Dysregulation of the cell cycle often results in diseases that are leading cause of mortality and morbidity in the world. Experimental research into cell cycle biology has revealed that progression of the cell cycle is regulated by cyclin-dependent kinases (CDKs) which are activated by cyclins and inhibited by CDK inhibitors. The cell cycle checkpoints are regulated by the CDKs which combine both the mitogenic and growth inhibitory signals that are responsible for the cell cycle transitions [
1.1. Cyclin-dependent kinases, functions, regulation and involvement in diseases
Cyclin-dependent kinases area family of serine or threonine protein kinases. Members of this family share the common characteristic of requiring the binding of a regulatory cyclin subunit for enzymatic activation, and may also require the phosphorylation of a threonine residue near the kinase active site for full enzymatic activity. They were originally identified as proteins that controlled cell cycle events but have also been discovered to be involved in other cellular processes. Animal cells contain at least thirteen CDKs, only four of which are directly involved in cell cycle control, namely CDK1, CDK2, CDK4 and CDK6. CDK7 and CDK9 are involved in cell growth and the others are involved in the control of CDK activity, nerve cell differentiation and the level of basal gene transcription (Table 1).
|CDK||Cyclin partner||Biological function|
|CDK1||Cyclin A, B||G2 and M phase|
|CDK2||Cyclin A, B, E||G1,S and M phase, apoptosis, transcription|
|CDK3||Cyclin C, E||G0 and G1 phase|
|CDK4||Cyclins D1, D2, D3||G1 phase, cell differentiation|
|CDK5||Cyclins D1, D3, p35, p37||Transcription, DNA damage response|
|CDK6||Cyclins D1, D2, D3||G1 phase|
|CDK7||Cyclin H||CDK-activating kinase, transcription, DNA repair|
|CDK9||Cyclins T1, T2a, T2b, K||Transcription, cell growth, cell differentiation, apoptosis|
Similar to other protein kinases, CDKs have a bi-lobed structure, and can undergo two conformational changes that inactivate the enzyme, should the partner cyclin be absent. These conformational changes were discovered through crystallographic studies on human CDK2. Firstly, a flexible loop present at the carboxyl- terminal lobe, called the T-loop or the activation loop, blocks the binding of protein substrates at the opening of the active site cleft. Secondly, in inactive CDKs, some catalytically important amino acid side chains are in conformations that do not allow efficient phosphate transfer. Upon cyclin binding two alpha helices induce conformational changes in the kinase that allow efficient catalysis. The PSTAIRE helix reorients the residues that interact with the phosphates of ATP and the L12 helix reconfigures the residues of the T-loop and the active site. A brief description of the main CDKs is given below.
CDK1 also known as the mitotic kinase [
CDK consists of298 amino acids in length as has a molecular weight of 33.9 kDa. The human CDK2 gene is located on Chromosome 12 at 12q13. The protein kinase is found in complex with its regulatory partners Cyclin E or Cyclin A. Cyclin E is necessary for the transition from phase G1 to S and the initiation of the S phase of the cell cycle while Cyclin A is required to progress through the S phase.CDK2 is regulated by its protein phosphorylation and by the inhibitors p21Cip1 and p27Kip1. Intriguingly, despite the key role of CDK2 in cell cycle regulation and the profound effects of CDK2 inhibitory compounds on cell fate, it has been reported also that CDK2 knockout mice are viable [
CDK4 is found complexed with Cyclin D and this complex is essential for the progression of cells through the G1 phase of the cell cycle. The protein consists of 303 amino acids and has a molecular weight of 34 kDa. The human CGK4 gene is located on Chromosome 12 at position 12q14. CDK4/Cyclin D is one of the kinases that phosphorylate the retinoblastoma protein family (Rb), which leads to dissociation of the pRb-E2F complex and activation of the transcription of genes required for the entry into the S phase. Mutations in the CDK4gene were all found to be associated with tumorigenesis.
CDK5 interacts with D1 and D3-type cyclins. The protein shows kinase activity only after interaction and activation by CDK5R1 (p35) or CDK5R2 (p39). Although p35 and p39 lack cyclin sequence homology, crystal structures show that p35 folds in a similar way as the cyclins.CDK5 has been found to modulate the metastatic potential of some malignancies, including breast and prostate carcinomas [
CDK6 has a size of 326 amino acids, a molecular weight of 40 kDa and the human CDK6 gene is located on chromosome 7 at position 7q21-22. Together with CDK4, CDK6 is known as G1-phase CDK and binds to Cyclin Ds, to form CDK6/Cyclin D complexes. The activity of thiskinase plays a significant role in the progression of cells through the G1 phase of the cell cycle [
The two kinases have shown differing substrate specificities in vitro– with CDK4 phosphorylating Thr-826 of pRb, while CDK6 targets Thr-821 – a result which also suggests that the CDK alone can direct substrate recognition [
CDK6 activity has been implicated in the inhibition of differentiation across a number of cell types. In murine erythroid leukaemia cells inhibition of CDK6 has been shown to induce terminal differentiation while inhibition of CDK4 did not have this effect [
CDK7 exists as a part of a three protein complex consisting of CDK7, Cyclin H and MAT1 (“ménage à trois”) that is also known as Cyclin-dependent kinase Activating Kinase (CAK) and is responsible for the phosphorylating activation of CDKs 1,2,4 and 6. This complex is also, along with another six proteins, part of the general transcription factor TFIIH, and so is involved in the early pre-initiation and initiation steps of transcription.
CAK either does not phosphorylate monomeric CDKs or does so only poorly, requiring the presence of the partner cyclin to cause a conformational change in the kinase, exposing the activation loop and allowing CAK to phosphorylate. Like other CDKs, CDK7 is phosphorylated on the activation loop, but this modification is not required for enzymatic activity, instead the presence of MAT1 in complex with CDK7 and Cyclin H can substitute for the activating phosphorylation.
