ROSCOVITINE – A CONTROLLER OF THE CYCLINS

by Selleckchem | Mar 20 2012

CDKs AND CANCER:

In cellular regulation which is one of the important processes, different enzymes are important and among these cyclin dependent kinases or CDKs play vital role. Mostly cancers are linked with malfunctioning of these CDKs [1]. There are two forms of these malfunctioning, one is the over expression of the CDKs gene and second is about the regulatory proteins of CDKs which may be absent or abnormal [2]. In the field of cancer treatment various inhibitor have been developed which inhibit the function of different vital enzymes. In case of CDKs the development of the unique compound to inhibit the activity of abnormal enzymatic activity is not as simple because the activity of different CDKs is time specific in the cell cycle, therefore a molecule should be well timed up with CDKs [3]. A good number of CDK inhibitors are developed and are mostly in clinical trials phases [4] among those Roscovitine CDK inhibitor is active inhibitor [5].

PHARMACOLOGICAL PROPERTIES OF ROSCOVITINE:

Roscovitine is a competitive inhibitor which competes with the substrate of CDKs that is ATP. Roscovitine IC50 is 0.65 µM, for proper inhibition of cyclin B and 0.7 µM for each of cyclin A and E. The Roscovitine structure based on a purine analogue so a ring structured molecule. Roscovitine solubility is very low in water but other solvents like ethanol and DMSO are used to make a 200mg/ml Roscovitine solution. When it is stored at -20^oC Roscovitine stability can be up to 2 years. The Roscovitine price a vial of 10 mg is about $50. If someone wants to buy Roscovitine it can be purchased from any of Roscovitine suppliers with trade name Seliciclib for research purposes.

The efficiency and therapeutic potential of Roscovitine has been analyzed during its pharmacokinetic studies on mice models and in human tumor cells its in vitro activity has been reported [6]. It is shown that this compound is very potent against inflammatory cellular apoptosis and these findings enhanced its demand for the inflammatory disorders [7]. Another function of this inhibitor is to inhibit the viral DNA replication, hence is potent for virus induced malignancies [8]. And in HSV (Herpes Simplex Virus) it checks the activation of promoter in viral genome [9]. Roscovitine also inhibits the cyclin E-CDK2 loading during HIV-DNA complex formation and this approach can lead to the HIV treatment along with nucleoside based treatment or Roscovitine alone[10][11]][12].

ROSCOVITINE AND CANCER TREATMENT:

The Roscovitine exposure to cells arrest the G1/S and G2/M phases of cell cycle [13] studied in breast cancer cells of epithelial [14]. It is also an inhibitor of apoptosis as it blocks the gene expression of Bcl that is anti-apoptotic factor, these results were found in the MM (multiple myeloma cells) due to these the balance between cellular proliferation and apoptosis is disturbed [15]. In MM treatment the Roscovitine combination with other anticancer agents including Doxorubicin and Bortezomib is also effective [16] and is a good combination for a synergistic effect and tolerated combination. In Neuroblastoma cells its combination with Nutlin-3 that is p53 activating agent is also effective [17]. During Roscovitine clinical trials the activity against ovarian cancer and MM is found as promising in a good number of patients in phase I evaluations [18]. Roscovitine was also applied for the NSCLC (non-small cell lung cancer) and previously treated cells were also analyzed along with the first-line and second-line therapeutics of clinical phases II-A or as a single drug in II-B phase trials in NSCLC patients. Therefore Roscovitine can be used as a single drug or in combination with other drugs to fight against cancers.

REFERENCES:

1. Malumbres, M.a.B., M., Cell cycle, CDKs and cancer: a changing paradigm. Nature reviews, 2009.

2. Malumbres, M.a.B., M., To cycle or not to cycle: a critical decision in cancer. Nature reviews, 2001.

3. Malumbres, M.e.a., CDK inhibitors in cancer therapy: what is next? Trends in pharmacological sciences, 2008.

4. Lapenna, S.a.G., A., Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov, 2009.

5. Azevedo, W.F.e.a., Inhibition of cyclin-dependent kinases by purine analogues: crystal structure of human cdk2 complexed with roscovitine. Eur J Biochem., 1997.

6. Raynaud, F.I.e.a., In vitro and In vivo Pharmacokinetic-Pharmacodynamic Relationships for the Trisubstituted Aminopurine Cyclin-Dependent Kinase Inhibitors Olomoucine, Bohemine and CYC202. Clin Cancer Res, 2005.

7. Rossi, A.G.e.a., Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nat Med., 2006.

8. Schang, L.M.e.a., Roscovitine, a specific inhibitor of cellular cyclin-dependent kinases, inhibits herpes simplex virus DNA synthesis in the presence of viral early proteins. J Virol., 2000.

9. Diwan, P.e.a., Roscovitine inhibits activation of promoters in herpes simplex virus type 1 genomes independently of promoter-specific factors. J Virol., 2004.

10. Agbottah, E.e.a., Antiviral activity of CYC202 in HIV-1-infected cells. J Biol Chem., 2005.

11. Pumfery, A.e.a., Potential use of pharmacological cyclin-dependent kinase inhibitors as anti-HIV therapeutics. Curr Pharm Des., 2006.

12. Sadaie, M.R.e.a., A novel approach to develop anti-HIV drugs: adapting non-nucleoside anticancer chemotherapeutics. Antiviral Res, 2004.

13. Planchais, S.e.a., Roscovitine, a novel cyclin-dependent kinase inhibitor, characterizes restriction point and G2/M transition in tobacco BY-2 cell suspension. Plant J., 1997.

14. Mgbonyebi, O.P.e.a., Roscovitine inhibits the proliferative activity of immortal and neoplastic human breast epithelial cells. Anticancer Res, 1998.

15. MacCallum, D.E.e.a., Seliciclib (CYC202, R-Roscovitine) induces cell death in multiple myeloma cells by inhibition of RNA polymerase II-dependent transcription and down-regulation of Mcl-1. Cancer Res, 2005.

16. Raje, N.e.a., Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma. Blood, 2005.

17. Ribasa, J.e.a., (R)-Roscovitine (CYC202, Seliciclib) sensitizes SH-SY5Y neuroblastoma cells to nutlin-3-induced apoptosis. Experimental Cell Research, 2006.

18. Benson, C.e.a., A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days. British Journal of Cancer, 2007.