2A). This is consistent with recent reports showing that MCL1 expression was decreased by dinaciclib in various cancer cells (Fu et al, 2011;Chen et al, 2015;Gregory et al, 2015;Varadarajan et al, 2015). We confirmed that dinaciclib inhibited both MCL1 and BCL-xL in stimulated primary cells and MEC-1 ( Fig 3F).…”

Section: Dinaciclib Inhibits Pro-survival Signals In Cll Cellssupporting

confidence: 93%

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Pro‐survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia

et al. 2016

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Short title: Effects of Dinaciclib on pro-survival signals in CLL. 2 SUMMARYDinaciclib is a cyclin-dependent kinase inhibitor with clinical potential in different cancers, including Chronic Lymphocytic Leukemia (CLL). In order to better understand its cytotoxic action, we characterized its effects on signalling pathways important for the survival of CLL cells. We found that dinaciclib induced apoptosis through the activation of caspases 8 and 9, which was independent of the presence of cytokines to mimic the environment of proliferation centres or IGVH mutation status. Moreover, treatment with dinaciclib led to the inhibition of oncogenic pathways normally activated in stimulated CLL cells, such as STAT3, NF-κB and p38. Also, PI3K/AKT and RAF/MEK/ERK pathways showed a transient and early activation, followed by a later, permanent inhibition. Dinaciclib was also able to block the expression of anti-apoptotic proteins of the BCL-2 family such as MCL-1 and BCL-xL. Finally, we show that low concentrations of dinaciclib enhanced cell sensitivity to ibrutinib and BCL-2 inhibitor ABT-199, two drugs with known effects on CLL. Taken together, our data show that dinaciclib targets multiple pro-survival signalling pathways in CLL, which provides a mechanistic explanation for its potent induction of apoptosis. They also support a therapeutic application of CDK inhibitors in CLL in combination with other relevant targeted therapies.

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Section: Dinaciclib Inhibits Pro-survival Signals In Cll Cellssupporting

confidence: 93%

“…reports showing that MCL-1 expression was decreased by dinaciclib in various cancer cells (Chen, et al 2015, Fu, et al 2011, Gregory, et al 2015, Varadarajan, et al 2015. As shown in Figure 3F, we confirmed that dinaciclib inhibited both MCL-1 and BCL-xL in stimulated primary cells and MEC-1.…”

Section: Dinaciclib Inhibits Pro-survival Signals In Cll Cellssupporting

confidence: 79%

Pro‐survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia

et al. 2016

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“…In this context, SNS-032 has already been reported to have radiosensitizing effects in lung cancer and increase the sensitivity of acute myeloid leukemia (AML) cells to Cytarabine. 36,37 Furthermore, the CDK inhibitor dinaciclib has been described to synergize with cisplatin in preclinical models of ovarian cancer, 38 and dual inhibition of Cdc7 and CDK9 by PHA-767491 suppresses hepatocarcinoma synergistically with 5-fluorouracil. 39 These data support our finding that new treatment regimens combining CDK inhibitors with conventional treatment strategies are promising approaches in pancreatic cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

CDK9 is a prognostic marker and therapeutic target in pancreatic cancer

et al. 2017

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Despite recent advances in diagnosis and therapy, prognosis of pancreatic cancer still remains very poor. Besides valid prognostic markers, novel therapeutic approaches are urgently needed. The family of cyclin-dependent kinases comprises 20 kinases which contribute to malignancy by promoting proliferation, migration, invasion, and apoptotic resistance of cancer cells. In this work, we investigated the role of CDK9 in pancreatic cancer. Immunohistochemical analysis of CDK9 expression in tumor and normal tissue of pancreatic cancer patients revealed an overexpression of CDK9 in pancreatic cancer tissue. In addition, high CDK9 expression in tumor tissue is associated with significantly shortened survival, especially in well-differentiated tumors. Moreover, the therapeutic potential of selective CDK9 inhibition on pancreatic cancer cells was evaluated by analysis of cell viability, long-term survival, and induction of apoptosis and characterized by western blotting and flow cytometry. Pharmacological CDK9 inhibition by SNS-032 drastically reduced cell viability in pancreatic cancer cells and potently suppressed long-term survival. Analyzing the mechanism of action revealed that CDK9 inhibition induced apoptosis and cell cycle arrest in a time-dependent manner by suppression of anti-apoptotic proteins. Furthermore, CDK9 inhibition potently enhances the therapeutic effect of chemotherapeutics in pancreatic cancer cells. In conclusion, we identified CDK9 as a negative prognostic marker in pancreatic cancer. Furthermore, pharmacological CDK9 inhibition is a novel and promising therapeutic approach for pancreatic cancer.