As a part of TFIIH CAK hyperphosphorylates the C-terminal domain (CTD) of the large subunit of RNA polymerase II, thus promoting the initiation of transcription, an event that CAK alone is unable to catalyse. CAK, as a part of TFIIH, is phosphorylated by CDK1/Cyclin B during mitosis – an event that causes the loss of the TFIIH’s CTD’s phosphorylating activity, and is at least in part responsible for the silencing of transcription during mitosis.
Temperature sensitive CDK7 mutants in C. elegans exhibit a block in the cell cycle which can be attributed to loss of CAK activity rather than any CTD phosphorylating function [
CDK8 is a 464 amino acid serine-threonine protein kinase with a molecular weight of 53.3 kDa whose gene CDK4 is located on chromosome 13 at position 13q12. The protein is located in the nucleus and along with CDK7 and CDK9 makes up the transcriptional CDKs (rCDKs) as they have all been identified as having role(s) in transcriptional control. Similar to CDK7 – CDK8 can also phosphorylate the C-terminal domain of RNA Polymerase II in vitro;however, its specificity is for residues Ser-2 and Ser-5, as opposed to the Ser-5 and Ser-7 targeted by CDK7. The cyclin partner for CDK8 is Cyclin C, which does not show cell cycle-dependent fluctuations in concentration; control of CDK8 activity is modulated rather by other factors, such as association with Mediator Complex Subunit 12 (MED12) [
CDK8 has been attributed to oncogenic potential in colon cancer cells due to effects observed on the Wnt/β-catenin pathway in cultured cells [
CDK9 is a 372 amino acid, 42.8 kDa serine-threonine kinase encoded by the CDK9 gene on chromosome 9 at position 9q34.1. The kinase has been found complexed with two cyclins, Cyclin T and Cyclin K. The kinase subunit forms the catalytic core of positive transcription elongation factor b (p-TEFb) [
Regulation of CDKs
Understanding the biological role and the regulation of cyclin-dependent kinases is important for selecting drug targets and developing strategies for modulating their activity for therapeutic purposes.
CDKs are regulated by several mechanisms, including transcription and translation of their subunits, heterodimerization with cyclins, post-translational modification by phosphorylation and dephosphorylation, and interactions with their natural inhibitors.The endogenous CDK inhibitors consist of two families, the INK4 family and the KIP (kinase inhibitor protein) family [
Members that fit into the INK4 family e.g.: p15INK4B and p16INK4A, inhibit CKD4 and CDK6; while members of the KIP family, e.g.: p21Cip1, p27Kip1 and p57Kip2, have diverse activities [
p16 is the main member of the INK4 family of inhibitors, which plays key role during the G1 and S phases of the cell cycle. The family includes p15, p16, p18 and p19 which tend to inactivate only the G1 CDK’s – CDK4 and CDK6. Prior to their attachment with cyclins, they form stable complexes with the CDK’s, and overexpression of cyclins will not separate them from the CDK. Due to the binding that occurs between the members of the p16 family and CDK4 or CDK6, it does not permit the phosphorylation and inactivation of pRb [
The proteins of the p21 family are important in the regulation of G1 phase of the cell cycle and include waf1 (also called p21), p27 and p57. Except for CDK1, they can inhibit most of the CDKs. Due to its binding with cyclins, they prevent the CDK from phosphorylating the pRb and unlike p16, these induce dissociation from E2F. The role of p21 in oncogenesis is still unclear, but it might act as a tumour suppressor since it plays the role of an inhibitor during the cell cycle [
p27 inhibits cyclin-dependent kinases that help in the regulation of the cell cycle through which cells progress. This inhibitor was initially discovered in cells that were arrested by transforming growth factor α (TGF-α) or by contact inhibition or after treatment with lovastatin. It is found to be in conjugation with CDK/Cyclin D complexes in those cells that proliferate, while in those G1 arrested cells it binds itself to CDK2/Cyclin E complexes. Hence it is crucial to which complex p27 binds and there remains a competition between CDK/Cyclin D and CDK2/Cyclin E complexes. If the former can sequester p27 from the latter then it can push the cell into the S phase. In the experimental studies related to breast cancer, Chiarle et al compared the levels of p27 and the activities of CyclinE and Cyclin D1-dependent kinases and found that an inverse correlation exists between CyclinE-dependent kinase and p27 [
The activity of p27 seems to increase on loss of adhesion to the extracellular matrix, in response to differentiation signals and by the signals of TGF-α, a growth inhibitory factor, while mitogenic factors cause its loss. [
1.2. CDK inhibitors as potential therapeutics.
As already mentioned CDKs are key regulators of cell cycle and other fundamental biological processes, such as transcription. Consequently the main effects of CDK inhibitors are induced via modulation of the cell cycle progression and inhibition of transcription.
Notably dysregulation of the cell cycle is a common event in tumorigenesis and leads to uncontrolled cell proliferation and independence from extracellular mitogenic signals. In a normal cell, initiation of the cell cycle is achieved through stimulation with growth factors. Such mitogenic stimulation results in a cascade of serine-threonine kinase activities resulting with induction of Cyclin D1 transcription. Cyclin D1 then binds to CDK4 and CDK6 to give active kinase complexes. The latter directly phosphorylates the retinoblastoma protein (Rb), causing dissociation of histone deacetylase 1, allowing histone acetylation, which is permissive for transcription. As a result key cell cycle regulators, such as Cyclin E are transcribed and translated. Cyclin E then forms a complex with CDK2, which further phosphorylates Rb with the release of the general transcription factor E2F. E2F stimulates the transcription of genes required for progression through to the synthesis phase of the cell cycle.
