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Multiple CDK inhibitor dinaciclib suppresses neuroblastoma growth via inhibiting CDK2 and CDK9 activity

Zhenghu Chen1,2, Zhenyu Wang3,4, Jonathan C Pang2

  • 1Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P. R. China.

Scientific Reports
|July 6, 2016
PubMed

Insights

Dinaciclib, a novel multiple-cyclin-dependent kinase (CDK) inhibitor, effectively reduced neuroblastoma (NB) cell proliferation by targeting CDK2 and CDK9. This compound also enhanced chemotherapy efficacy and showed antitumor activity in preclinical models, suggesting a promising treatment strategy for NB.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Neuroblastoma (NB) is a common childhood extracranial solid tumor causing significant cancer mortality.
  • Aberrant cyclin-dependent kinase (CDK) activation is implicated in NB tumor progression.
  • Targeting CDKs with small molecule inhibitors offers a potential therapeutic strategy for NB.

Purpose of the Study:

  • To evaluate the anti-proliferative effects and therapeutic potential of the novel multiple-CDK inhibitor dinaciclib in neuroblastoma.
  • To investigate dinaciclib's impact on CDK2 and CDK9 activity in NB cells.
  • To assess dinaciclib's efficacy in combination with standard chemotherapeutic agents and in preclinical NB models.

Main Methods:

  • Screening of dinaciclib against a panel of NB cell lines.
  • Assessment of CDK2 and CDK9 inhibition.
  • Evaluation of dinaciclib's synergistic effects with doxorubicin and etoposide.
  • In vivo studies using orthotopic xenograft and TH-MYCN transgenic mouse models of NB.

Main Results:

  • Dinaciclib demonstrated potent anti-proliferative activity against NB cell lines by inhibiting CDK2 and CDK9.
  • Dinaciclib significantly sensitized NB cells to doxorubicin and etoposide treatments.
  • Dinaciclib exhibited significant in vivo antitumor efficacy in both xenograft and transgenic NB mouse models.

Conclusions:

  • CDK2 and CDK9 are validated therapeutic targets in neuroblastoma.
  • Dinaciclib, by inhibiting CDK2 and CDK9, represents a promising therapeutic strategy and potential treatment option for NB patients.
  • Combination therapy involving dinaciclib may enhance treatment outcomes for NB.

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