The folding and export of proteins and hydrolysis of unfolded proteins are disbalanced in the endoplasmic reticulum (ER) of cancer cells, leading to so-called ER stress. Agents further augmenting this effect are used as anticancer drugs including clinically approved proteasome inhibitors bortezomib and carfilzomib. However, these drugs can affect normal cells, which also rely strongly on ER functions, leading, for example, to accumulation of reactive oxygen species (ROS). To address this problem, we have developed ER-targeted prodrugs activated only in cancer cells in the presence of elevated ROS amounts. These compounds are conjugates of cholic acid with N-alkylaminoferrocene-based prodrugs. We confirmed their accumulation in the ER of cancer cells, their anticancer efficacy, and cancer cell specificity. These prodrugs induce ER stress, attenuate mitochondrial membrane potential, and generate mitochondrial ROS leading to cell death via necrosis. We also demonstrated that the new prodrugs are activated in vivo in Nemeth-Kellner lymphoma (NK/Ly) murine model.

Danylo Halytsky Lviv National Medical University Pekarska str 69 79010 Lviv Ukraine

Department of Medicine 5 Heidelberg University Hospital Im Neuenheimer Feld 410 69120 Heidelberg Germany

Else Kröner Fresenius Stiftung Professorship Department of Otorhinolaryngology Head and Neck Surgery Section of Experimental Oncology and Nanomedicine Universitätsklinikum Erlangen Glückstraße 10a 91054 Erlangen Germany

Friedrich Alexander University Erlangen Nürnberg Department of Chemistry and Pharmacy Organic Chemistry Chair 2 Nikolaus Fiebiger Str 10 91058 Erlangen Germany

Hematology Department 1st Affiliated Hospital of Soochow University Suzhou China

Institute of Experimental Botany AS CR Prague Czech Republic

Takeda Pharma Vertrieb GmbH and Co KG Jägerstr 27 1017 Berlin Germany

Zobrazit více v PubMed

ECIS—European Cancer Information System: from https://ecis.jrc.ec.europa.eu, accessed on 25/08/2020© European Union, 2020.

Schirrmacher V., Int. J. Oncol. 2019, 54, 407–419. PubMed PMC

Vu T., Claret F. X., Front. Oncol. 2012, 2, 62. PubMed PMC

Koppenol W. H., Bounds P. L., Dang C. V., Nat. Rev. Cancer 2011, 11, 325–337; PubMed

Warburg O., Science 1956, 123, 309–314. PubMed

Antunes F., Cadenas R., FEBS Lett. 2000, 475, 121–126. PubMed

Szatrowski T. P., Nathan C. F., Cancer Res. 1991, 51, 794–798; PubMed

Halliwell B., Biochem. J. 2007, 401, 1–11. PubMed

King A. P., Wilson J. J., Chem. Soc. Rev. 2020, 49, 8113–8136. PubMed

Siwecka N., Rozpędek W., Pytel D., Wawrzynkiewicz A., Dziki A., Dziki Ł., Diehl J. A., Majsterek I., Int. J. Mol. Sci. 2019, 20, 4354. PubMed PMC

Daum S., Chekhun V., Todor I., Lukianova N., Shvets Y., Sellner L., Putzker K., Lewis J., Zenz T., Graaf I., Groothuis G., Casini A., Zozulia O., Hampel F., Mokhir A., J. Med. Chem. 2015, 58, 2015–2024. PubMed

Peter S., Aderibigbe B. A., Molecules 2019, 24, 3604; PubMed PMC

Patra M., Gasser G., Nat. Rev. Chem. 2017, 1, 0066.

Hwang C., Sinskey A. J., Lodish H. F., Science 1992, 257, 1496–1502. PubMed

Daum S., Babiy S., Konovalova H., Hofer W., Shtemenko A., Shtemenko N., Janko C., Alexiou C., Mokhir A., J. Inorg. Biochem. 2018, 178, 9–17. PubMed

Daum S., Reshetnikov V., Sisa M., Dumych T., Lootsik M. D., Bilyy R., Bila E., Janko C., Alexiou A., Herrmann M., Sellner L., Mokhir A., Angew. Chem. Int. Ed. 2017, 56, 15545–15549; PubMed

Angew. Chem. 2017, 129, 15751–15755.

Reshetnikov V., Daum S., Janko C., Karawacka W., Tietze R., Alexiou C., Paryzhak S., Dumych T., Bilyy R., Tripal P., Schmid B., Palmisano R., Mokhir A., Angew. Chem. Int. Ed. 2018, 57, 11943–11946; PubMed

Angew. Chem. 2018, 130, 12119–12122;

Reshetnikov V., Özkan H. G., Daum S., Janko C., Alexiou C., Sauer C., Heinrich M. R., Mokhir A., Molecules 2020, 25, 2545. PubMed PMC

Fus F., Yang Y., Lee H. Z. S., Top S., Carriere M., Bouron A., Pacureanu A., Cesar da Silva J., Salmain M., Vessières A., Cloetens P., Jaouen G., Bohic S., Angew. Chem. Int. Ed. 2019, 58, 3461–3465; PubMed

Angew. Chem. 2019, 131, 3499–3503.

Chen D., Cui Q. C., Yang H., Dau Q. P., Cancer Res. 2006, 66, 10425–10433; PubMed

Butcher K., Kannappan V., Kilari R. S., Morris M. R., McConville C., Armesilla A. L., Wang W., BMC Cancer 2018, 18, 753. PubMed PMC

Yang Q., Yao Y., Li K., Jiao L., Zhu J., Ni C., Li M., Dou Q. P., Yang H., Curr. Pharm. Des. 2019, 25, 3248–3256. PubMed

Ekinci E., Rohondia S., Khan R., Dou Q. P., Recent Pat. Anti-Cancer Drug Discovery 2019, 14, 113–132. PubMed

Gao P., Pan W., Li N., Tang B., Chem. Sci. 2019, 10, 6035–6071. PubMed PMC

Daum S., Toms J., Reshetnikov V., Özkan H. G., Hampel F., Maschauer S., Hakimioun A., Beierlein F., Sellner L., Schmitt M., Prante O., Mokhir A., Bioconjugate Chem. 2019, 30, 1077–1086. PubMed

Sun S. Y., Cancer Biol. Ther. 2010, 9, 109–110. PubMed PMC

Oyadomari S., Mori M., Cell Death Differ. 2004, 11, 381–389. PubMed