Dysregulation of the cell cycle occur through various mechanisms. They include: mutations leading to constitutive activation of the signal transduction pathways [
In addition to control of the cell cycle, some CDKs are involved in regulation of RNA polymerase II-mediated transcription. There are three RNA polymerase II (RNAPII) directed cyclin-dependent protein kinases which play roles in RNAPII activation. These are CDK7, 8 and 9, and they all phosphorylate the serine-rich C-terminal domain (CTD) of RNAPII to allow the consecutive attachment of the elongational transcription factors. Soon after initiation, CDK7 (the kinase subunit of transcription factor TFIIH) phosphorylates Serine 5, causing RNAPII to become arrested in the promoter-region due to its interaction with negative elongation factors (NELF). Phosphorylated Serine 5 also mediates the recruitment of mRNA capping enzymes. After capping, CDK9 phosphorylates Serine 2 which counteracts the suppressive action by NELF and allows RNAPII to advance from the promoter and so allows transcriptional elongation [
Importantly roscovitine inhibits RNAPII-mediated transcription, which downregulates the expression of anti-apoptotic proteins, such as Bcl-2, Mcl-1, survivin and others [
The amount of phosphorylated (active) RNAPII increases rapidly in response to hypertrophic stimuli, such as endothelin-1 (ET-1) and Angiotensin (Ang) II, due to increased phosphorylation of Ser-2 of the C-terminal domain–the serine rich region which is preferentially phosphorylated by CDK9. CDK9 is, therefore, the essential CTD kinase for hypertrophic growth – an observation further reinforced by much experimental data, such as that from Sano and Schneider(2004) [
Hypertrophic signalling pathways stimulate CDK9 activation by causing the dissociation of 7sk (a small nuclear RNA) from CDK9, unleashing CDK9 function. 7sk, when bound to CDK9, causes inhibition of the catalytic activity. Hypertrophic signals result in the liberation of functional P-TEFb (positive transcription elongation factor b) from its endogenous inhibitor, which is the CDK9/Cyclin T heterodimer. The following diagram (Fig. 1) helps to convey the activation of CDK9 by hypertrophic stimuli [
CDK9 is also involved in mitochondrial dysfunction, observed as a result of cardiac hypertrophy. This dual transcription role of CDK9 in both hypertrophic growth and in mitochondrial dysfunction further highlights the potential utility of CDK9 as a drug target for the inhibition cardiac hypertrophy. Overall, the activity of CDK9 is upregulated in cardiac hypertrophy, and consequently, CDK9 inhibition is a potentially attractive molecular target for therapeutic intervention in cardiac hypertrophy [
2. Discovery of roscovitine
It was in the laboratory of Pierre Guerrier at the Roscoff Biological Station that Laurent Meijer, after spells in the labs of Maurice Durchon in Lille and David Epel at Stanford, realised that starfish oocytes were perhaps the ideal model to study the role of protein phosphorylation in the prophase/metaphase transition of the cell cycle [
The use of protein phosphates and phosphatase inhibitors had led to the initial anecdotal identification of protein phosphorylation as a mechanism in the control of the cell cycle [
The central role of CDK1 and its requirement for cell division made it an immediate target for scientists interested in identifying potential anti-cancer agents. A radioactive in vitro kinase assay [
Further attempts to improve selectivity and potency of these substituted purines was carried out in the laboratories of MiroslavStrnad in Olomouc (Czech Republic) and Michel Legraverend at the Institute Marie Curie in Orsay(France) and resulted in the identification of the 6-(benzylamino)-2(R)-[[1-(hydroxymethyl)propyl]amino]-9-isopropylpurine (Fig.3), subsequently named roscovitine [
3. Chemical synthesis and physicochemical properties of roscovitine
We have synthesised (R)-roscovitine (CYC202) and its (S)-enantiomer [
We have also determined some of the physiochemical properties of roscovitine [
|Other names||(R)–Roscovitine, (S)-Roscovitine, CYC202, Seliciclib|
|Solubility||Soluble in DMSO (up to 50 mM) and in 50 mM HCL with the pH adjusted to 2.5|
|Atomic composition||C= 64.38%; H=7.39%; N=23.71%; O=4.51%|
|Rotation values||(R)-Roscovitine: [α]D20+ 56.3, (S)-Roscovitine: [α] D20-56.3|
|Absorption λ max||230nm and 292nm|
4. Inhibition of CDKs by R-roscovitine (CYC202)
De Azevedo et al. (1997) [
These studies also revealed that it is the (R)-enantiomer of roscovitine which is bound by CDK2 (this enantiomer is about twice as potent as the (S)-enantiomer in inhibiting cdc2/Cyclin B). This provides the rationale for clinical development of the (R)-enantiomer of roscovitine.
The specificity of roscovitine was demonstrated by Meijer et al. (1997) [
5. CYC202 inhibits cell growth in vitro
Due to the pivotal role of CDKs in a wide range of cellular functions, roscovitine has been suggested as a potential treatment for several diseases that involve the cell cycle. The effects of roscovitine have been studied in vitro in cell lines and in vivo in animal models. In vitro studies have been carried out in more than 100 cell lines, including the NCI-60 cell line panel of the national cancer institute (NCI).
