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Roscovitine, a small molecule CDK inhibitor induces apoptosis in multidrug-resistant human multiple myeloma cells

Oxane Komina1, Ellen Nosske, Margarita Maurer

  • 1Cell Cycle Regulation Group, Division, Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria.

Journal of Experimental Therapeutics & Oncology
|February 1, 2011
PubMed

Insights

Roscovitine effectively induces apoptosis in doxorubicin-resistant multiple myeloma cells by targeting cyclin-dependent kinases and transcription. This CDK inhibitor shows promise for overcoming drug resistance in cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Multiple myeloma is a malignancy characterized by uncontrolled cell proliferation and resistance to apoptosis.
  • Doxorubicin resistance is a significant clinical challenge in multiple myeloma treatment.
  • Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle and potential therapeutic targets in cancer.

Purpose of the Study:

  • To investigate the efficacy of Roscovitine (ROSC), a small molecule CDK inhibitor, against doxorubicin-resistant human multiple myeloma cells.
  • To determine if ROSC can overcome drug resistance mediated by P-glycoprotein (P-gp) overexpression.
  • To explore the mechanisms by which ROSC induces apoptosis in resistant myeloma cells.

Main Methods:

  • Utilized human multiple myeloma cell lines sensitive (RPMI-8226s) and resistant (RPMI-8226(DOX40)) to doxorubicin (DOX).
  • Assessed apoptosis induction by ROSC and DOX using hypoploid cell analysis.
  • Investigated ROSC's effect on P-gp overexpressing cells and its impact on pro-survival gene transcription.

Main Results:

  • Roscovitine significantly increased apoptosis in both doxorubicin-sensitive and -resistant myeloma cell lines.
  • Doxorubicin failed to induce significant apoptosis in the resistant RPMI-8226(DOX40) cell line at high doses.
  • Roscovitine demonstrated the capacity to induce apoptosis in doxorubicin-resistant cells overexpressing P-gp.
  • ROSC's inhibition of transcription of pro-survival genes (BCL2, MCL-1) and destabilization of survivin contributed to its efficacy.

Conclusions:

  • Roscovitine is a potent inducer of apoptosis in multidrug-resistant multiple myeloma cells.
  • ROSC exhibits therapeutic potential in overcoming doxorubicin resistance, possibly via P-gp modulation and transcription inhibition.
  • Targeting CDKs and transcription pathways with inhibitors like Roscovitine may offer a viable strategy for treating resistant myeloma.

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