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Xi-Nan Shi
Corresponding Author
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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: We used the combination of computational and experimental approaches to discover a CDK2/4/6 triple-inhibitor from FDA approved small-molecule drugs for the treatment of HCC.
Results: We identified vanoxerine dihydrochloride as a new CDK2/4/6 inhibitor, and a strong cytotoxic drug in human HCC QGY7703 and Huh7 cells (IC50: 3.79μM for QGY7703and 4.04μM for Huh7 cells). In QGY7703 and Huh7 cells, vanoxerine dihydrochloride treatment caused G1‑arrest, 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. Drug combination study indicated that vanoxerine dihydrochloride and 5-Fu produced synergistic cytotoxicity in vitro in Huh7 cells. Finally, in vivo study in BALB/C nude mice subcutaneously xenografted with Huh7 cells, vanoxerine dihydrochloride (40mg/kg, i.p.) injection for 21 days produced significant anti‑tumor activity (p<0.05), which was comparable to that achieved by 5-Fu (10mg/kg, i.p.), with the combination treatment resulted in synergistic effect. Immunohistochemistry staining of the tumor tissues also revealed significantly reduced expressions of Rb and CDK2/4/6in vanoxerine dihydrochloride treatment group.
Conclusions: The present study is the first report identifying a new CDK2/4/6 triple inhibitor vanoxerine dihydrochloride, and demonstrated that this drug represents a novel therapeutic strategy for HCC treatment.
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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Posted 06 Jan, 2021
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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
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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A new preprint design is coming!
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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
Xi-Nan Shi
Corresponding Author
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.
Version 3
Posted 06 Jan, 2021
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
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: We used the combination of computational and experimental approaches to discover a CDK2/4/6 triple-inhibitor from FDA approved small-molecule drugs for the treatment of HCC.
Results: We identified vanoxerine dihydrochloride as a new CDK2/4/6 inhibitor, and a strong cytotoxic drug in human HCC QGY7703 and Huh7 cells (IC50: 3.79μM for QGY7703and 4.04μM for Huh7 cells). In QGY7703 and Huh7 cells, vanoxerine dihydrochloride treatment caused G1‑arrest, 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. Drug combination study indicated that vanoxerine dihydrochloride and 5-Fu produced synergistic cytotoxicity in vitro in Huh7 cells. Finally, in vivo study in BALB/C nude mice subcutaneously xenografted with Huh7 cells, vanoxerine dihydrochloride (40mg/kg, i.p.) injection for 21 days produced significant anti‑tumor activity (p<0.05), which was comparable to that achieved by 5-Fu (10mg/kg, i.p.), with the combination treatment resulted in synergistic effect. Immunohistochemistry staining of the tumor tissues also revealed significantly reduced expressions of Rb and CDK2/4/6in vanoxerine dihydrochloride treatment group.
Conclusions: The present study is the first report identifying a new CDK2/4/6 triple inhibitor vanoxerine dihydrochloride, and demonstrated that this drug represents a novel therapeutic strategy for HCC treatment.
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