Meijer et al. (1997) [
We have investigated the potential for CYC202 to inhibit the growth of cultured tumour cells in vitro using a panel of nineteen different human tumour cell lines and three non-proliferating human cell lines [
We have also studied the minimum length of exposure to CYC202 required to achieve the maximum growth inhibitory effect using the human ovarian cancer cell line A2780, and determined a required exposure time of at least 16 hours – a period of time equal to approximately one cell cycle for A2780 cell line. Given that these cells are asynchronous, it is, therefore, likely that the molecular target must be inhibited during the appropriate phase of the cell cycle in order to cause growth arrest in the cells. In addition, we also evaluated the ability of CYC202 to induce cell cycle arrest and apoptosis in the human lung tumour cell line A549. Information on cell cycle distribution of the cells was obtained from DNA content analysis of ethanol-fixed, propidium iodide stained, A549 cells following treatment. The major effect observed following 24 and 48 hours exposure to 50 or 100µM CYC202 was the accumulation of a sub-G1 population of cells, indicative of induction of apoptosis. In addition, CYC202 caused accumulation of cells in the G2/M phases of the cell cycle at both concentrations investigated.In this study, the induction of apoptosis by CYC202 was quantified by DNA content analysis. Cells with a DNA content that is less than that of a cell in G1 (termed sub-G1 peak analysis) were scored as apoptotic. In a separate experiment the appearance of sub-G1 peaks was confirmed to be representative of apoptosis by TUNEL analysis of replicate samples. Apoptosis was detectable at 24 h in CYC202-treated cells. 48 hour exposure resulted in a small further increase in the proportion of apoptotic cells. TUNEL analysis also demonstrated that apoptotic cells (i.e. TUNEL positive) were produced from each of the cell cycle compartments. This indicates that the previously described G2 accumulation is not a result of selective induction of apoptosis from the other compartments (G1 and S) and is likely to be caused by inhibition of one or more cell cycle regulators.
Schutte et al. (1997) [
Alessi et al. (1998) [
Yakisichet al. (1999) [
Iseki et al., (1997) [
Mgbonyebi et al, (1998) [
In addition to its cytostatic and pro-apoptotic actions,roscovitine has also been reported to induce cell differentiation. In a study using the human non-small cell lung cancer cell line NCI-H348 [
The cellular effects of roscovitine have also been investigated in several non-mammalian models [
Roscovitine was reported to induce apoptosis in several cell lines, regardless of p53 status; surprisingly, roscovitine was more effective in inducing apoptosis in wild type p53 cells, compared to p53 null cells. Cell death has been detected in all phases of the cell cycle, and different mechanisms may be involved, including inhibition of the cell cycle due to p53 activation and inhibition of CDK7/CDK9-dependent transcription inhibiting RNA polymerase II enzyme [
The antitumor effects of roscovitine are mainly based on anti-proliferative and pro-apoptotic mechanisms; moreover, no resistance to roscovitine therapy has been reported so far [
Interestingly, tumor cells are more dependent on short-lived survival factors than normal cells. Thus, downregulation of these factors by roscovitine treatment has higher impact on tumor cells than on normal cells [
6. Anti-tumour activity of CYC202 in vivo
Roscovitine has been examined in a variety of cell lines from a number of different tissue types for anti-tumour activity in mouse xenograft models. Its anti-tumour activity is best described as mild, with reductions in tumour cell growth observed, rather than reductions in initial tumour cell volume. The compound has been delivered both orally and via intra-peritoneal injection, and a number of doses and dosing schedules have been employed. McClue and co-workers used the uterine cell line MES-SA/Dx5 and the colon cell line LOVO, which had been most sensitive to CYC202 in an in vitro, 19 member cell line panel. Mice bearing established tumours formed from LOVO were dosed with 100mg/kg CYC202 three times daily by intra-peritoneal injection for 5 days, and tumour growth was followed for 32 days post initiation of dosing, at which point CYC202 treated animals bore tumours that were approximately 55% of the volume of those of the control animals [
Most other studies using roscovitine as a single agent have seen similar anti-tumour activities in xenografts using cell lines of colon, lung, brain, breast and nasopharangeal origin [
Roscovitine has also been tested for anti-tumour activity in xenograft models in combination with ionising radiation and other small molecule kinase inhibitors, with sometimes impressive results (Table 4). Most striking is the anti-tumour activity seen with the combination of 50mg/kg roscovitine dosed twice per day for 5 days by intra-peritoneal injection, followed by a two day break, and a further 5 days of dosing in combination with a dose of 6Gy ionising radiation twice in the same dosing period. This treatment caused a reduction in tumour growth of around 95% in two Epstein-Barr Virus (EBV) positive cell lines derived from nasopharyngeal carcinomas [
In combination with other small molecule kinase inhibitors roscovitine has produced tumour growth inhibitions of around 75-93%, compared to untreated animals. Used together with erlotinib to treat mice carrying H358 (non-small cell lung cancer) tumours, Fleming and co-workers report that, when CYC202 was dosed at 50mg/kg twice per day for 5 days on / 2 days off for 28 days, and erlotinib was dosed orally, daily at 100mg/kg for all of the 28 days treatment period, tumour growth was reduced by 93% 7 weeks after the treatment was started. In the same study CYC202 alone, when dosed using the same schedule, failed to significantly inhibit tumour growth, and erlotinib inhibited only to 56% of untreated control, indicating some synergistic activity between the molecular targets of CYC202 and erlotinib.
Roscovitine has also been used successfully in combination with the small molecule PI3-Kinase inhibitor PIK-90 to inhibit growth of GBM43, glioma derived tumours, in immunodeficient mice. Dosedby intra-peritoneal injection at 50mg/kg, four times daily for 12 days together with PIK-90 four times per day at 40mg/kg, tumour volume was about 25% of that in untreated animals. Roscovitine when used as a single agent, inhibited growth by about 40% in the same model.
7. Pharmacokinetics and pharmacodynamics of roscovitine
7.1. Pharmacokinetics and metabolism of roscovitine
The pharmacokinetics of roscovitine was studied in mice, rats and humans. Vita et al. [
The distribution of roscovitine was highest in the lungs, followed by liver, fat, and kidney, while exposure to roscovitine in the brain was 30% of that observed in plasma (Figure 6).
