Monastrol: Unveiling the Mechanisms, Efficacy, and Therapeutic Potential – A Comprehensive Review
DOI:
https://doi.org/10.47611/jsrhs.v12i4.5300Keywords:
anti-cancer drugs, monastrol, kinesin-5 inhibitor, eg5 motor protein, cancer treatementAbstract
Cancer, one of the leading causes of death in the world, is characterized by the uncontrollable growth of defective cells in the body, creating lumps of cells known as tumors. Cells undergo uncontrollable growth when checkpoints in the cell cycle are overridden, allowing malignant cells to continue to grow without being killed. In recent studies, scientists have found that the compound monastrol is effective in arresting cells in the cell cycle and experiencing apoptosis or programmed cell death. Monastrol is of particular interest because it affects a kinesin called Eg5, a popular target for cancer therapies since it plays a crucial role in the formation of bipolar spindles during mitosis, which is responsible for dividing the cells. A kinesin is a class of protein that is involved in various cellular functions. Most importantly, their involvement in mitosis is what makes them important in cancer. By inhibiting the basal and microtubule stimulate ATPase activity of the Eg5 motor domain, the monastrol alters the ability of the Eg5 to generate force, thereby preventing it from maintaining the bipolar spindles and leading to cell death.
Downloads
References or Bibliography
Asraf, H., Avunie-Masala, R., Hershfinkel, M., & Gheber, L. (2015, June 2). Mitotic slippage and expression of survivin are linked to differential sensitivity of human cancer cell-lines to the kinesin-5 inhibitor monastrol. PLOS ONE. https://doi.org/10.1371/journal.pone.0129255
Beer, T. M., Goldman, B., Synold, T. W., Ryan, C. W., & et al. (2009, March 20). Southwest Oncology Group Phase II Study of Ispinesib in Androgen-Independent Prostate Cancer Previously Treated with Taxanes. Clinical Genitourinary Cancer. https://www.clinical-genitourinary-cancer.com/article/S1558-7673(11)70063-5/pdf
Chen, Y., Chow, J. P. H., & Poon, R. Y. C. (2012, May 1). Inhibition of EG5 acts synergistically with checkpoint abrogation in promoting mitotic catastrophe. American Association for Cancer Research. https://doi.org/10.1158/1541-7786.MCR-11-0491
Flaumenhaft, R. (2007, April 11). 3.07 Chemical Biology. Comprehensive Medicinal Chemistry II.
https://www.sciencedirect.com/science/article/abs/pii/B008045044X000808?via%3Dihub
Garcia-Saez, I., & Skoufias, D. A. (2020, December 11). EG5 targeting agents: From new anti-mitotic based inhibitor discovery to cancer therapy and resistance. Biochemical Pharmacology. https://www.sciencedirect.com/science/article/abs/pii/S0006295220306006
Gascoigne, K. E., & Taylor, S. S. (2008, July 24). Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. ScienceDirect. https://www.sciencedirect.com/science/article/pii/S1535610808002286
Guido, B. C., Ramos, L. M., Nolasco, D. O., Nobrega, C. C., Andrade, B. Y., Pic-Taylor, A., Neto, B. A., & Corrêa, J. R. (2015, April 14). Impact of kinesin EG5 inhibition by 3,4-dihydropyrimidin-2(1h)-one derivatives on various breast cancer cell features - BMC cancer. BioMed Central. https://doi.org/10.1186/s12885-015-1274-1
Hanif, H., Nazir, S., Mazhar, K., Waseem, M., Bano, S., & Rashid, U. (2017, September 11). Targeted delivery of mesoporous silica nanoparticles loaded monastrol into cancer cells: An in vitro study - applied nanoscience. SpringerLink. https://link.springer.com/article/10.1007/s13204-017-0593-8
Haque, S. A., Hasaka, T. P., Brooks, A. D., Lobanov, P. V., & Baas, P. W. (2004, February 12). Monastrol, a prototype anti-cancer drug that inhibits a mitotic kinesin, induces rapid bursts of axonal outgrowth from cultured postmitotic neurons. Cell Motility. https://onlinelibrary.wiley.com/doi/10.1002/cm.10176
Hassan, S. F., Rashid, U., Ansari, F. L., & Ul-Haq, Z. (2013, September). Bioisosteric approach in designing new monastrol derivatives: An investigation on their ADMET prediction using in silico derived parameters. ScienceDirect. https://www.sciencedirect.com/science/article/abs/pii/S1093326313001575?via%3Dihub
Jaiswal, P. K., Goel, A., & Mittal, R. D. (2015, April). Survivin: A molecular biomarker in cancer. The Indian journal of medical research. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4510718/#:~:text=Survivin%20can%20be%20co%2Dimmunoprecipitated,intrinsic%20pathway%20of%20apoptosis14
Jin, Q., Huang, F., Wang, X., Zhu, H., Xian, Y., Li, J., Zhang, S., & Ni, Q. (2017, July 10). High EG5 expression predicts poor prognosis in breast cancer. Oncotarget. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617498/
Kaan HY., Ulaganathan V., Rath O., Prokopcová H., Dallinger D., Kappe CO., Kozielski F., (2010, August 12). Structural basis for inhibition of EG5 by dihydropyrimidines: Stereoselectivity of antimitotic inhibitors enastron, dimethylenastron and fluorastrol. Journal of medicinal chemistry. https://pubmed.ncbi.nlm.nih.gov/20597485/
Karesenti, E., & Vernos, I. (2001, October 19). The mitotic spindle: A self-made machine. Science (New York, N.Y.). https://pubmed.ncbi.nlm.nih.gov/11641489/#:~:text=The%20mitotic%20spindle%20is%20a,the%20daughter%20cells%20during%20mitosis.
