|Kuznetsova, GM |
1ESC "Institute of Biology and Medicine", Taras Shevchenko National University of Kyiv
|Dopov. Nac. akad. nauk Ukr. 2019, 10:89-96|
Low-molecular-weight inhibitors of protein kinases are promising as antitumor agents due to their high efficiency and relatively low toxicity. However, the number of approved chemicals is not enough for needs of modern medicine. Maleimide derivative chloro-1-(4-chlorobenzyl)-4-((3-(trifluoromethyl)phenyl)amino)-1Hpyrrole- 2,5-dione (MI-1) is an inhibitor of a number of receptor and non-receptor tyrosine protein kinases. We have demonstrated that MI-1 causes apoptosis of transformed MG-63 (osteosarcoma) and SK-OV-3 (ovarian adenocarcinoma) cells, but virtually doesn’t affect the viability of normal AOB (alveolar osteoblasts) ones. Moreover, this compound inhibits the development of colorectal tumors in vivo similarly to common cytostatic 5-fluorouracil did. MI-1 mitigated manifestations and outcomes of the oxidative stress in organism and contributed to the normalization of redox balance impaired through carcinogenesis as well. That might be one of the mechanisms of realization of MI-1 antitumor activity. The compound also diminishes cancer-induced monocytosis and thrombocytosis and restores the values of liver function biochemical parameters with no impact on those of healthy animals. Hence, MI-1 has a perspective as a basis for the antitumor drugs development.
|Keywords: maleimide, protein kinases|
1. Gerber, D. E. (2008). Targeted therapies: a new generation of cancer treatments. Am. Fam. Physician, 77, No. 3, pp. 311-319.
2. Elez, E., Macarulla, T. & Tabernero, J. (2008). Handling side-effects of targeted therapies: safety of targeted therapies in solid tumours. Ann. Oncol., 19, Suppl.7, pp. vii146-vii152. doi: https://doi.org/10.1093/annonc/mdn476
3. Dubinina, G. G., Golovach, S. M., Kozlovsky, V. O., Tolmachov, A. O. & Volovenko, Yu. M. (2007). Antiproliferative action of the new derivatives of l-(4-R-benzyl)-3-R1-4-(R2-phenylamino)-1H-pyrrol-2,5-dione. J. Org. Pharm. Chem., 5, Iss. 1, pp. 39-49 (in Ukrainian).
4. Mosmann, T. (1983). Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Meth., 65, pp. 55-63. doi: https://doi.org/10.1016/0022-1759(83)90303-4
5. Perse, M. & Cerar, A. (2005). The dimethylhydrazine induced colorectal tumours in rat — experimental colorectal carcinogenesis. Radiol. Oncol., 39, No. 1, pp. 61-70.
6. Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., Dancey, J., Arbuck, S., Gwyther, S., Mooney, M., Rubinstein, L., Shankar, L., Dodd, L., Kaplan, R., Lacombe, D. & Verweij, J. (2009). New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur. J. Cancer, 45, No. 2, pp. 228-247. doi: https://doi.org/10.1016/j.ejca.2008.10.026
7. Pozharisski, K. M. (1990). Tumours of the intestines. In Pathology of tumours in laboratory animals, Vol. 1. (pp. 159-197). Lion: IARC.
8. Alemu, Y., Atomsa, A. & Sahlemariam, Z. (2006). Hematology. Jimma: EPHTI.
9. Filinska, O., Yablonska, S., Kharchuk, I., Mandryk, S., Kotlyar, I., Ostrovska, G. & Rybalcheko, V. (2010). Effect of maleimide derivative on oxidative stress and glutathione antioxidant system in 1,2-dimethylhydrazine induced colon carcinogenesis in rat. Ann. Univ. Mariae Curie-Sklodowska. DDD. Pharm., 23, No. 3, pp. 191-195.
10. Graham, J. (2002). Preparation of crude subcellular fractions by differential centrifugation. ScientificWorldJournal, 2, pp. 1638-1642. doi: https://doi.org/10.1100/tsw.2002.851
11. Burlaka, A. P. & Sidorik, Ye. P. (2006). Radical forms of oxygen and nitric oxide in the tumor process. Kyiv: Naukova Dumka (in Ukrainian).
12. Tabernero, J. (2007). The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents. Mol. Cancer Res., 5, No. 3, pp. 203-220. doi: https://doi.org/10.1158/1541-7786.MCR-06-0404
13. Lopez, J., Hesling, C., Prudent, J., Popgeorgiev, N., Gadet, R., Mikaelian, I., Rimokh, R., Gillet, G. & Gonzalo, P. (2012). Src tyrosine kinase inhibits apoptosis through the Erk1/2- dependent degradation of the death accelerator Bik. Cell Death Differ., 19, No. 9, pp. 1459-1469. doi: https://doi.org/10.1038/cdd.2012.21
14. Perse, M. & Cerar, A. (2011). Morphological and molecular alterations in 1,2 dimethylhydrazine and azoxymethane induced colon carcinogenesis in rats. J. Biomed. Biotechnol., 2011, Art. ID 473964, 14 p. doi: https://doi.org/10.1155/2011/473964
15. Wang, Y., Zhang, Y., Kathawala, R. J., & Chen, Z. (2014). Repositioning of tyrosine kinase inhibitors as antagonists of ATP-binding cassette transporters in anticancer drug resistance. Cancers (Basel), 6, No. 4, pp. 1925-1952. doi: https://doi.org/10.3390/cancers6041925