Three major metabolites were detected in plasma (Figure 7).
The first metabolite is the major metabolite. It is a carboxylated form of roscovitine, while the second metabolite is the glucuronide form of metabolite one. No metabolites were detected in the brain (Figure 8) [
Pharmacokinetics of roscovitine was investigated in BALB/c and Tg26 mice. These studies showed rapid and biphasic clearance of roscovitine from plasma following i.v., i.p. or oral administration [
The pharmacokinetics of roscovitine in humans were reported in two phase-I trials. Roscovitine was administered orally as a single dose (50 to 800mg) to healthy volunteers and the concentrations of roscovitine and its carboxylated metabolite were followed in plasma and urine. Roscovitine was found to undergo slow absorption from the gastrointestinal tract (GIT); however, the bioavailability of the drug was not affected by food intake. Roscovitine was found to have rapid metabolism and non-saturated high protein binding [
Twenty-one patients with a median age of 62 years (range: 39–73 years) were treated with roscovitine in doses of 100, 200 and 800mg twice daily for 7 days. The elimination half-life was found to be dose dependent and ranged between 2–5hr. Neither objective tumor responses nor inhibitions of retinoblastoma protein phosphorylation (PD endpoint) in mononuclear cells in peripheral blood were observed [
In vitro and in vivo metabolism of roscovitine was reported recently [
7.2. Chronopharmacology of roscovitine
Treatment effect of roscovitine in non-nude BDF1 male mice bearing Glasgow osteosarcoma xenografts was investigated in relation to biological circadian rhythm. Roscovitine was administered orally (300 mg/kg ×1 daily) for 5 days at Zeitgeber time 3 (ZT3, 3 hours after light onset), or ZT11, or ZT19. Roscovitine reduced tumor growth by 35% when administered during the active time of the mice (ZT19), and 55% when administered during their rest span (ZT3 or ZT11) [
7.3. Pharmacokinetics and pharmacodynamics of roscovitine in mouse bone marrow
Myelosuppression is the dose-limiting factor for the majority of conventional chemotherapeutic anticancer agents and one of the most frequent complications. Chemotherapy may induce partial or complete myeloablation of the bone marrow, which in general is dose dependent. Studies on hematotoxicity in vitro and in animal models help to predict possible side effects before the start of clinical trials.
In a recent study, we investigated the myelosuppressive potential of roscovitine on bone marrow cells in vitro and in vivo in Balb/c mice. Bone marrow was incubated in vitro with roscovitine at concentrations of 25–250µM for 4hr and viability was studied using resazurin assay. Bone marrow cell viability was decreased in a concentration-dependent manner. At a concentration of 250µM, cell viability was significantly (p=0.015) reduced to 70%, compared to control mice, while significant effect was observed at lower concentrations. These results were in agreement with the findings that roscovitine induced apoptosis of mature neutrophils [
The myelosuppressive effect of roscovitine on hematopoietic progenitors was studied using clonogenic assay [
We further studied the myelosuppressive effect of roscovitine in vivo in female Balb/c mice. Mice were treated with roscovitine, and bone marrow cells were cultured in the MethoCult media and assessed for clonogenic growth. After the administration of a single dose of roscovitine up to 250mg/kg, no myelosuppressive effect was detected. However, the administration of roscovitine at 175mg/kg twice daily for 4 days resulted in only transient inhibition of the BFU-E colonies, which was observed one day after the last dose of roscovitine. Colony formation capacity of bone marrow was recovered 5 days after the last dose of roscovitine (Figure 9).
The lack of activity of roscovitine on hematopoietic progenitors in vivo was not expected, since an inhibitory effect in vitro was observed, along with the reported activity on different xenografts in vivo [
7.4. Age-dependent kinetics and pharmacodynamics of roscovitine in rat brain
In the field of pediatric medicine, especially when the drug has a narrow therapeutic window, age-dependent pharmacokinetics becomes an important issue. Unfortunately, scaling down the PK data from adults to pediatrics has proved not to be predictive enough for many drugs [
A recent study reported the effects of age on the pharmacokinetics of roscovitine and investigated the effect of roscovitine on two neuronal targets, CDK5 and Erk1/2, in different regions of the brain [
|PK parameters||Plasma||Frontal Cortex||Hippocampus||Cerebellum|
|AUC (h.µg/ml)||3.01 ± 0.21||0.71 ± 0.14||0.58 ± 0.03||0.62 ± 0.06|
|Tα (h)||0.081 ± 0.05||0.045 ± 0.02||0.062 ± 0.012||0.062 ± 0.018|
|Tβ (h)||0.54 ± 0.26||0.35 ± 0.13||0.36 ± 0.15||0.42 ± 0.18|
|Cmax (µg/ml)||17.71 ± 4.42||4.47 ± 0.70||4.64 ± 0.81||3.81 ± 1.22|
|Vss(ml)||650 ± 223||1095 ± 167||2056 ± 219||1909 ± 484|
|CL (ml/h)||1637 ± 118||7262 ± 1612||8737 ± 452||8139 ± 727|
Abbreviations: AUC, area under the concentration-time curve; Tα, absorption half-life; Tβ, elimination half-life; Cmax, maximum reached concentration; Vss, volume of distribution at steady state; CL, clearance.
