Editing Spindle checkpoint (section)

=== SAC cancer therapies ===
[[Image:taxol.svg|thumb|right|The chemical structure of paclitaxel or TAXOL, a mitotic inhibitor used in cancer chemotherapy]]
Advances in this field have led to the introduction of development of some therapies targeted at spindle assembly defects. Older treatments such as vinca alkaloids and taxanes target microtubules that accompany mitotic spindle formation via disruption of microtubule dynamics which engage the SAC arresting the cell and eventually leading to its death.<ref name="Zhou2005">{{cite journal | vauthors = Zhou J, Giannakakou P | title = Targeting microtubules for cancer chemotherapy | journal = Current Medicinal Chemistry. Anti-Cancer Agents | volume = 5 | issue = 1 | pages = 65–71 | date = January 2005 | pmid = 15720262 | doi = 10.2174/1568011053352569 }}</ref> [[Taxol]] and [[Docetaxel]], which can induce [[mitotic catastrophe]], both are still used in the treatment of breast cancer, ovarian cancer and other types of epithelial cancer.<ref>{{Cite journal |last1=Denisenko |first1=Tatiana V. |last2=Sorokina |first2=Irina V. |last3=Gogvadze |first3=Vladimir |last4=Zhivotovsky |first4=Boris |date=2016-01-01 |title=Mitotic catastrophe and cancer drug resistance: A link that must to be broken |url=https://www.sciencedirect.com/science/article/pii/S1368764615000564 |journal=Drug Resistance Updates |language=en |volume=24 |pages=1–12 |doi=10.1016/j.drup.2015.11.002 |pmid=26830311 |issn=1368-7646|url-access=subscription }}</ref> However, these treatments are often characterized by high rates of side effects and drug resistance.

Other targets within the network of regulators that influence the SAC are also being pursued; strong interest has shifted towards the [[aurora kinase]] proteins.<ref name="Carvajal 2006">{{cite journal | vauthors = Carvajal RD, Tse A, Schwartz GK | title = Aurora kinases: new targets for cancer therapy | journal = Clinical Cancer Research | volume = 12 | issue = 23 | pages = 6869–75 | date = December 2006 | pmid = 17145803 | doi = 10.1158/1078-0432.CCR-06-1405 | doi-access = free }}</ref> The kinase gene [[Aurora A]] when amplified acts as an oncogene overriding the SAC leading to abnormal initiation of anaphase and subsequent aneuploidy and also resistance to TAXOL .<ref name="Anand2003">{{cite journal | vauthors = Anand S, Penrhyn-Lowe S, Venkitaraman AR | title = AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol | journal = Cancer Cell | volume = 3 | issue = 1 | pages = 51–62 | date = January 2003 | pmid = 12559175 | doi = 10.1016/S1535-6108(02)00235-0 | doi-access = free }}</ref> Excitingly, a small molecule inhibitor of Aurora A has shown antitumor effects in an in vivo model suggesting that this might be a good target for further clinical development.<ref name="Harrington2004">{{cite journal | vauthors = Harrington EA, Bebbington D, Moore J, Rasmussen RK, Ajose-Adeogun AO, Nakayama T, Graham JA, Demur C, Hercend T, Diu-Hercend A, Su M, Golec JM, Miller KM | title = VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo | journal = Nature Medicine | volume = 10 | issue = 3 | pages = 262–7 | date = March 2004 | pmid = 14981513 | doi = 10.1038/nm1003 | s2cid = 12918452 }}</ref> [[Aurora B]] inhibitors, which are also in clinical development lead to abnormal kinetochore to microtubule attachment and abrogate the mitotic checkpoint as well.<ref name=" Carvajal 2006"/> Survivin is also an attractive molecular target for clinical therapeutic development as it acts as a major node in a multitude of pathways, one of which is spindle formation and checkpoint control.<ref name="Altieri2008">{{cite journal | vauthors = Altieri DC | title = Survivin, cancer networks and pathway-directed drug discovery | journal = Nature Reviews. Cancer | volume = 8 | issue = 1 | pages = 61–70 | date = January 2008 | pmid = 18075512 | doi = 10.1038/nrc2293 | s2cid = 25597711 }}</ref> Even further approaches have included a look at inhibition of mitotic motor proteins like KSP. These inhibitors, which have recently entered clinical trials, cause mitotic arrest and by engaging the spindle assembly checkpoint and induce apoptosis.<ref name="Tao2005">{{cite journal | vauthors = Tao W, South VJ, Zhang Y, Davide JP, Farrell L, Kohl NE, Sepp-Lorenzino L, Lobell RB | title = Induction of apoptosis by an inhibitor of the mitotic kinesin KSP requires both activation of the spindle assembly checkpoint and mitotic slippage | journal = Cancer Cell | volume = 8 | issue = 1 | pages = 49–59 | date = July 2005 | pmid = 16023598 | doi = 10.1016/j.ccr.2005.06.003 | doi-access = free }}</ref><ref name= Sinha2019>{{citation | last1 = Sinha | first1 = D. | last2 = Duijf | first2 = P.H.G. | last3 = Khanna | first3 = K.K. | year = 2019 | title = Mitotic slippage: an old tale with a new twist | journal = Cell Cycle | volume = 18 | issue = 1 | pages = 7–15 | doi = 10.1080/15384101.2018.1559557 | pmid = 30601084| pmc = 6343733 }}</ref>