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

Chen XX, Xie FF, Zhu XJ, Lin F, Pan SS, Gong LH, Qiu JG, Zhang WJ, Jiang QW, Mei XL, Xue YQ, Qin WM, Shi Z, Yan XJ - Oncotarget (2015)

Bottom Line: Dinaciclib alone actively induced cell growth inhibition, cell cycle arrest and apoptosis with the increased intracellular ROS levels, which were accompanied by obvious alterations of related proteins such as CDKs, Cyclins, Mcl-1, XIAP and survivin.Pretreatment with N-acety-L-cysteine significantly blocked ROS generation but only partially rescued apoptosis triggered by dinaciclib.Altogether, dinaciclib potently synergizes with cisplatin in preclinical models of ovarian cancer, indicating this beneficial combinational therapy may be a promising strategy for treatment of ovarian cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

ABSTRACT
Ovarian cancer is one of the most lethal of woman cancers, and its clinical therapeutic outcome currently is unsatisfied. Dinaciclib, a novel small molecule inhibitor of CDK1, CDK2, CDK5 and CDK9, is assessed in clinical trials for the treatment of several types of cancers. In this study, we investigated the anticancer effects and mechanisms of dinaciclib alone or combined with cisplatin in ovarian cancer. Dinaciclib alone actively induced cell growth inhibition, cell cycle arrest and apoptosis with the increased intracellular ROS levels, which were accompanied by obvious alterations of related proteins such as CDKs, Cyclins, Mcl-1, XIAP and survivin. Pretreatment with N-acety-L-cysteine significantly blocked ROS generation but only partially rescued apoptosis triggered by dinaciclib. Moreover, the combination of dinaciclib with cisplatin synergistically promoted cell cycle arrest and apoptosis, and inhibited the subcutaneous xenograft growth of ovarian cancer in nude mice. Altogether, dinaciclib potently synergizes with cisplatin in preclinical models of ovarian cancer, indicating this beneficial combinational therapy may be a promising strategy for treatment of ovarian cancer.

No MeSH data available.


Related in: MedlinePlus

ROS was critical for the anticancer effect of dinaciclib in ovarian cancer cellsA2780 and OVCAR3 cells were treated with dinaciclib at the indicated times and concentrations, stained with DHE and photographed under florescent microscope. The representative micrographs (A) of three independent experiments were shown. Cells were also treated with 0.03 μM dinaciclib for 48 h in the presence or absence of 5mM NAC pretreatment for 1h, stained with DHE and photographed under fluorescent microscope. The apoptosis was detected by FCM with Annexin V/PI staining. The proportions of Annexin V+/PI− and Annexin V+/PI+ cells indicated the early and late stage of apoptosis. The representative micrographs (B), charts and quantified results (C, D) of three independent experiments were shown. DI: Dinaciclib. *P < 0.05 and **P < 0.01 vs. corresponding control.
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Figure 4: ROS was critical for the anticancer effect of dinaciclib in ovarian cancer cellsA2780 and OVCAR3 cells were treated with dinaciclib at the indicated times and concentrations, stained with DHE and photographed under florescent microscope. The representative micrographs (A) of three independent experiments were shown. Cells were also treated with 0.03 μM dinaciclib for 48 h in the presence or absence of 5mM NAC pretreatment for 1h, stained with DHE and photographed under fluorescent microscope. The apoptosis was detected by FCM with Annexin V/PI staining. The proportions of Annexin V+/PI− and Annexin V+/PI+ cells indicated the early and late stage of apoptosis. The representative micrographs (B), charts and quantified results (C, D) of three independent experiments were shown. DI: Dinaciclib. *P < 0.05 and **P < 0.01 vs. corresponding control.

Mentions: ROS plays an important role in tumorigenesis and chemotherapy of most anticancer drugs [20]. To assess the role of ROS in the anticancer effect of dinaciclib in ovarian cancer cells, we used dihydroethidium (DHE) as ROS fluorescent probe, which can be oxidized by ROS to oxide ethidium that binds with DNA to emit the detectable red fluorescence [21], to stain cells treated with dinaciclib. As shown in Figure 4A, dinaciclib enhanced the fluorescent signals of DHE in both A2780 and OVCAR3 cells in the concentration-and time-dependent manners, suggesting the intracellular ROS levels were enhanced after dinaciclib treatment. To further verify the relationship between dinaciclib induced apoptosis and ROS generation, both cells were treated with dinaciclib for 48h in the presence or absence of the antioxidative agent NAC pretreatment for 1h and stained with DHE. The dinaciclib-induced DHE fluorescent signals were totally reversed by NAC in both cells (Figure 4B). Moreover, cell apoptosis was detected by FCM with Annexin V/PI staining. The dinaciclib-induced apoptosis were partially blocked by NAC in both cells (Figure 4C and 4D), suggesting dinaciclib can induce both ROS dependent and independent apoptosis.


