In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R‐roscovitine)

Abstract

CDK2 inhibitors have been proposed as effective anti-cancer therapeutics. We show here that CYC202 (R-roscovitine) is a potent inhibitor of recombinant CDK2/cyclin E kinase activity (IC 50 ‫؍‬ 0.10 M) with an average cytotoxic IC 50 of 15.2 M in a panel of 19 human tumour cell lines, and we also demonstrate selectivity for rapidly proliferating cells over non-proliferating cells. A study of the cell cycle effects of CYC202 in Lovo colorectal carcinoma cells showed that the major effect was not the predicted arrest in one part of the cycle, but rather an induction of cell death from all compartments of the cell cycle. The maximum tolerated dose given intravenously to mice was in excess of 20 mg/kg. Doses up to 2,000 mg/kg were tolerated when administered orally in mice. Following repeated intraperitoneal administration (3 times daily for 5 days) of 100 mg/kg to nude mice bearing the Lovo human colorectal tumour, CYC202 induced a significant antitumour effect with a 45% reduction in tumour growth compared to controls. A second experiment using the human uterine xenograft MESSA-DX5 treated with orally administered CYC202 (500 mg/kg 3 times daily for 4 days) also exhibited a significant reduction in the rate of growth of the tumour (62%). These data, showing enzyme and cellular potency together with antitumour activity, confirm the potential of CDK2 inhibitors such as CYC202 as anticancer drugs. © 2002 Wiley-Liss, Inc. Key words: cyclin-dependent kinase inhibitors; CYC202; roscovitine; cell cycle; anti-tumour efficacyCyclin-dependent kinases (CDKs) are key regulators in the process of cell cycle progression. 1 These enzymes are activated by periodic formation of complexes with cyclins, which are proteins that are present only at specific stages of the cell cycle. CDK4 and CDK6, coupled with their partner cyclin D, are responsible for progression through G1, whereas CDK2 in combination with cyclin E is responsible for normal progression from G1 into S phase. CDK2/cyclin A is required for progression through S phase, and CDK1/cyclin B is necessary for mitosis to occur. 2 These CDK/ cyclin complexes are regulated in turn by stoichiometric association with small proteins, cyclin-dependent kinase inhibitors (CDKIs), such as p19, p16, p15, p21 and p27, which are members of the INK4 and WAF1/KIP1 class of CDK inhibitor. Mutation and/or deletion of some of these CDKIs has been shown in many human neoplasias. 3 Hence control of the cell cycle through CDKs, by means of small molecule CDK inhibitors, has been of great interest as a novel cancer treatment strategy. Questions remain, however, regarding the importance of CDK selectivity for this type of agent. Both CDK2 and CDK4 have been targeted for small molecule inhibitor development, and recent results suggest that CDK2 antagonists may induce apoptosis selectively in transformed cells regardless of p53 status, 4 while the function of CDK4 has now been linked to modulation of the rate of cellular growth and has been suggested to be (in Drosophila at least) dispensable for cel...

The cyclin‐dependent kinase inhibitor R‐roscovitine down‐regulates Mcl‐1 to override pro‐inflammatory signalling and drive neutrophil apoptosis

“…CDK are important regulators of cell-cycle progression but also gene transcription [31]. R-roscovitine has been extensively evaluated as a cancer therapeutic both independently and in combination with other drugs [31,32]. We have shown previously that R-roscovitine not only promotes neutrophil apoptosis in vitro but does so in the presence of powerful survival factors [23].…”

Antiproliferative effects of sapacitabine (CYC682), a novel 2′-deoxycytidine-derivative, in human cancer cells

“…Considering that this compound may be amenable to clinical trials in combination with other anticancer agents, combinations of sapacitabine with several anticancer agents commonly used in practice, such as gemcitabine, oxaliplatin, doxorubicin, docetaxel and seliciclib, a novel CDK inhibitor (McClue et al, 2002;Meijer and Raymond, 2003), were also explored. Nucleosides enter the cell via the human equilibrative nucleoside transporter 1 (hENT1).…”

R-Roscovitine simultaneously targets both the p53 and NF-κB pathways and causes potentiation of apoptosis: implications in cancer therapy

“…12 It has been reported to have antitumor activity against several cancer cell lines. 11,13,14 It can also induce apoptosis in multiple myeloma cells, 15 primary B-cell chronic lymphatic leukemia cells 16 and also maturing cerebellar granule neurons. 17 Another study demonstrated the ability of RRoscovitine to promote resolution of inflammation and inflammatory cell apoptosis associated with the loss of expression of Mcl-1.…”