{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T06:25:01Z","timestamp":1778394301281,"version":"3.51.4"},"reference-count":30,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T00:00:00Z","timestamp":1669161600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ERDF PostDoc Latvia","award":["1.1.1.2\/VIAA\/2\/18\/375"],"award-info":[{"award-number":["1.1.1.2\/VIAA\/2\/18\/375"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The restoration of the efficacy of antitumor medicines is a cornerstone in the combat with multidrug resistant (MDR) cancers. The overexpression of the ABCB1 transporter is a major obstacle to conventional doxorubicin therapy. The synergy of ABCB1 suppression and PARP1 activity inhibition that hampers malignant cell DNA repair could be a powerful tool in anticancer therapy. Herein, we report the design and synthesis of three novel olaparib conjugates with selenophenoquinolinones, their ability to reverse doxorubicin resistance in uterus sarcoma cells as well as their mechanism of action. It was found that the most potent chemosensitizer among studied compounds preserves PARP1 inhibitory activity and attenuates cells\u2019 resistance to doxorubicin by inhibiting ABCB1 transporter activity. These results demonstrate that the conjugation of PARP inhibitors with selenophenoquinolinones is a prospective direction for the development of agents for the treatment of MDR cancers.<\/jats:p>","DOI":"10.3390\/pharmaceutics14122571","type":"journal-article","created":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T02:25:36Z","timestamp":1669256736000},"page":"2571","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Olaparib Conjugates with Selenopheno[3,2-c]quinolinone Inhibit PARP1 and Reverse ABCB1-Related Multidrug Resistance"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4549-1993","authenticated-orcid":false,"given":"Marina","family":"Makrecka-Kuka","sequence":"first","affiliation":[{"name":"Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jelena","family":"Vasiljeva","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pavels","family":"Dimitrijevs","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pavel","family":"Arsenyan","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/s41523-022-00411-3","article-title":"PARP Inhibition in Breast Cancer: Progress Made and Future Hopes","volume":"8","author":"Tung","year":"2022","journal-title":"npj Breast Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1093\/annonc\/mdz192","article-title":"A Decade of Clinical Development of PARP Inhibitors in Perspective","volume":"30","author":"Mateo","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.tcb.2019.07.008","article-title":"PARP Inhibitor Resistance: A Tug-of-War in BRCA-Mutated Cells","volume":"29","author":"Noordermeer","year":"2019","journal-title":"Trends Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1007\/s40265-022-01703-5","article-title":"PARP Inhibition, a New Therapeutic Avenue in Patients with Prostate Cancer","volume":"82","author":"Flippot","year":"2022","journal-title":"Drugs"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"221","DOI":"10.2217\/pgs-2019-0113","article-title":"PARP Inhibitors: A Tsunami of Indications in Different Malignancies","volume":"21","author":"Haddad","year":"2020","journal-title":"Pharmacogenomics"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Boussios, S., Karihtala, P., Moschetta, M., Karathanasi, A., Sadauskaite, A., Rassy, E., and Pavlidis, N. (2019). Combined Strategies with Poly (ADP-Ribose) Polymerase (PARP) Inhibitors for the Treatment of Ovarian Cancer: A Literature Review. Diagnostics, 9.","DOI":"10.3390\/diagnostics9030087"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/bjc.2016.203","article-title":"ABCB1 (MDR1) Induction Defines a Common Resistance Mechanism in Paclitaxel- and Olaparib-Resistant Ovarian Cancer Cells","volume":"115","author":"Vaidyanathan","year":"2016","journal-title":"Br. J. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41571-021-00532-x","article-title":"Understanding and Overcoming Resistance to PARP Inhibitors in Cancer Therapy","volume":"18","author":"Dias","year":"2021","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.taap.2016.09.020","article-title":"Characterization of Acquired Paclitaxel Resistance of Breast Cancer Cells and Involvement of ABC Transporters","volume":"310","author":"Daniel","year":"2016","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/s41568-018-0005-8","article-title":"Revisiting the Role of ABC Transporters in Multidrug-Resistant Cancer","volume":"18","author":"Robey","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.tranon.2019.04.007","article-title":"Overexpressed ABCB1 Induces Olaparib-Taxane Cross-Resistance in Advanced Prostate Cancer","volume":"12","author":"Lombard","year":"2019","journal-title":"Transl. