The Kinetochore as Target for Cancer Drug Development
Due to diverse and complex genetic abnormalities in different cancers, there are no silver bullets in cancer treatment. According to the NCI (www.cancer.gov/), chemotherapy, together with radiotherapy and surgery, are the three major modalities of cancer treatment.
As uncontrolled proliferation is the most distinctive characteristic of cancer cells, many anticancer drugs directly inhibit growth. These include drugs that target DNA or nucleotide metabolism and cell division. In a cell division cycle, mitosis is the phase during which duplicated sister chromatids physically separate from each other to produce two genetically identical daughter cells. Chemical compounds that interfere with this process should in principle be efficient inhibitors of cell proliferation. However, currently available anticancer drugs of this class are limited to two types of plant alkaloids: taxanes (docetaxel, paclitaxel) and vinca alkaloids (vinblastine, vincristine, vindesine, vinorelbine)....
KeywordsAurora Kinase Mitotic Arrest Kinetochore Protein Spindle Checkpoint Mitotic Checkpoint
- Burkard, M.E., et al., Chemical genetics reveals the requirement for Polo-like kinase 1 activity in positioning RhoA and triggering cytokinesis in human cells. Proc Natl Acad Sci USA, 2007. 104(11): 4383–8.Google Scholar
- Chan, G.K., Yen, T. J., The mitotic checkpoint: a signaling pathway that allows a single unattached kinetochore to inhibit mitotic exit, in Progress in Cell Cycle Research, L. Meijer, Jezequel, A., and Roberge, M., Editor. 2003, Editions “Life in Progress”: Roscoff, France. 431–439.Google Scholar
- Kops, G.J., D.R. Foltz, and D.W. Cleveland, Lethality to human cancer cells through massive chromosome loss by inhibition of the mitotic checkpoint. Proc Natl Acad Sci U S A, 2004. 101(23): 8699–704.Google Scholar
- Michel, L., et al., Complete loss of the tumor suppressor MAD2 causes premature cyclin B degradation and mitotic failure in human somatic cells. Proc Natl Acad Sci U S A, 2004. 101(13): 4459–64.Google Scholar
- Munster, P.N., et al., Modulation of Hsp90 function by ansamycins sensitizes breast cancer cells to chemotherapy-induced apoptosis in an RB- and schedule-dependent manner. See: E. A. Sausville, Combining cytotoxics and 17-allylamino, 17-demethoxygeldanamycin: sequence and tumor biology matters. Clin Cancer Res, 2001. 7(8): 2228–36.PubMedGoogle Scholar