Olaparib is a potent poly (ADP-ribose) polymerase inhibitor currently used in targeted therapy for treating cancer cells with BRCA mutations. Here we investigate the possible interference of olaparib with daunorubicin (Daun) metabolism, mediated by carbonyl-reducing enzymes (CREs), which play a significant role in the resistance of cancer cells to anthracyclines. Incubation experiments with the most active recombinant CREs showed that olaparib is a potent inhibitor of the aldo-keto reductase 1C3 (AKR1C3) enzyme. Subsequent inhibitory assays in the AKR1C3-overexpressing cellular model transfected human colorectal carcinoma HCT116 cells, demonstrating that olaparib significantly inhibits AKR1C3 at the intracellular level. Consequently, molecular docking studies have supported these findings and identified the possible molecular background of the interaction. Drug combination experiments in HCT116, human liver carcinoma HepG2, and leukemic KG1α cell lines showed that this observed interaction can be exploited for the synergistic enhancement of Daun's antiproliferative effect. Finally, we showed that olaparib had no significant effect on the mRNA expression of AKR1C3 in HepG2 and KG1α cells. In conclusion, our data demonstrate that olaparib interferes with anthracycline metabolism, and suggest that this phenomenon might be utilized for combating anthracycline resistance.

Department of Biochemical Sciences Faculty of Pharmacy in Hradec Kralove Charles University Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

Department of Pharmacology and Toxicology Faculty of Pharmacy in Hradec Kralove Charles University Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

Zobrazit více v PubMed

Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2018;68:394–424. doi: 10.3322/caac.21492. PubMed DOI

Piska K., Koczurkiewicz P., Bucki A., Wójcik-Pszczoła K., Kołaczkowski M., Pękala E. Metabolic Carbonyl Reduction of Anthracyclines—Role in Cardiotoxicity and Cancer Resistance. Reducing Enzymes as Putative Targets for Novel Cardioprotective and Chemosensitizing Agents. Investig. New Drugs. 2017;35:375–385. doi: 10.1007/s10637-017-0443-2. PubMed DOI PMC

Cortés-Funes H., Coronado C. Role of Anthracyclines in the Era of Targeted Therapy. Cardiovasc. Toxicol. 2007;7:56–60. doi: 10.1007/s12012-007-0015-3. PubMed DOI

Burgess D.J., Doles J., Zender L., Xue W., Ma B., McCombie W.R., Hannon G.J., Lowe S.W., Hemann M.T. Topoisomerase Levels Determine Chemotherapy Response In Vitro and In Vivo. Proc. Natl. Acad. Sci. USA. 2008;105:9053–9058. doi: 10.1073/pnas.0803513105. PubMed DOI PMC

Capelôa T., Benyahia Z., Zampieri L.X., Blackman M.C., Sonveaux P. Metabolic and Non-Metabolic Pathways That Control Cancer Resistance to Anthracyclines. Semin. Cell Dev. Biol. 2020;98:181–191. doi: 10.1016/j.semcdb.2019.05.006. PubMed DOI

Schaupp C.M., White C.C., Merrill G.F., Kavanagh T.J. Metabolism of Doxorubicin to the Cardiotoxic Metabolite Doxorubicinol Is Increased in a Mouse Model of Chronic Glutathione Deficiency: A Potential Role for Carbonyl Reductase 3. Chem. Biol. Interact. 2014;234:154–161. doi: 10.1016/j.cbi.2014.11.010. PubMed DOI PMC

Malátková P., Wsól V. Carbonyl Reduction Pathways in Drug Metabolism. Drug Metab. Rev. 2013;46:96–123. doi: 10.3109/03602532.2013.853078. PubMed DOI

Edwardson D.W., Narendrula R., Chewchuk S., Mispel-Beyer K., Mapletoft J.P., Parissenti A.M. Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines. Curr. Drug Metab. 2015;16:412–426. doi: 10.2174/1389200216888150915112039. PubMed DOI PMC

