ROSCOVITINE – CONTROLLING THE CYCLINS

by Selleckchem | Mar 13 2012

Introduction: Cyclin-dependant kinase Inhibitors:

Another family of proteins that are involved in the regulation of cellular growth are the cyclin dependant kinases (CDK’s). These enzymes are known to be involved in the regulation of the cell cycle (Mitosis (M phase) – Gap phase (G1) – Synthesis (S) – Gap phase (G2)) as well as regulating transcription, mRNA and differentiation of nerve cells.[1;2] CDK’s contain not much more than a kinase domain and are serine / threonine phosphorylators. The substrate for CDK’s is a regulatory protein called cyclin of which 12 are known. The activity of CDK’s is restricted to the CDK – complex which in human cells there are at least 9 known variations. Different CDK-complexes are involved at different stages of the cell cycle process each one controlling one or more factors. In current theory CDK’s are the diving motivation behind each phase of the cell cycle and deviations in the CDK activity from the normal can cause unregulated proliferation or simple a tumor. Hence direct targeting of the aberrant CDK activity would ideally be a therapeutic possibility. However, with CDK activity essential for all cell cycle processes there was no theoretical distinction between tumor and normal cells hence significant toxicology could be expected[3]. Recently new research changed this theory; it indicated that tumor cell cycle was controlled by an interphase CDK that was specific to the tumor cell. With this inhibitors of CDK activity could now be implemented against tumor growth patterns [4]. For this purpose smaal molecule inhibitors were designed, of which the Roscovitine CDK inhibitor is one of several being tested in certain tumor types.

Roscovitine (Seliciclib, CYC202) Chemical Structure

Roscovitine: Properties and Availability

Roscovitine is marketed under the trade name of Seliciclib but has also been known as CYC 202 in literature. Roscovitine structure clearly indicates that it is a tri substituted purine with activity for 3 of the 12 known ligands for cyclin dependant kinases The structure of Roscovitine also contains one chiral centre on the butanol side chain. The marketed product Roscovitine refers to the R isomer of this structure and the molecule is occasionally listed a (R) – Roscovitine. No indication is given whether the (S) - Roscovitine has clinical activity. The Roscovitine IC50 for its targets are cyclin A (0.7µM) cyclin B (0.65µM), and cyclin E (0.7µM). Roscovitine solubility in water is extremely poor but Roscovitine is soluble in DMSO and ethanol. Solutions of up to 200 mg/ml are obtainable in DMSO. Roscovitine stability is listed for its powdered form and this can be stored for upwards of 2 years at -20^oC. Researchers can buy Roscovitine from a variety of Roscovitine suppliers although Roscovitine price is dependant on the supplier. The price of a 10 mg vial can range from $69 up to $800, researchers are advised to shop very carefully for this product.

Roscovitine: Preclinical investigation

As earlier as 1997 Roscovivitine has demonstrated anti-tumor activity, when it was tested in gastric cancer cells the cell cycle was found to be halted in the G2/M.[5] Subsequently it was proved effective in breast cancer cells inhibiting DNA synthesis, induced cell death and proliferative activity.[6] Interestingly Roscovitine was also found to inhibit MDM2 expression which led to the activation of p53, this fact lends Roscovitine to use as a combination agent to restore p53 activity. [7] Roscovitine has been tested against a variety of human tumor cell lines and reported as been a potent inhibitor as a single agent or in combination with traditional chemotherapy. [8]

Roscovitine: Clinical status

In a combination with antiestrogen therapy Roscovitine demonstrated inhibition of proliferation for breast cancer cell lines but the conclusion draw from the results was that activity was extremely dependant on cellular context.[9;10] In a phase 1 study Roscovitine was used in patients with advance malignancies, the MTD was determined as 250 mg BID for 5 days in three week cycles, patients generally demonstrated stable disease over the course of the study.[11] In another phase 1 study over a course of 18 weeks treatment 8 out of 22 patients with advanced malignancies demonstrated tumor stabilization, no other tumor response was observed.[12]

References

1. Morgan DO. Cell cycle control in normal and neoplastic cells. Curr Opin Genet Dev 1992; 2(1):33-37.

2. Morgan DO. Principles of CDK regulation. Nature 1995; 374(6518):131-134.

3. Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 2009; 9(3):153-166.

4. Malumbres M. Physiological relevance of cell cycle kinases. Physiol Rev 2011; 91(3):973-1007.

5. Iseki H, Ko TC et al. Cyclin-dependent kinase inhibitors block proliferation of human gastric cancer cells. Surgery 1997; 122(2):187-194.

6. Mgbonyebi OP, Russo J et al. Roscovitine induces cell death and morphological changes indicative of apoptosis in MDA-MB-231 breast cancer cells. Cancer Res 1999; 59(8):1903-1910.

7. Lu W, Chen L et al. Activation of p53 by roscovitine-mediated suppression of MDM2 expression. Oncogene 2001; 20(25):3206-3216.

8. Raynaud FI, Whittaker SR et al. In vitro and in vivo pharmacokinetic-pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine and CYC202. Clin Cancer Res 2005; 11(13):4875-4887.

9. Zulehner N, Maurer M et al. Effect of anti-estrogen combined with roscovitine, a selective CDK inhibitor, on human breast cancer cells differing in expression of ER. J Exp Ther Oncol 2011; 9(1):17-25.

10. Nair BC, Vallabhaneni S et al. Roscovitine confers tumor suppressive effect on therapy-resistant breast tumor cells. Breast Cancer Res 2011; 13(3):R80.

11. Le TC, Faivre S et al. Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies. Eur J Cancer 2010; 46(18):3243-3250.

12. Benson C, White J et al. 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. Br J Cancer 2007; 96(1):29-37.