Cancer CDKs

Collins I, Garrett MD. 2005. Targeting the cell division cycle in cancer CDK and cell cycle checkpoint kinase inhibitors. Curr Opin Pharmacol 5 366-373. 

The rationale behind CDK inhibition during anticancer treatment is to stop hyperactive cell cycles and to inhibit the activity of cyclins that are frequently overexpressed in human cancer. 

Growth inhibition by TGF- 3, associated with inhibition of c-myc, cdks, reduction in cyclin D1 levels, and inhibition of cdk-4-associated Rb kinase activity, as well as induction of cdk inhibitors pi5 and p27, has been noted in intestinal epithelial cells. Loss of responsiveness to growth inhibition from TGF- 3 occurs in many cell types including breast, colorectal carcinoma, and pancreatic carcinoma cells. Mutational inactivation of T 3RH represents one mechanism of this process, which in many cases, leads to the development of gastrointestinal cancer. Thirteen percent of colorectal carcinomas are thought to be associated with a replication error (RER) or microsatellite instability phenotype. Subsequent inactivation of T 3RII and... 

Choi YH, Kang HS, Yoo MA. (2003) Suppression of human prostate cancer cell growth by betalapachone via down-regulation of pRB phosphorylation and induction of Cdk inhibitor p21(WAFl/CIPl). J Biochem Mol Biol 36 223-229. 

Roche has reported a 2,4-diaminopyrimidine 42 (Ro-4584820) to be a Phase I clinical candidate [48,103]. Compound 42 is a pan-CDK inhibitor (CDKl K = 0.001 ptM CDK2 K[ = 0.003 p.M CDK4 K[ = 0.001 p.M), consequently it induces both G1 and G2 cell cycle arrest in tumor cell lines. It is a potent inhibitor of tumor cell proliferation in both the HCT-116 colon cancer (IC50 = 0.080 tiM) and the H460A (IC50 = 0.055 p.M) lung cancer cell lines. 

Akiyama T, Yoshida T, Tsujita T, Shimizu M, Mizukami T, Okabe M, Akinaga S (1997) G1 phase accumulation induced by UCN-01 is associated with dephosphorylation of Rb and CDK2 proteins as well as induction of CDK inhibitor p21/CiplAVAFl/Sdil in p53-mutated human epidermoid carcinoma A431 cells. Cancer Res 57 1495-1501... 

Wang Q, Worland PJ, Clark JL, Carlson BA, Sausville EA (1995) Apoptosis in 7-hydroxystaurosporine-treated T lymphoblasts correlates with activation of cy-clin-dependent kinases 1 and 2. Cell Growth Differ 6 927-936 Wang J, Walsh K (1996) Resistance to apoptosis conferred by CDK inhibiors during myocyte differentiation. Science 273 359-361 Wang Q, Fan S, Eastman A, Worland PJ, Sausville EA, O Connor PM (1996) UCN-01 a potent abrogator of G1 checkpoint function in cancer cells with disrupted P53. J Natl Cancer Inst 88 956-965... 

Resveratrol exerts antitumor effects partly by arresting the growth of various cancer cells in culture [Kundu and Surh, 2004]. The inhibition of ornithine decarboxylase (ODC), a biochemical hallmark of tumor promotion, has been shown to account for the antiproliferative and antitumor effects of resveratrol [Schneider et al., 2000 Ulrich et al., 2007]. Aberrant changes in cell-cycle machinery are considered as the biochemical basis of abnormal proliferation of transformed cells. Major cell-cycle regulatory proteins include various cyclins, cyclin-dependent kinases (Cdk), Cdk inhibitors, and check point kinases (Chkl... 

Keppler et al. have synthesised Ru11 and Os11 arene complexes with paullones as ligands to confer solubility on these otherwise insoluble cyclin-dependent kinase (CDK) inhibitors [152]. No dramatic differences between the ruthenium and the osmium complexes were found in the IC50 values against A549, CHI and SW480 cancer cell lines. 

Figure 24.23. Cyclin expression is regulated according to the cell cycle. (A) The regulatory subunits of the cyclin-dependent kinases (CDKs) are referred to as cyclins because these proteins are synthesized and degraded during the cell cycle. (Adapted from Weinberg RA Biology of Cancer 2007.) (B) Specific cyclins bind to and activate specific CDKs, and this propels the cell through specific stages of the cell cycle.

CDKs are considered a potential target for anti-cancer medication the aim is to selectively interrupt the cell-cycle regulation in cancer cells by interfering with CDK action, causing the ceU to die. Currently some CDK inhibitors are undergoing clinical trials. 

Pol II is not the only target of Cdks. Cell-cycle kinases also control transcription by phosphorylation of TBPs and TBP-associated factors, TAFs although, at least in yeast, TAFs seem not to be obligatory for transcription. Tumour suppressors, such as p53, which are controlled by phosphorylation by Cdks, link transcription and the cell cyde. i Breakdown of transcriptional control by tumour suppressors is related to cancer. This is discussed in Part 4. 

More CKIs have been identified. Each of these proteins is a potential regulator of the cell cycle. Since malfunctions in the cydin-Cdk control of the cell cycle lead to uncontrolled proliferation and may cause cancer, interest in the development of effective CKIs is great. 

P61-A6 inhibited proliferation of a variety of human cancer cell lines including pancreatic cancer cell lines PANC-1, MiaPaCa2, CFpac-1, HPAC as well as breast cancer cell lines MDA-MB231, BT474, and MCF-7 [14]. The proliferation inhibition was associated with the increase of G1 phase cells. We also observed that P61-A6 increases the level of a Cdk inhibitor p21 ° . This increase was due to increased expression of as examined by... 

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