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

Chen XX, Xie FF, Zhu XJ, Lin F, Pan SS, Gong LH, Qiu JG, Zhang WJ, Jiang QW, Mei XL, Xue YQ, Qin WM, Shi Z, Yan XJ - Oncotarget (2015)

ROS was critical for the anticancer effect of dinaciclib in ovarian cancer cellsA2780 and OVCAR3 cells were treated with dinaciclib at the indicated times and concentrations, stained with DHE and photographed under florescent microscope. The representative micrographs (A) of three independent experiments were shown. Cells were also treated with 0.03 μM dinaciclib for 48 h in the presence or absence of 5mM NAC pretreatment for 1h, stained with DHE and photographed under fluorescent microscope. The apoptosis was detected by FCM with Annexin V/PI staining. The proportions of Annexin V+/PI− and Annexin V+/PI+ cells indicated the early and late stage of apoptosis. The representative micrographs (B), charts and quantified results (C, D) of three independent experiments were shown. DI: Dinaciclib. *P < 0.05 and **P < 0.01 vs. corresponding control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4558126&req=5

Figure 4: ROS was critical for the anticancer effect of dinaciclib in ovarian cancer cellsA2780 and OVCAR3 cells were treated with dinaciclib at the indicated times and concentrations, stained with DHE and photographed under florescent microscope. The representative micrographs (A) of three independent experiments were shown. Cells were also treated with 0.03 μM dinaciclib for 48 h in the presence or absence of 5mM NAC pretreatment for 1h, stained with DHE and photographed under fluorescent microscope. The apoptosis was detected by FCM with Annexin V/PI staining. The proportions of Annexin V+/PI− and Annexin V+/PI+ cells indicated the early and late stage of apoptosis. The representative micrographs (B), charts and quantified results (C, D) of three independent experiments were shown. DI: Dinaciclib. *P < 0.05 and **P < 0.01 vs. corresponding control.
Mentions: ROS plays an important role in tumorigenesis and chemotherapy of most anticancer drugs [20]. To assess the role of ROS in the anticancer effect of dinaciclib in ovarian cancer cells, we used dihydroethidium (DHE) as ROS fluorescent probe, which can be oxidized by ROS to oxide ethidium that binds with DNA to emit the detectable red fluorescence [21], to stain cells treated with dinaciclib. As shown in Figure 4A, dinaciclib enhanced the fluorescent signals of DHE in both A2780 and OVCAR3 cells in the concentration-and time-dependent manners, suggesting the intracellular ROS levels were enhanced after dinaciclib treatment. To further verify the relationship between dinaciclib induced apoptosis and ROS generation, both cells were treated with dinaciclib for 48h in the presence or absence of the antioxidative agent NAC pretreatment for 1h and stained with DHE. The dinaciclib-induced DHE fluorescent signals were totally reversed by NAC in both cells (Figure 4B). Moreover, cell apoptosis was detected by FCM with Annexin V/PI staining. The dinaciclib-induced apoptosis were partially blocked by NAC in both cells (Figure 4C and 4D), suggesting dinaciclib can induce both ROS dependent and independent apoptosis.

Bottom Line: Dinaciclib alone actively induced cell growth inhibition, cell cycle arrest and apoptosis with the increased intracellular ROS levels, which were accompanied by obvious alterations of related proteins such as CDKs, Cyclins, Mcl-1, XIAP and survivin.Pretreatment with N-acety-L-cysteine significantly blocked ROS generation but only partially rescued apoptosis triggered by dinaciclib.Altogether, dinaciclib potently synergizes with cisplatin in preclinical models of ovarian cancer, indicating this beneficial combinational therapy may be a promising strategy for treatment of ovarian cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

ABSTRACT
Ovarian cancer is one of the most lethal of woman cancers, and its clinical therapeutic outcome currently is unsatisfied. Dinaciclib, a novel small molecule inhibitor of CDK1, CDK2, CDK5 and CDK9, is assessed in clinical trials for the treatment of several types of cancers. In this study, we investigated the anticancer effects and mechanisms of dinaciclib alone or combined with cisplatin in ovarian cancer. Dinaciclib alone actively induced cell growth inhibition, cell cycle arrest and apoptosis with the increased intracellular ROS levels, which were accompanied by obvious alterations of related proteins such as CDKs, Cyclins, Mcl-1, XIAP and survivin. Pretreatment with N-acety-L-cysteine significantly blocked ROS generation but only partially rescued apoptosis triggered by dinaciclib. Moreover, the combination of dinaciclib with cisplatin synergistically promoted cell cycle arrest and apoptosis, and inhibited the subcutaneous xenograft growth of ovarian cancer in nude mice. Altogether, dinaciclib potently synergizes with cisplatin in preclinical models of ovarian cancer, indicating this beneficial combinational therapy may be a promising strategy for treatment of ovarian cancer.

No MeSH data available.


Related in: MedlinePlus