The exposure to roscovitine expressed as AUC was 22-fold higher in pup plasma and 100-fold higher in pup brain tissue, compared to that seen in adult rats (Figure 10). However, no significant difference was observed between roscovitine AUC in plasma and AUCs in different brain regions in pups. On the contrary, in adult rats the AUC of roscovitine in the brain was about 25% of that found in plasma (Table 6). The maximum observed concentration (cmax) was significantly (p22µg/g) in pup brain tissue, compared to that found in plasma. However, 4-fold higher cmax was found in plasma, compared to that observed in the brain (17.7µg/ml and about 4µg/g, respectively) of adult rats. The high concentrations of roscovitine found in pup brain tissue indicate that roscovitine passes freely through the blood brain barrier (BBB).
This difference in roscovitine kinetics might be due to the immaturity of the CYP450 enzymes responsible for roscovitine metabolism [
Most chemotherapeutic agents do not cross the blood brain barrier (BBB) and do not reach the CNS in high enough concentrations to eliminate tumor cells despite high systemic exposure. Roscovitine was highly presented in the brain of rat pups, and the exposure was observed in all studied regions (e.g. hippocampus, cerebral cortex and cerebellum). The brain exposure to roscovitine was 100% of that found in plasma, which can be compared to about 25% of that found in the brain of adult rats. The high distribution to the brain could be explained by an age-dependent variation in the maturity and function of the BBB. Butt et al. have reported that the BBB of the rat reaches full maturity 3–4 weeks after birth. [
Roscovitine concentrations in plasma and brain of rat pups were higher than the IC50(10–15µM) reported for cancer cell lines for more than 8 hours. However, this level of exposure was achieved only for short time (
Roscovitine has been reported to be a potent inhibitor of CDK5 that has an important function in the developing brain, such as neuronal migration [
The unexpected high concentrations of roscovitine in the brain of rat pups led us to assess the expression of p35 as an indicator of CDK5 activity. It is well known that the inhibition of p35 phosphorylation by CDK5 stabilizes it and delays its proteasomal degradation [
CDK5 was found to inhibit Erk1/2 phosphorylation by a MEK1 and RasGRF2 mediated mechanism. Moreover, it was reported that the inhibition of CDK5 by roscovitine increased the levels of phosphorylated Erk1/2 (active form) in neuronal cells in vitro [
These results show that roscovitine levels in the brain of rat pups were sufficient to inhibit CDK5, resulting in increased phosphorylation of Erk1/2.
7.5. Summary and future outlook
Cyclin-dependent kinases (CDKs) are essential kinases and play a key role in cell cycle progression and RNA transcription. The deregulation of CDKs has been described in several diseases, including cancer. The cyclin dependent kinase inhibitors (CDKIs) are synthetic small heterocyclic compounds that compete with ATP and inhibit the phosphorylation of the target substrates. Based on this knowledge, exposure of tumor cells to CDKIs will result in both cell cycle arrest and apoptosis.
2,6,9-trisubstituted purines are among the first described CDK inhibitors [
The absence of myelosuppression, reported in preclinical and clinical studies of roscovitine [
- Changes of the administration form to increase the half-life of the drug may result in changes in biodistribution and higher exposure to roscovitine, and thus change its toxicity profile.
- Radiation therapy increases the permeability of the blood-bone marrow barrier [
160]. A combination of roscovitine with radiotherapy may increase the myelotoxicity of roscovitine.
- Higher bone marrow exposure to roscovitine and thus a higher toxicity risk may occur in pediatric patients due to age-dependent pharmacokinetics [
Age-dependent pharmacokinetics is not a unique factor for roscovitine. Age-dependent pharmacokinetics has been reported for several drugs, including cisplatin, busulfan, thioguanine, etoposide, lamivudine, and mycophenolate mofetil [
8. Clinical results from investigation of Seliciclib in clinical trials
To date, CYC202 has been evaluated in several phase I and II studies sponsored by Cyclacel Pharmaceuticals Inc. as Seliciclib, and has shown signs of anti-cancer activity in approximately 240 out of 450 patients.
In a phase I trial Seliciclib was used to treat 21 pre-treated patients with refractory solid tumours. Dosing was started at 100mg twice per day for 7 days in a 3 week cycle and dose was escalated 100% after at least 3 patients had been treated at a given dose. Dose-limiting toxicities were seen with the 800mg dose schedule and included fatigue, rash, hyponatraemia, and hypokalaemia, with other reactions seen, including increased creatinine, vomiting, and indications of abnormal liver function. Pharmacokinetic analyses showed that Seliciclib reached a maximum plasma concentration between 1 and 4 hours post dosing and that elimination half-life was between 2 and 5 hours. Stable disease was observed in 8 patients, including an ovarian cancer patient who was stable over 18 weeks of treatment. No tumour responses were observed [
In another phase I trial dosing Seliciclib orally as a single agent, 56 patients were dosed while examining 3 different dosing schedules. Schedule A dosed Seliciclib twice per day for 5 days every 3 weeks, schedule B dosed twice-daily for 10 days followed by a 2 week break, and schedule C dosed twice-daily for 3 days every 2 weeks. Dosing was initiated at 100mg Seliciclib twice per day with dose incremented up to 1600mg Seliciclib twice per day in schedule A, and 1800mg twice per day inschedule C. Schedule B was discontinued, due to the appearance of toxicities at lower doses than the alternative schedules. Pharmacokinetic analysis of plasma samples showed that exposure to Seliciclib was dose-dependent. The dose-limiting toxicities experienced by patients were hypokalaemia, asthaenia, nausea, and vomiting, with other reactions seen, including increases in serum creatinine and indications of liver toxicity. A single patient with a hepatocellular carcinoma had a partial response and other patients had periods of stable disease. The recommended dose for subsequent studies was concluded to be 1250mg twice per day for 5 days in a 21 day cycle, or 1600mg of Seliciclib twice per day for 3 days in a 14 day cycle [
