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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

Dinaciclib synergized with cisplatin to inhibit the subcutaneous xenograft growth of ovarian cancer in nude miceEach mouse was injected subcutaneously with A2780 cells (2 × 106 in 100 μl of medium) under the shoulder. When the subcutaneous tumors were approximately 0.3 × 0.3 cm2 (two perpendicular diameters) in size, mice were randomized into four groups, and were injected intraperitoneally with vehicle alone (20% hydroxypropyl-β-cyclodextrin), dinaciclib alone (25 mg/kg), cisplatin alone (2 mg/kg), or a combination of dinaciclib and cisplatin every four days. The body weights of mice and tumor volume were recorded. The mice were anaesthetized after experiment, and tumor tissue was excised from the mice and weighted. The original tumors (A), tumor volume (B), tumor weight (C), net body weight (without tumor) (D) and summary data (E) were shown. The values presented are the means ± SD for each group. DI: Dinaciclib; DDP: Cisplatin. *P < 0.05 and **P < 0.01 vs. corresponding control.
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Figure 7: Dinaciclib synergized with cisplatin to inhibit the subcutaneous xenograft growth of ovarian cancer in nude miceEach mouse was injected subcutaneously with A2780 cells (2 × 106 in 100 μl of medium) under the shoulder. When the subcutaneous tumors were approximately 0.3 × 0.3 cm2 (two perpendicular diameters) in size, mice were randomized into four groups, and were injected intraperitoneally with vehicle alone (20% hydroxypropyl-β-cyclodextrin), dinaciclib alone (25 mg/kg), cisplatin alone (2 mg/kg), or a combination of dinaciclib and cisplatin every four days. The body weights of mice and tumor volume were recorded. The mice were anaesthetized after experiment, and tumor tissue was excised from the mice and weighted. The original tumors (A), tumor volume (B), tumor weight (C), net body weight (without tumor) (D) and summary data (E) were shown. The values presented are the means ± SD for each group. DI: Dinaciclib; DDP: Cisplatin. *P < 0.05 and **P < 0.01 vs. corresponding control.

Mentions: To test the synergistic antitumor effects of dinaciclib and cisplatin in vivo, we generated the subcutaneous xenograft tumor models by transplanting A2780 cells into nude mice. As shown in Figure 7A and 7B, compared with dinaciclib or cisplatin alone treatment, co-treatment with dinaciclib and cisplatin clearly inhibited the tumors growth by reducing the volume and weight of A2780 tumors. The inhibition rates of tumor growth in the combined group were 80.7%, which were significantly higher than those in cisplatin (42.8%) or dinaciclib (57.7%) alone group (Figure 7C). Nevertheless, the net body weights (without tumor) of mice in the combined group were lower than those in control group, suggesting co-treatment of dinaciclib and cisplatin at the indicated dose caused certain side effects in mice (Figure 7B).


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)

Dinaciclib synergized with cisplatin to inhibit the subcutaneous xenograft growth of ovarian cancer in nude miceEach mouse was injected subcutaneously with A2780 cells (2 × 106 in 100 μl of medium) under the shoulder. When the subcutaneous tumors were approximately 0.3 × 0.3 cm2 (two perpendicular diameters) in size, mice were randomized into four groups, and were injected intraperitoneally with vehicle alone (20% hydroxypropyl-β-cyclodextrin), dinaciclib alone (25 mg/kg), cisplatin alone (2 mg/kg), or a combination of dinaciclib and cisplatin every four days. The body weights of mice and tumor volume were recorded. The mice were anaesthetized after experiment, and tumor tissue was excised from the mice and weighted. The original tumors (A), tumor volume (B), tumor weight (C), net body weight (without tumor) (D) and summary data (E) were shown. The values presented are the means ± SD for each group. DI: Dinaciclib; DDP: Cisplatin. *P < 0.05 and **P < 0.01 vs. corresponding control.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Dinaciclib synergized with cisplatin to inhibit the subcutaneous xenograft growth of ovarian cancer in nude miceEach mouse was injected subcutaneously with A2780 cells (2 × 106 in 100 μl of medium) under the shoulder. When the subcutaneous tumors were approximately 0.3 × 0.3 cm2 (two perpendicular diameters) in size, mice were randomized into four groups, and were injected intraperitoneally with vehicle alone (20% hydroxypropyl-β-cyclodextrin), dinaciclib alone (25 mg/kg), cisplatin alone (2 mg/kg), or a combination of dinaciclib and cisplatin every four days. The body weights of mice and tumor volume were recorded. The mice were anaesthetized after experiment, and tumor tissue was excised from the mice and weighted. The original tumors (A), tumor volume (B), tumor weight (C), net body weight (without tumor) (D) and summary data (E) were shown. The values presented are the means ± SD for each group. DI: Dinaciclib; DDP: Cisplatin. *P < 0.05 and **P < 0.01 vs. corresponding control.
Mentions: To test the synergistic antitumor effects of dinaciclib and cisplatin in vivo, we generated the subcutaneous xenograft tumor models by transplanting A2780 cells into nude mice. As shown in Figure 7A and 7B, compared with dinaciclib or cisplatin alone treatment, co-treatment with dinaciclib and cisplatin clearly inhibited the tumors growth by reducing the volume and weight of A2780 tumors. The inhibition rates of tumor growth in the combined group were 80.7%, which were significantly higher than those in cisplatin (42.8%) or dinaciclib (57.7%) alone group (Figure 7C). Nevertheless, the net body weights (without tumor) of mice in the combined group were lower than those in control group, suggesting co-treatment of dinaciclib and cisplatin at the indicated dose caused certain side effects in mice (Figure 7B).

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