Acta Univ. Agric. Silvic. Mendelianae Brun. 2019, 67(6), 1407-1417 | DOI: 10.11118/actaun201967061407
Towards an Understanding of Specific Response of Metallothionein (Sub)Isoforms to Exposure to Platinum-Based Anticancer Drugs
- Department of Chemistry and Biochemistry, Mendel University in Brno, Zemědělská 1, 613 00 Brno, Czech Republic
Metallothioneins (MTs) are small cysteine-rich proteins involved in a number of pathophysiological processes. Particularly their linkage to cancer processes has been vastly studied and it is well known that MTs can inactivate metal-based cytostatics or scavenge free radicals. These processes result in pronounced chemoresistance and a poor prognosis for patients. Despite this knowledge, involvement of specific (sub)isoforms into this phenomenon requires further elucidation. Our results identified CisPt as the cytostatic which provoked the highest cell death exp followed by CarboPt and OxaliPt. Fluorescence microscopy visualized the oxidative cell stress. After application of 24hIC50 values, the reactive oxygen species (ROS) were visually produced. Our results also showed that MT 1, 2 and 3 expression manifested the highest qPCR activity after CisPt treatment (both healthy and cancer cells). While evaluating the expression of the protein level in the healthy and cancer cells treated by the cytotoxics we concluded that for MT1 and MT3 it was low under all three cytostatic treatments. Cancer cells had higher protein expression levels than healthy cells. In case of MT1/2 for cancer cells was highest under CisPt treatment.
Keywords: Cancer treatment, metal-based cytostatic, metallothioneins, mRNA and protein expression, qPCR activity
Grants and funding:
The research was part of the research project Towards the Understanding a Metal-Tumor-Metabolism, number 115844-2, financed by ERC, project coordinator V. Adam.
Received: September 10, 2019; Accepted: October 31, 2019; Published: December 22, 2019 Show citation
ACS | AIP | APA | ASA | Harvard | Chicago | IEEE | ISO690 | MLA | NLM | Turabian | Vancouver |
References
- BUCHTELOVA, H., DOSTALOVA, S., MICHALEK, P., KRIZKOVA, S., STRMISKA, V., KOPEL, P., HYNEK, D., RICHTERA, L., RIDOSKOVA, A., ADAM, P., KYNICKY, J., BRTNICKY, M., HEGER, Z. and ADAM, V. 2017. Size-related cytotoxicological aspects of polyvinylpyrrolidone-capped platinum nanoparticles. Food and Chemical Toxicology, 105: 337-346. DOI: 10.1016/j.fct.2017.04.043
Go to original source...
- BUCHTELOVA, H., STRMISKA, V., DOSTALOVA, S., MICHALEK, P., KRIZKOVA, S., KOPEL, P., HYNEK, D., RICHTERA, L., ADAM, V. and HEGER, Z. 2017. pH-Responsive Hybrid Organic-Inorganic Ruthenium Nanoparticles for Controlled Release of Doxorubucin. Particle Systems Characterization, 34(11): 1700289. DOI: 10.1002/ppsc.201700289
Go to original source...
- BUCHTELOVA, H., STRMISKA, V., SKUBALOVA, Z., DOSTALOVA, S., MICHALEK, P., KRIZKOVA, S., HYNEK, D., KALINA, L., RICHTERA, L., MOULICK, A., ADAM, V. and HEGER, Z. 2018. Improving cytocompability of CdTe quantum dots by Schiff-base-coordinated lanthanides surface doping. J. Nanobiotechnol, 16: 43. DOI: 10.1186/s12951-018-0369-7
Go to original source...
- COYLE, P., PHILCOX, J., CAREY, L. et al. 2002. Metallothionein: the multipurpose protein. Cellular and Molecular Life Sciences, 59(4): 627-647. DOI: 10.1007/s00018-002-8454-2
Go to original source...
- DICKINSON, B. C. and CHANG, C. J. 2011. Chemistry and biology of reactive oxygen species in signaling or stress responses. Nat. Chem. Biol., 7(8): 504-511. DOI: 10.1038/nchembio.607
Go to original source...
- DOSTALOVA, S., CERNA, T., HYNEK, D., KOUDELKOVA, Z., VACULOVIC, T., KOPEL, P., HRABETA, J., HEGER, Z., VACULOVICOVA, M., ECKSCHLAGER, T., STIBOROVA, M. and ADAM, V. 2016. Site-Directed Conjugation of Antibodies to Apoferritin Nanocarrier for Targeted Drug Delivery to Prostate Cancer Cells. ACS Applied Materials & Interfaces, 8(23): 14430-14441. DOI: 10.1021/acsami.6b04286
Go to original source...
- DOSTALOVA, S., POLANSKA, H., SVOBODOVA, M., BALVAN, J., KRYSTOFOVA, O., HADDAD, Y., KRIZKOVA, S., MASARIK, M., ECKSCHLAGER, T., STIBOROVA, M., HEGER, Z. and ADAM, V. 2018. Prostate-Specific Membrane Antigen-Targeted Site-Directed Antibody-Conjugated Apoferritin Nanovehicle Favorably Influences in Vivo Side Effects of Doxorubicin. Scientific Reports, 8: 8867. DOI: 10.1038/s41598-018-26772-z
Go to original source...