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“…Dinaciclib (formerly SCH727965) is a potent inhibitor of CDK 1, 2, 5, and 9 with 50% inhibitory concentrations in the nanomolar range (27). In preclinical studies, dinaciclib has been shown to arrest cell-cycle progression, induce activation of caspase-8, -9 and related apoptosis, and inhibit tumor growth in multiple types of cancer (17,(27)(28)(29)(30). In addition, early-phase clinical trials have shown that this drug was well tolerated (31) and has significant single-agent activity against relapsed and refractory chronic lymphocytic leukemia (31) and multiple myeloma (32), supporting its potential for the treatment of human malignancies.…”

Section: Introductionmentioning

confidence: 99%

Targeting CDK1 and MEK/ERK Overcomes Apoptotic Resistance in BRAF-Mutant Human Colorectal Cancer

Zhang

Kawakami

Liu

et al. 2018

Molecular Cancer Research

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The mutation occurs in approximately 8% of human colorectal cancers and is associated with therapeutic resistance that is due, in part, to reactivation of MEK/ERK signaling cascade. Recently, pathway analysis identified cyclin-dependent kinase 1 (CDK1) upregulation in a subset of human colorectal cancers. Therefore, it was determined whether CDK1 antagonism enhances the efficacy of MEK inhibition in colorectal cancer cells. colorectal cancer cell lines expressing CDK1 were sensitized to apoptosis upon siRNA knockdown or small-molecule inhibition with RO-3306 (CDK1 inhibitor) or dinaciclib (CDK1, 2, 5, 9 inhibitors). Combination of RO-3306 or dinaciclib with cobimetinib (MEK inhibitor) cooperatively enhanced apoptosis and reduced clonogenic survival versus monotherapy. Cells isogenic or ectopic for displayed resistance to CDK1 inhibitors, as did cells with ectopic expression of constitutively active CDK1 inhibitors induced a -dependent apoptosis shown by caspase-8 restoration in deficient NB7 cells that enhanced dinaciclib-induced CASP3 cleavage. CDK inhibitors suppressed pro-CASP8 phosphorylation at S387, as shown by drug withdrawal, which restored p-S387 and increased mitosis. In a colorectal cancer xenograft model, dinaciclib plus cobimetinib produced significantly greater tumor growth inhibition in association with a caspase-dependent apoptosis versus either drug alone. The Cancer Genome Atlas (TCGA) transcriptomic dataset revealed overexpression of CDK1 in human colorectal cancers versus normal colon. Together, these data establish CDK1 as a novel mediator of apoptosis resistance in colorectal cancers whose combined targeting with a MEK/ERK inhibitor represents an effective therapeutic strategy. CDK1 is a novel mediator of apoptosis resistance in colorectal cancers whose dual targeting with a MEK inhibitor may be therapeutically effective..

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Cyclin-dependent kinase inhibitor dinaciclib potently synergizes with cisplatin in preclinical models of ovarian cancer

Cited by 49 publications

References 52 publications

Pro‐survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia

Pro‐survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia

CDK9 is a prognostic marker and therapeutic target in pancreatic cancer

Targeting CDK1 and MEK/ERK Overcomes Apoptotic Resistance in BRAF-Mutant Human Colorectal Cancer

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