Bains O.S., Grigliatti T.A., Reid R.E., Riggs K.W. Naturally Occurring Variants of Human Aldo-Keto Reductases with Reduced In Vitro Metabolism of Daunorubicin and Doxorubicin. J. Pharmacol. Exp. Ther. 2010;335:533–545. doi: 10.1124/jpet.110.173179. PubMed DOI

Hofman J., Malcekova B., Skarka A., Novotna E., Wsol V. Anthracycline Resistance Mediated by Reductive Metabolism in Cancer Cells: The Role of Aldo-Keto Reductase 1C3. Toxicol. Appl. Pharmacol. 2014;278:238–248. doi: 10.1016/j.taap.2014.04.027. PubMed DOI

Desmond J.C., Mountford J.C., Drayson M.T., Walker E.A., Hewison M., Ride J.P., Luong Q.T., Hayden R.E., Vanin E.F., Bunce C.M. The Aldo-Keto Reductase AKR1C3 is a Novel Suppressor of Cell Differentiation That Provides a Plausible Target for the Non-Cyclooxygenase-Dependent Antineoplastic Actions of Nonsteroidal Anti-Inflammatory Drugs. Cancer Res. 2003;63:505–512. PubMed

Birtwistle J., Hayden R.E., Khanim F.L., Green R.M., Pearce C., Davies N.J., Wake N., Schrewe H., Ride J.P., Chipman J.K., et al. The Aldo-Keto Reductase AKR1C3 Contributes to 7,12-Dimethylbenz(a)Anthracene-3,4-Dihydrodiol Mediated Oxidative DNA Damage in Myeloid Cells: Implications for Leukemogenesis. Mutat. Res. Mol. Mech. Mutagen. 2009;662:67–74. doi: 10.1016/j.mrfmmm.2008.12.010. PubMed DOI

Penning T.M., Byrns M.C. Steroid Hormone Transforming Aldo-Keto Reductases and Cancer. Ann. N.Y. Acad. Sci. 2009;1155:33–42. doi: 10.1111/j.1749-6632.2009.03700.x. PubMed DOI PMC

Sun S.-Q., Gu X., Gao X.-S., Li Y., Yu H., Xiong W., Yu H., Wang W., Li Y., Teng Y., et al. Overexpression of AKR1C3 Significantly Enhances Human Prostate Cancer Cells Resistance to Radiation. Oncotarget. 2016;7:48050–48058. doi: 10.18632/oncotarget.10347. PubMed DOI PMC

Matsunaga T., Wada Y., Endo S., Soda M., El-Kabbani O., Hara A. Aldo–Keto Reductase 1B10 and Its Role in Proliferation Capacity of Drug-Resistant Cancers. Front. Pharmacol. 2012;3:5. doi: 10.3389/fphar.2012.00005. PubMed DOI PMC

Bortolozzi R., Bresolin S., Rampazzo E., Paganin M., Maule F., Mariotto E., Boso D., Minuzzo S., Agnusdei V., Viola G., et al. AKR1C Enzymes Sustain Therapy Resistance in Paediatric T-ALL. Br. J. Cancer. 2018;118:985–994. doi: 10.1038/s41416-018-0014-0. PubMed DOI PMC

Varatharajan S., Abraham A., Zhang W., Shaji R.V., Ahmed R., Abraham A., George B., Srivastava A., Chandy M., Mathews V., et al. Carbonyl Reductase 1 Expression Influences Daunorubicin Metabolism in Acute Myeloid Leukemia. Eur. J. Clin. Pharmacol. 2012;68:1577–1586. doi: 10.1007/s00228-012-1291-9. PubMed DOI

Marin J.J., Briz O., Rodríguez-Macias G., Díez-Martín J.L., Macias R. Role of Drug Transport and Metabolism in the Chemoresistance of Acute Myeloid Leukemia. Blood Rev. 2016;30:55–64. doi: 10.1016/j.blre.2015.08.001. PubMed DOI