- DOSTALOVA, S., VASICKOVA, K., HYNEK, D., KRIZKOVA, S., RICHTERA, L., VACULOVICOVA, M., ECKSCHLAGER, T., STIBOROVA, M., HEGER, Z. and ADAM, V. 2017. Apoferritin as an ubiquitous nanocarrier with excellent shelf life. International Journal of Nanomedicine, 12: 2265-2278. DOI: 10.2147/IJN.S130267
Go to original source...
- KRĘŻEL, A. and MARET, W. 2007. Different redox states of metallothionein/thionein in biological tissue. Biochem. Journal, 402(Pt 3): 551-558. DOI: 10.1042/BJ20061044
Go to original source...
- KRĘŻEL, A. and MARET, W. 2017. The Functions of Metamorphic Metallothioneins in Zinc and Copper Metabolism. International Journal of Molecular Sciences, 18(6): 1237. DOI: 10.3390/ijms18061237
Go to original source...
- KRIZKOVA, S., RYVOLOVA, M., HRABETA, J., ADAM, V., STIBOROVA, M. T. and KIZEK, R. 2012. Metallothioneins and zinc in cancer diagnosis and therapy. Journal of Pharmaceutical and Biomedical Analysis, 44(4): 287-301.
Go to original source...
- KRIZKOVA, S., KEPINSKA, M., EMRI, G., ECKSCHLAGER, T., STIBOROVA, M., POKORNA, P., HEGER, Z. and ADAM, V. 2018. An insight into the complex roles of metallothioneins in malignant diseases with emphasis on (sub)isoforms/isoforms and epigenetics phenomena. Pharmacology & Therapeutics, 183: 90-117. DOI: 10.1016/j.pharmthera.2017.10.004
Go to original source...
- KRIZKOVA, S., KEPINSKA, M., EMRI, G., MERLOS RODRIGO, A. M., TMEJOVA, K., NERUDOVA, D., KIZEK, R. and ADAM, V. 2016. Microarray analysis of metallothioneins in human diseases - A review. Journal of Pharmaceutical and Biomedical Analysis, 117: 464-473. DOI: 10.1016/j.jpba.2015.09.031
Go to original source...
- LAI, Y.-H., KUO, C., KUO, T. M. and CHEN, H. H. W. 2018. Modulating Chemosensitivity of Tumors to Platinum-Based Antitumor Drugs by Transcriptional Regulation of Copper Homeostasis. International Journal of Molecular Sciences, 19(5): 1486. DOI: 10.3390/ijms19051486
Go to original source...
- LIVAK, K. J. and SCHMITTGEN, T. D. 2001. Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 22DDCT Method. Methods, 25(4), 402-408. DOI: 10.1006/meth.2001.1262
Go to original source...
- MCGEE, H. M., WOODS, G. M., BENNETT, B. and CHUNG, R. S. 2010. The two faces of metallothionein in carcinogenesis: photoprotection against UVR-induced cancer and promotion of tumor survival. Photochemical & Photobiological Sciences, 4: 586-596. DOI: 10.1039/b9pp00155g
Go to original source...
- MERLOS RODRIGO, A. M., DOSTALOVA, S., BUCHTELOVA, H., STRMISKA, V., MICHALEK, P., KRIZKOVA, S., VICHA, A., JENCOVA, P., ECKSCHLAGER, T., STIBOROVA, M., HEGER Z. and ADAM, V. 2017. Comparative gene expression profiling of human metallothionein-3 up-regulation in neuroblastoma cells and its impact on susceptibility to cisplatin. Oncotarget, 9: 4427-4439.
Go to original source...
- NEJDL, L., KUDR, J., MOULICK, A., HEGEROVA, D., RUTTKAY-NEDECKY, B., GUMULEC, J. et al. 2017. Platinium nanoparticles induce damage to DNA abd inhibit DNA replication. PLoS One, 12(7). e0180798. DOI: 10.1371/journal.pone.0180798
Go to original source...
- PENG, D., HU, T.-L., JIANG, A., WASHINGTON, M. K., MOSKALUK, C. A., SCHNEIDER-STOCK, R. et al. 2011. Location-Specific Epigenetic Regulation of the Metallothionein 3 Gene in Esophageal Adenocarcinomas. PLoS One, 6(7): e22009. DOI: 10.1371/journal.pone.0022009
Go to original source...
- SI, M. and LANG, J. 2018. The roles of metallothioneins in carcinogenesis. Journal of Hematology & Oncology, 11: 107. DOI: 10.1186/s13045-018-0645-x
Go to original source...
- SKOWRON, M. A., MELNIKOVA, M., VAN ROERMUND, J. G. H., ROMANO, A., ALBERS, P., THOMALE, J., SCHULZ, W. A., NIEGISCH G. and HOFFMANN, M. J. 2018. Multifaceted Mechanisms of Cisplatin Resistance in Long-Term Treated Urothelial Carcinoma Cell Lines. International Journal of Molecular Sciences, 19(2): 590. DOI: 10.3390/ijms19020590
Go to original source...
- WONG, D. L. and STILLMAN, M. J. 2018. Capturing platinum in cisplatin: kinetic reactions with recombinant human apo-metallothionein 1a. Metallomics, 10: 713-721. DOI: 10.1039/C8MT00029H
Go to original source...
- ZALEWSKA, M., TREFON, J. and MILNEROWICZ, H. 2014. The role of metallothionein interactions with other proteins. Proteomics, 14(11): 1343-1356. DOI: 10.1002/pmic.201300496
Go to original source...
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY NC ND 4.0), which permits non-comercial use, distribution, and reproduction in any medium, provided the original publication is properly cited. No use, distribution or reproduction is permitted which does not comply with these terms.