CYC202 has also been tested in a phase I trial in combination with the current first line treatment for NSCLC Gemcitabine 1000mg/m2+ Cisplatin 75mg/m2. A total of 27 patients were enrolled and were dosed in a 21 day cycle with current first line NSCLC therapy (Gemcitabine 1000mg/m2i.v. (days 5 and 12) and Cisplatin 75mg/m2 i.v. (day 5) plus oral twice per day CYC202 at either 400mg, 800mg or 1200mg (days 1–4, 8–11, 15–18, respectively). No dose limiting toxicities (DLT) were seen at the lowest dose of CYC202 from 2 patients enrolled, 3 DLTs were seen in the 800mg CYC202 cohort from 19 patients dosed, and 3 DLTs were seen in the 1200mg CYC202 cohort from 6 patients dosed. The toxicities observed were: elevated GGT, nausea, vomiting, hypokalaemia. Haematological toxicity was low. The maximum tolerated dose (MTD) was determined as 800mg CYC202 in combination with Gemcitabine (1000mg/m2) and Cisplatin (75mg/m2) within the dose schedule described above [
Interim results are available from an initial tolerability section of a phase I clinical trial in which 23 patients with nasopharyngeal cancer and other solid tumours were dosed orally with CYC202. Patients were divided into 2 groups, one was dosed with twice-daily 400mg of CYC202 for 4 days per week for 2 weeks and the other group was dosed with 800mg of CYC202 for 4 days per week for 2 weeks. 10 patients with NPC were enrolled in this section of the trial and 7 had stable disease while on trial. Thirteen patients with other advanced solid tumours were enrolled in the tolerability and 4 of these patients had stable disease while on trial. Seven patients had progressive disease and 5 patients could not be evaluated. Dose-limiting toxicities (grade 3 increase in ALT or AST (n=3) and treatment delay of >2 weeks due to grade 1 creatinine (n=1)) were observed in 4 patients, and so both dosing regimes were considered as tolerable and could be advanced to a randomised phase of the trial, uniquely with NPC patients [
In another trial in nasopharyngeal cancer patients with locally advanced disease 20 patients were treated twice-daily with either 800mg or 400mg of CYC202 on days 1 to 3 and 8 to 12. Three patients were treated at the 800mg twice-daily schedule and 2 of these had dose limiting toxicities (grade 3 liver toxicity and grade 2 vomiting), none of the 13 patients dosed at 400mg twice-daily showed any significant signs of toxicity. Tumour biopsies were taken at day 1 (just prior to dosing) and on day 13 (after dosing had ceased). Fifty percent of the 14 evaluable patients showed signs of a reduction in tumour volume and were associated with increases in levels of apoptosis, necrosis, and reductions in plasma EBV DNA levels following dosing [
Seliciclib was tested in a randomised phase II clinical trial in which 187 Non-Small Cell Lung Cancer (NSCLC) patients, with at least two prior treatments, were dosed with 1200mg of the drug twice per day for 3 days in a 2 week cycle. Although there was no statistically significant difference in the primary endpoint of progression free survival relative to placebo, patients treated with Seliciclib had a longer median survival (388 days compared to 218 days) and the study showed that Seliciclib was safe at the dose level and regime used in the study (Cyclacel website – www.cyclacel.com).
Phase I clinical trial with dose expansion to determine the maximum tolerated dose of liposomal Doxorubicin in combination with Seliciclib for the treatment of patients with metastatic triple negative breast cancer was initiated in 2011 (Cyclacel website – www.cyclacel.com).
Seliciclib has been entered into novel clinical trials in combination with other drugs. Phase 1 escalation trial started in 2013 of a nucleoside analogue Sapacitabine (CYC682), and Seliciclib, as an orally-administered sequential treatment regimen in patients with advanced solid tumours (Cyclacel website – www.cyclacel.com).
Investigators at Vall d’Hebron University Hospital and Cyclacel collaborated to study the combination of Seliciclib and the Epidermal Growth Factor Receptor (EGFR) inhibitor Erlotininb (Tarceva®) in patients with advanced solid tumours. The study aimed to identify the recommended dose of Seliciclib and Erlotinib, and investigated the pharmacokinetics of the combination and some potential pharmacodynamic markers (Cyclacel website – www.cyclacel.com).
In addition to cancer, Seliciclib has been evaluated in clinical trials for other disorders. In 2013 scientists at the University of Newcastle, together with colleagues at the University of Birmingham and Glasgow, initiated a clinical trial aiming to investigate the utility of Seliciclib in the treatment of patients with rheumatoid arthritis, who have not responded to current conventional treatments.
9. Potential therapeutic applications of Roscovitine
Polcystic Kidney Disease
Polycystic kidney disease (PKD) is one of the most common life-threatening genetic diseases, affecting some 12.5 million people across the globe. The condition is normally inherited in a dominant Mendelian manner, but can also be passed on recessively, and causes the formation of multiple, fluid-filled cysts in the kidneys, causing massive enlargement and leading to a reduction kidney function. Three genes have been linked to the condition all of which manifest similar phenotypes. Polycycstic Kidney Disease 1 (PKD1) is the most common genetic mutation and accounts for about 85% of dominantly inherited cases. It is located on chromosome 16 and encodes polycystin-1 (PC-1), a 4303 amino acid transmembrane glycoprotein involved in Wnt and GPCR-coupled signalling and in mediating calcium channel activity [
This increased renal cell proliferation has been targeted using roscovitine, an approach that has met with some success. Mouse models of both indolent (jck) and aggressive(cpk) forms of the disease show inhibition of disease progress and improvements of renal function when the mice are treated with roscovitine [
Roscovitine has also been tested in a number of animal models of the kidney disease glomerulonephritis. Pippin and co-workers showed that the CDK inhibitor caused a reduction in mesangial cell proliferation and improved renal function in rats with experimental mesangialglomerulonephritis (Thy1 model) [
Systemic lupus erythrematosus (SLE or Lupus) is an autoimmune disease that can affect many parts of the body. It is characterised by the activation and proliferation of autoreactive T and B cells and the production of autoantibodies targeting endogenous antigens or nuclear antigens. This results in inflammation and tissue damage, and, in addition, antibody-immune complexes can precipitate and invoke a further immune response [
Viruses, such as papilloma- or adeno-virus that can replicate only in dividing cells, have a requirement for cellular CDK activity to drive the cell into and through the phase of the cell cycle in which they are replication competent. Viruses, such as HIV and HSV, which can replicate in non-dividing cells, have a less obvious requirement for CDK activity, although some studies have revealed that, at least in vitro, replication of many of these viruses can be inhibited by small molecule inhibitors of the CDKs, such as roscovitine.