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4206","DOI":"10.1158\/1078-0432.CCR-19-4121","article-title":"EVOLVE: A Multicenter Open-Label Single-Arm Clinical and Translational Phase II Trial of Cediranib plus Olaparib for Ovarian Cancer after PARP Inhibition Progression","volume":"26","author":"Lheureux","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"561936","DOI":"10.3389\/fonc.2020.561936","article-title":"Clinical Perspective of FDA Approved Drugs With P-Glycoprotein Inhibition Activities for Potential Cancer Therapeutics","volume":"10","author":"Lai","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1002\/1097-0142(19950201)75:3<815::AID-CNCR2820750311>3.0.CO;2-R","article-title":"A Phase III Randomized Study of Oral Verapamil as a Chemosensitizer to Reverse Drug Resistance in Patients with Refractory Myeloma. A Southwest Oncology Group Study","volume":"75","author":"Dalton","year":"1995","journal-title":"Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4077","DOI":"10.1182\/blood-2010-04-277269","article-title":"Zosuquidar, a Novel Modulator of P-Glycoprotein, Does Not Improve the Outcome of Older Patients with Newly Diagnosed Acute Myeloid Leukemia: A Randomized, Placebo-Controlled Trial of the Eastern Cooperative Oncology Group 3999","volume":"116","author":"Cripe","year":"2010","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Bukowski, K., Kciuk, M., and Kontek, R. (2020). Mechanisms of Multidrug Resistance in Cancer Chemotherapy. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093233"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1002\/cmdc.202000131","article-title":"Antitumour Anthracyclines: Progress and Perspectives","volume":"15","author":"Carvalho","year":"2020","journal-title":"ChemMedChem"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.drup.2016.05.001","article-title":"Overcoming ABC Transporter-Mediated Multidrug Resistance: Molecular Mechanisms and Novel Therapeutic Drug Strategies","volume":"27","author":"Li","year":"2016","journal-title":"Drug Resist. Updat."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13046-018-0772-9","article-title":"The PARP Inhibitor Olaparib Potentiates the Effect of the DNA Damaging Agent Doxorubicin in Osteosarcoma","volume":"37","author":"Park","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100212","DOI":"10.1016\/j.esmoop.2021.100212","article-title":"Olaparib in Combination with Pegylated Liposomal Doxorubicin for Platinum-Resistant Ovarian Cancer Regardless of BRCA Status: A GEICO Phase II Trial (ROLANDO Study)","volume":"6","author":"Guerra","year":"2021","journal-title":"ESMO Open"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Spengler, G., Gajd\u00e1cs, M., Mar\u0107, M.A., Dom\u00ednguez-\u00c1lvarez, E., and Sanmart\u00edn, C. (2019). Organoselenium Compounds as Novel Adjuvants of Chemotherapy Drugs\u2014A Promising Approach to Fight Cancer Drug Resistance. Molecules, 24.","DOI":"10.3390\/molecules24020336"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Macedo, L.B., Nogueira-Librelotto, D.R., Mathes, D., de Vargas, J.M., da Rosa, R.M., Rodrigues, O.E.D., Vinardell, M.P., Mitjans, M., and Rolim, C.M.B. (2022). Overcoming MDR by Associating Doxorubicin and PH-Sensitive PLGA Nanoparticles Containing a Novel Organoselenium Compound\u2014An In Vitro Study. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14010080"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Szemer, N., Dobiasov, S., Salard, N., Habibullah, G., Sevilla-hern, C., Benito-lama, M., Alonso-mart, F., Viktorov, J., and Spengler, G. (2021). Cyano- and Ketone-Containing Selenoesters as Multi-Target Compounds against Resistant Cancers. Cancers, 13.","DOI":"10.3390\/cancers13184563"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Mar\u0107, M.A., Dom\u00ednguez-\u00e1lvarez, E., Latacz, G., Doroz-P\u0142onka, A., Sanmart\u00edn, C., Spengler, G., and Handzlik, J. (2022). Pharmaceutical and Safety Profile Evaluation of Novel Selenocompounds with Noteworthy Anticancer Activity. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14020367"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1007\/s10593-014-1419-1","article-title":"The Synthesis and Cytotoxic Properties of Selenopheno[3,2-c]- and Selenopheno-[2,3-c]Quinolones","volume":"49","author":"Arsenyan","year":"2014","journal-title":"Chem. Heterocycl. Compd."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"11851","DOI":"10.1039\/C9NJ01682A","article-title":"Selenopheno[2,3-:f] Coumarins: Novel Scaffolds with Antimetastatic Activity against Melanoma and Breast Cancer","volume":"43","author":"Arsenyan","year":"2019","journal-title":"New J. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7424","DOI":"10.1039\/D2NJ00340F","article-title":"Development of Prospective Non-Toxic Inhibitors of ABCB1 Activity and Expression in a Series of Selenophenoquinolinones","volume":"46","author":"Vasiljeva","year":"2022","journal-title":"New J. Chem"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5367","DOI":"10.1021\/acs.jmedchem.8b00576","article-title":"Examination of Diazaspiro Cores as Piperazine Bioisosteres in the Olaparib Framework Shows Reduced DNA Damage and Cytotoxicity","volume":"61","author":"Reilly","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4100","DOI":"10.1016\/j.bmc.2017.05.058","article-title":"Olaparib Hydroxamic Acid Derivatives as Dual PARP and HDAC Inhibitors for Cancer Therapy","volume":"25","author":"Yuan","year":"2017","journal-title":"Bioorganic Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"12584","DOI":"10.1021\/acsomega.9b01106","article-title":"Small-Molecule Poly(ADP-Ribose) Polymerase and PD-L1 Inhibitor Conjugates as Dual-Action Anticancer Agents","volume":"4","author":"Ofori","year":"2019","journal-title":"ACS Omega"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/12\/2571\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:24:52Z","timestamp":1760145892000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/12\/2571"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,23]]},"references-count":30,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["pharmaceutics14122571"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14122571","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,23]]}}}