Cyclin-Dependent Kinase Inhibitor P1446A Induces Apoptosis in a JNK/p38 MAPK-Dependent Manner in Chronic Lymphocytic Leukemia B-Cells

Paiva, Cody; Godbersen, J. Claire; Soderquist, Ryan S.; Rowland, Taylor; Kilmarx, Sumner E.; Spurgeon, Stephen E.; Brown, Jennifer R.; Srinivasa, Sreesha P.; Danilov, Alexey V.

doi:10.1371/journal.pone.0143685

Cited by 32 publications

(17 citation statements)

References 62 publications

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“…We selected other drugs that have been studied in the context of leukaemia, such as MG-132 (a proteasome inhibitor (Guo and Peng 2013)), ibrutinib (a BTK inhibitor , Danilov 2013), vemurafenib (a V600E BRAF inhibitor (Samuel, et al 2014)), ver155008 (a HSP70 inhibitor (Reikvam, et al 2013)), BX-912 (a PDK1 inhibitor targeting PI3K/Akt pathway (Feldman, et al 2005)) and fedratinib (a Jak/STAT pathway inhibitor (Pardanani, et al 2007)). As shown in Figure 1A, dinaciclib demonstrated more than 100-fold greater inhibitory effects on the metabolic activity of MEC-1 than any of the other drugs tested, confirming its potential as a therapeutic approach for CLL and consistent with recent results that showed the strong cytotoxic effects of CDK inhibitors in CLL (Johnson, et al 2012, Paiva, et al 2015, Sylvan, et al 2016. We determined that the effects of dinaciclib on cell viability were the consequence of a dose-dependent increase in cell death but not cell cycle arrest, as tested by PI staining ( Figure 1B).…”

Section: Resultssupporting

confidence: 87%

“…It has been previously reported that CDK inhibitors promote apoptosis in different cancer cells via suppression of Rb phosphorylation (Fu, et al 2011, Parry, et al 2010 or in a JNK/p38-dependent manner (Paiva, et al 2015). Our data showed that this requires the activation of caspase 8 and 9, suggesting an involvement of both the extrinsic and intrinsic pathways.…”

Section: Discussionsupporting

confidence: 69%

“…showing that CDK inhibitors sensitize CLL cells to BH3 mimetics like ABT-737 (Paiva, et al 2015). For ibrutinb, the increase in cell death was from ~50 to ~90%.…”

Section: (Bcl-2 Inhibitor) Iburitinib (Btk Inhibitor) and Entosplentmentioning

confidence: 96%

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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: Resultssupporting

confidence: 87%

Section: Discussionsupporting

confidence: 69%

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

et al. 2016

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“…MAPK signaling is frequently activated in several cancers and is responsible for apoptosis [47]. Baik et al reported that cordycepin induced apoptosis through an extrinsic pathway and the activation of p38 MAPK in U87 cells [48].…”

Section: Figurementioning

confidence: 99%

Raddeanin a Suppresses Glioblastoma Growth by Inducing ROS Generation and Subsequent JNK Activation to Promote Cell Apoptosis

Peng

Wang

Shu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Raddeanin A (RA), an active pharmacological ingredient from Anemone raddeana Regel, plays an important role in tumor suppression. In this study, we assessed the potentially therapeutic effect of RA on glioblastoma and its underlying mechanisms. Methods: Cell viability was examined using the MTT assay. Invasive and migratory capacities were examined using Transwell and wound healing assays. Apoptosis was determined by Hoechst staining, flow cytometry, DCFH-fluorescent probe and immunohistochemical staining. Autophagy was detected by transmission electron microscopy and western blotting. A U251 glioma xenograft model was established to evaluate the effect of RA in vivo. Results: The data demonstrated that RA inhibited viability, and abrogated the invasive/migratory abilities of glioblastoma cells. In addition, RA induced apoptosis by reactive oxygen species (ROS)/ Jun N-terminal kinase (JNK) signaling in glioblastoma. Conversely, the antioxidant N-Acetyl-L-cysteine (NAC) and pan-caspase inhibitor z-VAD-fmk attenuated RA-induced apoptosis by scavenging ROS and inactivating caspase-3. Furthermore, the inhibition of autophagy by 3-MA exacerbated apoptosis through ROS generation and JNK phosphorylation. In vivo, RA exhibited a curative effect on U251-derived xenografts in nude mice. Conclusions: The results of this study suggest that RA suppressed the growth of glioblastoma, thus serving as a promising and potential strategy for glioblastoma chemotherapy.

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“…Voruciclib, a CDK4/6 inhibitor, has shown promising anti-cancer effects in combination with the BRAF inhibitor, vemurafenib in advanced BRAF-mutant melanoma [17]. More recent studies have shown that voruciclib enhances the sensitivity of the proteasome inhibitor, bortezomib, in triple negative breast cancer xenografts [18].…”

Section: Introductionmentioning

confidence: 99%

Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi-Drug Resistance in Cancer Cells

Gupta

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: The overexpression of ATP-Binding Cassette (ABC) transporters has known to be one of the major obstacles impeding the success of chemotherapy in drug resistant cancers. In this study, we evaluated voruciclib, a CDK 4/6 inhibitor, for its chemo-sensitizing activity in ABCB1- and ABCG2- overexpressing cells. Methods: Cytotoxicity and reversal effect of voruciclib was determined by MTT assay. The intracellular accumulation and efflux of ABCB1 and ABCG2 substrates were measured by scintillation counter. The effects on expression and intracellular localization of ABCB1 and ABCG2 proteins were determined by Western blotting and immunofluorescence, respectively. Vanadate-sensitive ATPase assay was done to determine the effect of voruciclib on the ATPase activity of ABCB1 and ABCG2. Flow cytometric analysis was done to determine the effect of voruciclib on apoptosis of ABCB1 and ABCG2-overexpressing cells and docking analysis was done to determine the interaction of voruciclib with ABCB1 and ACBG2 protein. Results: Voruciclib significantly potentiated the effect of paclitaxel and doxorubicin in ABCB1-overexpressing cells, as well as mitoxantrone and SN-38 in ABCG2-overexpressing cells. Voruciclib moderately sensitized ABCC10- overexpressing cells to paclitaxel, whereas it did not alter the cytotoxicity of substrates of ABCC1. Furthermore, voruciclib increased the intracellular accumulation and decreased the efflux of substrate anti-cancer drugs from ABCB1- or ABCG2-overexpressing cells. However, voruciclib did not alter the expression or the sub-cellular localization of ABCB1 or ABCG2. Voruciclib stimulated the ATPase activity of both ABCB1 and ABCG2 in a concentration-dependent manner. Lastly, voruciclib exhibited a drug-induced apoptotic effect in ABCB1- or ABCG2- overexpressing cells. Conclusion: Voruciclib is currently a phase I clinical trial drug. Our findings strongly support its potential use in combination with conventional anti-cancer drugs for cancer chemotherapy.

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Cyclin-Dependent Kinase Inhibitor P1446A Induces Apoptosis in a JNK/p38 MAPK-Dependent Manner in Chronic Lymphocytic Leukemia B-Cells

Cited by 32 publications

References 62 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

Raddeanin a Suppresses Glioblastoma Growth by Inducing ROS Generation and Subsequent JNK Activation to Promote Cell Apoptosis

Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi-Drug Resistance in Cancer Cells

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