CDK INHIBITOR AGAINST CELL CYCLE DYSREGULATION

The cell Cycle

One of the most important discoveries of the 20^th century was the revelations of how cells were governed and regulated in their growth patterns. This process was described in a cell cycle pathway along with regulatory mechanism and quality control functions. Each individual cell is capable of replicating itself but is not always in the processes of doing so. This resting state is referred to as the G₀ phase. An extracellular signal is sent to the cell via the cell surface receptors that trigger the cell to enter the G1 phase. This is the first step in cell replication and the cell gathers nutrients as well as protein building blocks from the systemic circulation, this allows the cell to increases in size. Control proteins regulate the amount of material gathered by the cell and the size to which in grows. If certain specifications are met the cell moves from the G1 phase to the S phase of the process. In the S phase the cell nucleus receives a signal that trigger the duplication of the DNA strands. Upon completion of this process the cell enters the G2 phase which allows for control proteins to verify that everything has been correctly copied, the cell is of sufficient size and sufficient nutrients are available to feed the two cells during the process. Once the check has been completed signals are sent that trigger the M phase to start. The M phase is when the cell under goes mitosis to divided into two equal cells. After mitosis the two cells are left in the G0 phase again, until they have recovered from the division process and are ready to go again.[1-8]

Cyclin and Cyclin Dependent Kinases

Controlling all aspects of the cell cycle process are the cyclin and cyclin dependant kinases. These proteins were discovered by the legendary Nobel prize winners Nurse, Hunt and Hartwell and they determined that the complex of the two proteins is the activie form while when separated they are inactive. There seems to be several isoforms of CDK’s in the human system (at last count 11 had been characterized) and several isoforms of the cyclin molecule (9 in human). The formation of a dimer between the two proteins is the governing pricnciple behind their action. Each combination governs a different aspect of the cell cycle process. In the G1 phase CDK2 – cyclin E, CDK3- cyclin c, CDK4-cyclin D and CDK6 – cyclin D provide the quality assurance and regulatory process. In G1/S transitional state the CDK2-cyclin A is the key regulator, while CDK5-p35, CDK7 – Cyclin H and CDK8-cyclin C regulates the DNA transcription. CDK11-cyclin L is thought to be involved in the M phase of the cycle but this is current unknown for sure. Typically the initial work in this field concentrated on the CDK1 and CDK2 proteins for inhibition but more recently a greater affect can be achieved if the CDK3 and CDK4 are inhibited [8-19].

Mechanism of cyclin inhibition:

CDK antagonists occur naturally as a control mechanism for the cell cycle process, this is a redundant mechanism in case the regular function fails form any reason. By studying the action of these CDK kinase inhibitors it was possible to design a small molecule CDK selective inhibitor which could insert itself into the Tyrosine kinase domain and prevent phosphorylation. This in turn would prevent signaling to the tumor, thereby, rendering the cell useless [20]. Such cells tend to be cleaned and delivery of the signal halted at this point. CDK specific inhibitors have been developed such as flavopiridol and UCN-01 and are being clinically developed further. Research can buy CDK inhibitors from most biochemical suppliers at reasonable prices.

Clinical Status: CDK inhibitors

CDK inhibitor in clinical trials have been initiated in several diseases such as CML, ALL, leukemia Breast and Arthritis both as the single therapeutic agent and in combination of traditional chemotherapeutic molecules. Some success has been seen in anti-tumor activity but resistance is still common [21].

References

    1.    van den Heuvel S. Cell-cycle regulation. WormBook 2005;1-16.

    2.    Swanton C. Cell-cycle targeted therapies. Lancet Oncol 2004; 5(1):27-36.

    3.    Berthet C, Kaldis P. Cell-specific responses to loss of cyclin-dependent kinases. Oncogene 2007; 26(31):4469-4477.

    4.    Pucci B, Giordano A. Cell cycle and cancer. Clin Ter 1999; 150(2):135-141.

    5.    Dash BC, El-Deiry WS. Cell cycle checkpoint control mechanisms that can be disrupted in cancer. Methods Mol Biol 2004; 280:99-161.

    6.    Fotedar R, Fotedar A. Cell cycle control of DNA replication. Prog Cell Cycle Res 1995; 1:73-89.

    7.    Golias CH, Charalabopoulos A et al. Cell proliferation and cell cycle control: a mini review. Int J Clin Pract 2004; 58(12):1134-1141.

    8.    Uhlmann F, Bouchoux C et al. A quantitative model for cyclin-dependent kinase control of the cell cycle: revisited. Philos Trans R Soc Lond B Biol Sci 2011; 366(1584):3572-3583.

    9.    Nebreda AR. CDK activation by non-cyclin proteins. Curr Opin Cell Biol 2006; 18(2):192-198.

  10.    Blank HM, Totten JM et al. CDK control of membrane-bound organelle homeostasis. Cell Cycle 2006; 5(5):486-488.

  11.    Gitig DM, Koff A. Cdk pathway: cyclin-dependent kinases and cyclin-dependent kinase inhibitors. Methods Mol Biol 2000; 142:109-123.

  12.    Golsteyn RM. Cdk1 and Cdk2 complexes (cyclin dependent kinases) in apoptosis: a role beyond the cell cycle. Cancer Lett 2005; 217(2):129-138.

  13.    Zhang J, Herrup K. Cdk5 and the non-catalytic arrest of the neuronal cell cycle. Cell Cycle 2008; 7(22):3487-3490.

  14.    Xie Z, Tsai LH. Cdk5 phosphorylation of FAK regulates centrosome-associated miocrotubules and neuronal migration. Cell Cycle 2004; 3(2):108-110.

  15.    Lalioti V, Pulido D et al. Cdk5, the multifunctional surveyor. Cell Cycle 2010; 9(2):284-311.

  16.    Lopes JP, Agostinho P. Cdk5: multitasking between physiological and pathological conditions. Prog Neurobiol 2011; 94(1):49-63.

  17.    Canduri F, Perez PC et al. CDK9 a potential target for drug development. Med Chem 2008; 4(3):210-218.

  18.    Uchida T, Kinoshita T et al. CDKN2 (MTS1/p16INK4A) gene alterations in hematological malignancies. Leuk Lymphoma 1997; 24(5-6):449-461.

  19.    Lange C, Calegari F. Cdks and cyclins link G1 length and differentiation of embryonic, neural and hematopoietic stem cells. Cell Cycle 2010; 9(10):1893-1900.

  20.    Cicenas J, Valius M. The CDK inhibitors in cancer research and therapy. J Cancer Res Clin Oncol 2011; 137(10):1409-1418.

  21.    Wesierska-Gadek J, Kramer MP. The impact of multi-targeted cyclin-dependent kinase inhibition in breast cancer cells: clinical implications. Expert Opin Investig Drugs 2011; 20(12):1611-1628.