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  • CDK5 inhibition in vitro and in vivo induces cell death in myeloma and overcomes the obstacle of bortezomib resistance.

CDK5 inhibition in vitro and in vivo induces cell death in myeloma and overcomes the obstacle of bortezomib resistance.

International journal of molecular medicine (2020-04-03)
Hailong Tang, Li Xu, Xi Cen, Li Yang, Juan Feng, Guang Li, Huafeng Zhu, Shan Gao, Yan Yu, Yaping Zhao, Zhiqiang Tian, Liping Hou, Shuchun Yu, Guangxun Gao
ABSTRACT

The emergence of new drugs is a major feature of the treatment history of multiple myeloma (MM), which also reflects the current incurability of MM. As a unique member of cyclin dependent kinase (CDK) family, CDK5 participates in numerous tumorigenic or non‑tumorigenic processes. The aim of this study is to investigate the effects of CDK5 on the viability of MM cells and bortezomib resistance using western blotting, immunohistochemistry, transient transfection, MTT assays, cell cycle analysis, apoptosis assays and a myeloma xenograft mouse model. The present study found that MM patients with high CDK5 expression in the bone marrow do not respond well to bortezomib, have higher DS stage and worse prognosis. Genetic and pharmacological (dinaciclib) inhibition of CDK5 triggers MM cell viability inhibition. Dinaciclib induces G2/M arrest and apoptosis of MM cells. In vivo experiments with myeloma xenograft mice indicate that dinaciclib significantly reduces the volume of tumors with good tolerance. Dinaciclib combined with bortezomib exerts a synergistic anti‑myeloma activity accompanied by inhibiting the activation of the nuclear factor‑κB pathway. This study demonstrates the important role of CDK5 in the pathogenesis, viability, prognosis and resistance to bortezomib of MM, laying a solid theoretical foundation for further clinical use of CDK5 inhibitors.

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Roche
Kit di rilevamento della morte cellulare in situ, POD, sufficient for ≤50 tests
Sigma-Aldrich
Adenosine 5′-diphosphoribose sodium salt, ≥93%
Sigma-Aldrich
MISSION® esiRNA, targeting human CDK5