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Background Cyclin-dependent kinases 2/4/6 (CDK2/4/6) play critical roles in cell cycle progression, and their deregulations are hallmarks of hepatocellular carcinoma (HCC).
Methods Here we combined computational and experimental approaches to discover a CDK2/4/6 triple-inhibitor from FDA approved small-molecule drugs for the treatment of HCC.
Results Based on molecular docking results, vanoxerine dihydrochloride was found to exhibit strongest cytotoxic effect on human HCC QGY7703 and Huh7 cells (IC50: 3.79 µM for QGY7703and 4.04 µM for Huh7 cells). Vanoxerine dihydrochloride treatment caused G1arrest, induced apoptosis, and reduced the expressions of CDK2/4/6, cyclin D/E, retinoblastoma protein (Rb), as well as the phosphorylation of CDK2/4/6 and Rb in QGY7703 and Huh7 cells. In addition, combined vanoxerine dihydrochloride and 5-Fu produced synergistic cytotoxicity in Huh7 cells. Finally, in vivo studies in preclinical animal model of BALB/C mice subcutaneously xenografted with Huh7 cells, we showed that injection of vanoxerine dihydrochloride (40 mg/kg, i.p.) produced significant antitumor activity (p < 0.05), comparable to that achieved by 5-Fu (10 mg/kg, i.p.), with the combination treatment resulted in strongest effect.
Conclusions The present study is the first to identify a CDK2/4/6 triple inhibitor vanoxerine dihydrochloride, and demonstrate that it represents a novel therapeutic strategy for HCC treatment alone or in combination with 5-Fu.
Keywords
Cyclin-dependent kinases 2/4/6, hepatocellular carcinoma, vanoxerine dihydrochloride, triple inhibitor, drug combination
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View the published article at Molecular Medicine.
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On 17 Dec, 2020
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Received 22 Nov, 2020
Editorial decision: Minor revision
On 22 Nov, 2020
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Received 13 Nov, 2020
Reviewer #3 agreed
On 13 Nov, 2020
Review #3 received
Received 13 Nov, 2020
Reviewer #2 agreed
On 11 Nov, 2020
Reviewer #1 agreed
On 12 Oct, 2020
Reviewers invited
Invitations sent on 07 Oct, 2020
Editor assigned
On 14 Sep, 2020
Submission checks complete
On 13 Sep, 2020
Editor invited
On 13 Sep, 2020
Version 1
Posted 27 May, 2020
No comments provided
Editorial decision: Major revision
On 28 Jun, 2020
Review #2 received
Received 27 Jun, 2020
Reviewer #3 agreed
On 17 Jun, 2020
Reviewer #2 agreed
On 16 Jun, 2020
Review #1 received
Received 06 Jun, 2020
Editor invited
On 28 May, 2020
Editor assigned
On 28 May, 2020
Reviewers invited
Invitations sent on 28 May, 2020
Reviewer #1 agreed
On 28 May, 2020
Submission checks complete
On 20 May, 2020
First submitted
On 14 May, 2020
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Subject Areas
Molecular Genetics
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See the published version of this preprint at Molecular Medicine.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Molecular Medicine.
No community comments so far
Editor assigned
On 17 Dec, 2020
Editorial decision: Accept
On 17 Dec, 2020
Submission checks complete
On 17 Dec, 2020
Editor invited
On 17 Dec, 2020
No comments provided
Review #1 received
Received 22 Nov, 2020
Editorial decision: Minor revision
On 22 Nov, 2020
Review #2 received
Received 13 Nov, 2020
Reviewer #3 agreed
On 13 Nov, 2020
Review #3 received
Received 13 Nov, 2020
Reviewer #2 agreed
On 11 Nov, 2020
Reviewer #1 agreed
On 12 Oct, 2020
Reviewers invited
Invitations sent on 07 Oct, 2020
Editor assigned
On 14 Sep, 2020
Submission checks complete
On 13 Sep, 2020
Editor invited
On 13 Sep, 2020
Version 1
Posted 27 May, 2020
No comments provided
Editorial decision: Major revision
On 28 Jun, 2020
Review #2 received
Received 27 Jun, 2020
Reviewer #3 agreed
On 17 Jun, 2020
Reviewer #2 agreed
On 16 Jun, 2020
Review #1 received
Received 06 Jun, 2020
Editor invited
On 28 May, 2020
Editor assigned
On 28 May, 2020
Reviewers invited
Invitations sent on 28 May, 2020
Reviewer #1 agreed
On 28 May, 2020
Submission checks complete
On 20 May, 2020
First submitted
On 14 May, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Molecular Genetics
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Molecular Medicine.
Background Cyclin-dependent kinases 2/4/6 (CDK2/4/6) play critical roles in cell cycle progression, and their deregulations are hallmarks of hepatocellular carcinoma (HCC).
Methods Here we combined computational and experimental approaches to discover a CDK2/4/6 triple-inhibitor from FDA approved small-molecule drugs for the treatment of HCC.
Results Based on molecular docking results, vanoxerine dihydrochloride was found to exhibit strongest cytotoxic effect on human HCC QGY7703 and Huh7 cells (IC50: 3.79 µM for QGY7703and 4.04 µM for Huh7 cells). Vanoxerine dihydrochloride treatment caused G1arrest, induced apoptosis, and reduced the expressions of CDK2/4/6, cyclin D/E, retinoblastoma protein (Rb), as well as the phosphorylation of CDK2/4/6 and Rb in QGY7703 and Huh7 cells. In addition, combined vanoxerine dihydrochloride and 5-Fu produced synergistic cytotoxicity in Huh7 cells. Finally, in vivo studies in preclinical animal model of BALB/C mice subcutaneously xenografted with Huh7 cells, we showed that injection of vanoxerine dihydrochloride (40 mg/kg, i.p.) produced significant antitumor activity (p < 0.05), comparable to that achieved by 5-Fu (10 mg/kg, i.p.), with the combination treatment resulted in strongest effect.
Conclusions The present study is the first to identify a CDK2/4/6 triple inhibitor vanoxerine dihydrochloride, and demonstrate that it represents a novel therapeutic strategy for HCC treatment alone or in combination with 5-Fu.
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Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
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