Verma K., Zang T., Penning T.M., Trippier P.C. Potent and Highly Selective Aldo–Keto Reductase 1C3 (AKR1C3) Inhibitors Act as Chemotherapeutic Potentiators in Acute Myeloid Leukemia and T-Cell Acute Lymphoblastic Leukemia. J. Med. Chem. 2019;62:3590–3616. doi: 10.1021/acs.jmedchem.9b00090. PubMed DOI PMC

Penning T.M. The Aldo-Keto Reductases (AKRs): Overview. Chem. Interact. 2015;234:236–246. doi: 10.1016/j.cbi.2014.09.024. PubMed DOI PMC

Drew Y. The Development of PARP Inhibitors in Ovarian Cancer: From Bench to Bedside. Br. J. Cancer. 2015;113:S3–S9. doi: 10.1038/bjc.2015.394. PubMed DOI PMC

Rottenberg S., Jaspers J.E., Kersbergen A., Van Der Burg E., Nygren A.O.H., Zander S.A.L., Derksen P.W.B., De Bruin M., Zevenhoven J., Lau A., et al. High Sensitivity of BRCA1-Deficient Mammary Tumors to the PARP Inhibitor AZD2281 Alone and in Combination with Platinum Drugs. Proc. Natl. Acad. Sci. USA. 2008;105:17079–17084. doi: 10.1073/pnas.0806092105. PubMed DOI PMC

Bixel K., Hays J.L. Olaparib in the Management of Ovarian Cancer. Pharm. Pers. Med. 2015;8:127–135. doi: 10.2147/PGPM.S62809. PubMed DOI PMC

Fong P.C., Boss D.S., Yap T.A., Tutt A.N.J., Wu P., Mergui-Roelvink M., Mortimer P., Swaisland H., Lau A., O’Connor M.J., et al. Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers. N. Engl. J. Med. 2009;361:123–134. doi: 10.1056/NEJMoa0900212. PubMed DOI

Gallotta V., Conte C., D’Indinosante M., Capoluongo E., Minucci A., De Rose A.M., Ardito F., Giuliante F., Di Giorgio A., Zannoni G.F., et al. Prognostic Factors Value of Germline and Somatic Brca in Patients Undergoing Surgery for Recurrent Ovarian Cancer with Liver Metastases. Eur. J. Surg. Oncol. 2019;45:2096–2102. doi: 10.1016/j.ejso.2019.06.023. PubMed DOI

Faraoni I., Consalvo M.I., Aloisio F., Fabiani E., Giansanti M., Di Cristino F., Falconi G., Tentori L., Veroli A., Curzi P., et al. Cytotoxicity and Differentiating Effect of the Poly(ADP-Ribose) Polymerase Inhibitor Olaparib in Myelodysplastic Syndromes. Cancers. 2019;11:1373. doi: 10.3390/cancers11091373. PubMed DOI PMC

Maifrede S., Nieborowska-Skorska M., Sullivan-Reed K., Dasgupta Y., Podszywalow-Bartnicka P., Le B.V., Solecka M., Lian Z., Belyaeva E.A., Nersesyan A., et al. Tyrosine Kinase Inhibitor–Induced Defects in DNA Repair Sensitize FLT3(ITD)-Positive Leukemia Cells to PARP1 Inhibitors. Blood. 2018;132:67–77. doi: 10.1182/blood-2018-02-834895. PubMed DOI PMC

Faraoni I., Aloisio F., De Gabrieli A., Consalvo M.I., Lavorgna S., Voso M.T., Albano F., Graziani G. The Poly(ADP-Ribose) Polymerase Inhibitor Olaparib Induces up-Regulation of Death Receptors in Primary Acute Myeloid Leukemia Blasts by NF-κB Activation. Cancer Lett. 2018;423:127–138. doi: 10.1016/j.canlet.2018.03.008. PubMed DOI

Meng X.W., Koh B.D., Zhang J.-S., Flatten K.S., Schneider P.A., Billadeau D.D., Hess A.D., Smith B.D., Karp J.E., Kaufmann S.H. Poly(ADP-Ribose) Polymerase Inhibitors Sensitize Cancer Cells to Death Receptor-mediated Apoptosis by Enhancing Death Receptor Expression. J. Biol. Chem. 2014;289:20543–20558. doi: 10.1074/jbc.M114.549220. PubMed DOI PMC