Human Cytomegalovirus (HCMV) is a double stranded DNA virus member of the β-Herpes family of viruses. Exposure rates across the general population are high but infection in healthy individuals rarely has any serious effects, however, immune-compromised individuals can develop retinitis, pneumonitis or gastroenteritis, increasing morbidity and mortality. These complications are more commonly seen in HIV infected patients [
HIV-1 gene expression is controlled by the viral Tat transactivator as well as host cell transcription factors (reviewed in 198–200). Tat promotes efficient transcriptional elongation from the HIV-LTR, increasing the proportion of full length transcripts transcribed [
Herpes viruses are one of the groups of viruses that carry genes for protein kinases in their genome [
Roscovitine has been tested in a variety of animal models of inflammatory disease, including pleurisy, arthritis, and lung injury [
In a bleomycin-induced lung injury model mice treated with roscovitine saw a reduction in the number of neutrophils present in fluid from bronchial lavage and a reduction in inflammation. Importantly, roscovitine led to an increase in survival of the treated animals compared to untreated [
Pneumonia remains one of the most common infections in the world with around 450 million cases per year, resulting in about 4 million deaths. Typically caused by viral or bacterial infections, pneumonia is an inflammatory condition causing the alveoli to fill with fluid, reducing blood oxygenation levels [
Scleroderma is a chronic autoimmune condition that affects approximately 240 million individuals worldwide and is characterised by the formation of an excess of fibrous connective tissue (fibrosis), either cutaneously or systemically, resulting in changes in the vasculature. In a tissue culture model roscovitine inhibited the expression of collagen, fibronectin and connective tissue growth factor (CTGF) in growth-arrested normal and systemic sclerosis (SSc) fibroblasts. This reduction in expression of sclerotic proteins was the result of a decrease in transcription of the genes rather than any effect on cell cycle, and was not reversed by treatment with the pro-fibrotic cytokines IL-6 or TGF-β [
Ischaemic strokes arise when blood flow to a part of the brain is restricted, leading to tissue damage and loss of function in the area affected. Neuroprotective therapies are being sought to counter ischaemic injury and CDKs (being involved in apoptosis, they are one of the groups of drug targets being examined) [
Glaucoma is a term used to describe a number of eye disorders caused by changes in intraocular pressure. Most commonly associated with increased intraocular pressure it can, if left untreated, lead to irreversible retinal damage and blindness. Roscovitine has been shown to induce a relaxation of the pig trabecular meshwork, a zone around the cornea responsible for draining aqueous humour from the eye, suggesting a possible role in the control of intraocular pressure (IOP). CDKs have been reported to be involved in cellular responses to increased IOP, the cause of retinal cell damage. Both R- and S-roscovitine have been tested in vivo in a model of rabbit glaucoma and both have shown beneficial effects in reducing the IOP. S-roscovitine was thought by the authors to be of greater potential benefit, because in vitro R-roscovitine, in contrast to S-roscovitine, amplified the effects of the Endosplasmic Reticular Stress, inducing compound tunicamycin, and increased oxygen-glucose deprivation induced cell death [
Paroxysmal attacks are brief spasms or seizures often associated with other disorders, including multiple sclerosis, encephalitis, head trauma, stroke, and epilepsy, amongst others [
γ-aminobutyric acid (GABA) is a mammalian neurotransmitter and is a key molecule in controlling neuronal excitability throughout the nervous system. It functions primarily at inhibitory synapses in the brain by binding to two classes of transmembrane receptors in the plasma membrane, leading to hyperpolarisation of the neuron, and causing an inhibitory effect on neurotransmission by reducing the possibility of a successful action potential. Small molecules with the capacity to alter GABA receptor activity have the potential to be of use in the treatment of epilepsy and similar neurological conditions. Roscovitine has been shown to increase GABA mediated current in rat hippocampal neurons, without modifying GABAA receptors. The compound leads to an increase in neuronal GABA concentration and suppresses spiking in hippocampal pyramidal cells, a characteristic that may ultimately be beneficial in the prevention of paroxysmal activity [
Ischaemia-Reperfusion Injury (IR)
After a period of ischaemia (lack of oxygen) caused by lack of blood flow, a tissue can be damaged once oxygenation is reinstated. During or following transplant or bypass surgery, stroke or myocardial infaction ischaemia can pose serious problems when inflammation and oxidative stress can occur [
In another study Topaloglu and colleagues [
As described above roscovitine has been tested pre-clinically in a wide variety of disease models and has shown potential therapeutic benefit in many. Further research is required in orderto ascertain whether the initial signs seen in these model systems are sufficient to warrant the significant financial investment to progress roscovitine or, more likely, a closely related molecule, along the drug development pathway. Initially discovered as a molecule that caused arrest in the cell cycle by blocking CDK2 activity, it is worthy of note how many of the potential therapeutic applications of the compound take advantage of the effects of roscovitine on the transcriptional CDKs.
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