Kohle, F., Ackfeld, R., Hommen, F., Klein, I., Svaina, M. K. R., Schneider, C., Fink, G. R., Barham, M., Vilchez, D., & Lehmann, H. C. (2023, June 9). Kinesin-5 inhibition improves neural regeneration in experimental autoimmune neuritis - journal of Neuroinflammation. BioMed Central. https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-023-02822-w
Leal-Esteban, L. C., & Fajas, L. (2020, February 5). Cell cycle regulators in cancer cell metabolism. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. https://www.sciencedirect.com/science/article/pii/S0925443920300600
Lee, H.-S., Lee, N. C. O., Kouprina, N., Kim, J.-H., Kagansky, A., Bates, S., Trepel, J. B., Pommier, Y., Sackett, D., & Larionov, V. (2016, February 14). Effects of anticancer drugs on chromosome instability and new clinical implications for tumor-suppressing therapies. American Association for Cancer Research. https://doi.org/10.1158/0008-5472.CAN-15-1617
Maliga, Z., Kapoor, T. M., & Mitchison, T. J. (2002, September 19). Evidence that monastrol is an allosteric inhibitor of the mitotic kinesin EG5. ScienceDirect. https://www.sciencedirect.com/science/article/pii/S1074552102002120
Maliga, Z., & Mitchison, T. J. (2006, February 27). Small-molecule and mutational analysis of allosteric EG5 inhibition by monastrol - BMC chemical biology. SpringerLink. https://link.springer.com/article/10.1186/1472-6769-6-2
Marques, L. A., Semprebon, S. C., Niwa, A. M., D’Epiro, G. F. R., Sartori, D., Fátima, Â. de F. de, Ribeiro, L. R., & Mantovani, M. S. (2016, September 3). Antiproliferative activity of monastrol in human adenocarcinoma (MCF-7) and non-tumor (HB4A) breast cells. Naunyn-Schmiedeberg’s archives of pharmacology. https://pubmed.ncbi.nlm.nih.gov/27592117/
Nakai, R., Iida, S., Takahashi, T., Tsujita, T., Okamoto, S., Takada, C., Akasaka, K., Ichikawa, S., Ishida, H., Kusaka, H., Akinaga, S., Murakata, C., Honda, S., Nitta, M., Saya, H., & Yamashita, Y. (2009, April 30). K858, a novel inhibitor of mitotic kinesin EG5 and antitumor agent, induces cell death in cancer cells. American Association for Cancer Research. https://aacrjournals.org/cancerres/article/69/9/3901/553112/K858-a-Novel-Inhibitor-of-Mitotic-Kinesin-Eg5-and
Nakazawa, J., Yajima, J., Usui, T., Ueki, M., Takatsuki, A., Imoto, M., Toyoshima, Y. Y., & Osada, H. (2003, January 6). A novel action of terpendole E on the motor activity of ... - Cell Press. Cell Chemical Biology. https://www.cell.com/cell-chemical-biology/fulltext/S1074-5521(03)00020-6
Noatynska, A., Gotta, M., & Meraldi, P. (2012, December 24). Mitotic spindle (dis)orientation and disease: Cause or consequence?. The Journal of cell biology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3529530/
Ogunwa, T. H., Laudadio, E., Galeazzi, R., & Miyanishi, T. (2019, April 16). Insights into the molecular mechanisms of EG5 inhibition by (+)-morelloflavone. MDPI. https://www.mdpi.com/1424-8247/12/2/58
Skoufias, D. A., DeBonis, S., Saoudi, Y., Lebeau, L., Crevel, I., Cross, R., & et al. (2005, October 31). S-Trityl-L-cysteine Is a Reversible, Tight Binding Inhibitor of the Human Kinesin Eg5 That Specifically Blocks Mitotic Progression*. Journal of Biological Chemistry. https://www.jbc.org/article/S0021-9258(20)55627-5/fulltext
Teranishi, T., Murokawa, T., Enomoto, M., & Kuwahara, S. (2015, January 2). Synthesis of (±)-terpendole e. OUP Academic. https://academic.oup.com/bbb/article/79/1/11/5920258?login=false
Torres, B., Uchôa, F., Crestani, A., Eifler-lima, V., Costa, T., (2014, February 26). Bioanalytical method for the quantification of the monastrol derivative anticancer candidate lasom 65 in pre-clinical pharmacokinetic investigations. Química Nova. https://www.readcube.com/articles/10.5935/0100-4042.20140082?tab=summary
Wu, W., Jingbo, S., Xu, W., Liu, J., Huang, Y., Sheng, Q., & Lv, Z. (2018, July). S-trityl-L-cysteine, a novel EG5 inhibitor, is a potent chemotherapeutic strategy in neuroblastoma. Oncology letters. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019882/
Zhang B;Senator D;Wilson CJ;Ng SC; (2005, October 15). Development of a high-throughput robotic fluorescence-based assay for HSEG5 inhibitor screening. Analytical biochemistry. https://pubmed.ncbi.nlm.nih.gov/16125662/
Zhang, W., Zhai, L., Lu, W., Boohaker, R. J., Padmalayam, I., & Li, Y. (2016, August). Discovery of novel allosteric EG5 inhibitors through structure-based Virtual Screening. Chemical biology & drug design. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936947/
Published
How to Cite
Issue
Section
Copyright (c) 2023 Anoushka Kolluru, Siddharth Sivalanka, Shreyan Phadke; Gayathri Renganathan
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Copyright holder(s) granted JSR a perpetual, non-exclusive license to distriute & display this article.