Park H.J., Bae J.S., Kim K.M., Moon Y.J., Park S.-H., Ha S.H., Hussein U.K., Zhang Z., Park H.S., Park B.-H., et al. The PARP Inhibitor Olaparib Potentiates the Effect of the DNA Damaging Agent Doxorubicin in Osteosarcoma. J. Exp. Clin. Cancer Res. 2018;37:107. doi: 10.1186/s13046-018-0772-9. PubMed DOI PMC

Eetezadi S., Evans J.C., Shen Y.T., De Souza R., Piquette-Miller M., Allen C. Ratio-Dependent Synergism of a Doxorubicin and Olaparib Combination in 2D and Spheroid Models of Ovarian Cancer. Mol. Pharm. 2018;15:472–485. doi: 10.1021/acs.molpharmaceut.7b00843. PubMed DOI

Del Conte G., Sessa C., Von Moos R., Viganò L., Digena T., Locatelli A., Gallerani E., Fasolo A., Tessari A., Cathomas R., et al. Phase I Study of Olaparib in Combination With Liposomal Doxorubicin in Patients With Advanced Solid Tumours. Br. J. Cancer. 2014;111:651–659. doi: 10.1038/bjc.2014.345. PubMed DOI PMC

Kassner N., Huse K., Martin H.-J., Gödtel-Armbrust U., Metzger A., Meineke I., Brockmöller J., Klein K., Zanger U.M., Maser E., et al. Carbonyl Reductase 1 Is a Predominant Doxorubicin Reductase in the Human Liver. Drug Metab. Dispos. 2008;36:2113–2120. doi: 10.1124/dmd.108.022251. PubMed DOI

Byrns M.C., Jin Y., Penning T.M. Inhibitors of Type 5 17β-Hydroxysteroid Dehydrogenase (AKR1C3): Overview and Structural Insights. J. Steroid Biochem. Mol. Biol. 2011;125:95–104. doi: 10.1016/j.jsbmb.2010.11.004. PubMed DOI PMC

Lovering A.L., Ride J.P., Bunce C.M., Desmond J.C., Cummings S.M., White S.A. Crystal Structures of Prostaglandin D211-Ketoreductase (AKR1C3) in Complex with the Nonsteroidal Anti-Inflammatory Drugs Flufenamic Acid and Indomethacin. Cancer Res. 2004;64:1802–1810. doi: 10.1158/0008-5472.CAN-03-2847. PubMed DOI

Krogh-Madsen M., Bender B.C., Jensen M.K., Nielsen O.J., Friberg L.E., Honoré P.H. Population Pharmacokinetics of Cytarabine, Etoposide, and Daunorubicin in the Treatment for Acute Myeloid Leukemia. Cancer Chemother. Pharmacol. 2012;69:1155–1163. doi: 10.1007/s00280-011-1800-z. PubMed DOI

Food and Drug Administration Approval Date(s) and History, Letters, Labels, Reviews for NDA 208558.Efficacy-New Indication. [(accessed on 15 January 2020)]; Available online: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=208558.

Murai J., Huang S.-Y.N., Das B.B., Renaud A., Zhang Y., Doroshow J.H., Ji J., Takeda S., Pommier Y. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res. 2012;72:5588–5599. doi: 10.1158/0008-5472.CAN-12-2753. PubMed DOI PMC

Gunderson C.C., Moore K. Olaparib: An Oral PARP-1 and PARP-2 Inhibitor with Promising Activity in Ovarian Cancer. Future Oncol. 2015;11:747–757. doi: 10.2217/fon.14.313. PubMed DOI

Hintzpeter J., Seliger J.M., Hofman J., Martin H.-J., Wsol V., Maser E. Inhibition of Human Anthracycline Reductases by Emodin—A Possible Remedy for Anthracycline Resistance. Toxicol. Appl. Pharmacol. 2016;293:21–29. doi: 10.1016/j.taap.2016.01.003. PubMed DOI

Mateo J., Lord C., Serra V., Tutt A., Balmaña J., Castroviejo-Bermejo M., Cruz C., Oaknin A., Kaye S., De Bono J. A Decade of Clinical Development of PARP Inhibitors in Perspective. Ann. Oncol. 2019;30:1437–1447. doi: 10.1093/annonc/mdz192. PubMed DOI PMC

Aschenbrenner D.S. Olaparib Approved for Metastatic Pancreatic Cancer. AJN Am. J. Nurs. 2020;120:22–23. doi: 10.1097/01.NAJ.0000660008.32418.6c. PubMed DOI

European Medicines Agency Guideline on the Investigation of Drug Interactions. CPMP/EWP/560/95/Rev. 1 Corr. 2**. [(accessed on 20 May 2020)];2012 Available online: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-drug-interactions-revision-1_en.p.

Adeniji A.O., Chen M., Penning T.M. AKR1C3 as a Target in Castrate Resistant Prostate Cancer. J. Steroid Biochem. Mol. Biol. 2013;137:136–149. doi: 10.1016/j.jsbmb.2013.05.012. PubMed DOI PMC

Penning T.M. Aldo-Keto Reductase (AKR) 1C3 Inhibitors: A Patent Review. Expert Opin. Ther. Pat. 2017;27:1329–1340. doi: 10.1080/13543776.2017.1379503. PubMed DOI PMC

Schweizer M.T., Yu E.Y. AR-Signaling in Human Malignancies: Prostate Cancer and Beyond. Cancers. 2017;9:7. doi: 10.3390/cancers9010007. PubMed DOI PMC

Novotna R., Wsol V., Xiong G., Maser E. Inactivation of the Anticancer Drugs Doxorubicin and Oracin by Aldo–Keto Reductase (AKR) 1C3. Toxicol. Lett. 2008;181:1–6. doi: 10.1016/j.toxlet.2008.06.858. PubMed DOI

Škarydová L., Nobilis M., Wsól V. Role of Carbonyl Reducing Enzymes in the Phase I Biotransformation of the Non-Steroidal Anti-Inflammatory Drug Nabumetone In Vitro. Xenobiotica. 2012;43:346–354. doi: 10.3109/00498254.2012.720048. PubMed DOI

Trott O., Olson A.J. AutoDock Vina: Improving the Speed and Accuracy of Docking With a New Scoring Function, Efficient Optimization, and Multithreading. J. Comput. Chem. 2009;31:455–461. doi: 10.1002/jcc.21334. PubMed DOI PMC

Morris G.M., Huey R., Lindstrom W., Sanner M.F., Belew R.K., Goodsell D.S., Olson A.J. AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility. J. Comput. Chem. 2009;30:2785–2791. doi: 10.1002/jcc.21256. PubMed DOI PMC

Irwin J.J., Sterling T., Mysinger M.M., Bolstad E.S., Coleman R.G. ZINC: A Free Tool to Discover Chemistry for Biology. J. Chem. Inf. Model. 2012;52:1757–1768. doi: 10.1021/ci3001277. PubMed DOI PMC

Dassault Systèmes BIOVIA . Discovery Studio Visualizer, v20.1.0.19295. Dassault Systèmes; San Diego, CA, USA: 2019.

Chou T.-C. Drug Combination Studies and Their Synergy Quantification Using the Chou-Talalay Method. Cancer Res. 2010;70:440–446. doi: 10.1158/0008-5472.CAN-09-1947. PubMed DOI

Novotná E., Büküm N., Hofman J., Flaxová M., Kouklíková E., Louvarová D., Wsol V. Aldo-Keto Reductase 1C3 (AKR1C3): A Missing Piece of the Puzzle in the Dinaciclib Interaction Profile. Arch. Toxicol. 2018;92:2845–2857. doi: 10.1007/s00204-018-2258-0. PubMed DOI

Bruton's Tyrosine Kinase Inhibitor Zanubrutinib Effectively Modulates Cancer Resistance by Inhibiting Anthracycline Metabolism and Efflux