The novel anthracenedione, pixantrone, lacks redox activity and inhibits doxorubicinol formation in human myocardium: Insight to explain the cardiac safety of pixantrone in doxorubicin-treated patients

Journal of Pharmacology and Experimental Therapeutics

Volumn 344, Issue 2, 2013, Pages 467-478

  Salvatorelli, Emanuela ^a   Menna, Pierantonio ^a   Paz, Odalys Gonzalez ^a   Chello, Massimo ^a   Covino, Elvio ^a   Singer, Jack W ^b   Minotti, Giorgio ^a  

^a UNIVERSITY CAMPUS BIO MEDICO   (Italy)

^b Cell Therapeutics Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACONITATE HYDRATASE; DOXORUBICIN; DOXORUBICINOL; DRUG METABOLITE; HYDROGEN PEROXIDE; MITOXANTRONE; OXIDE; PIXANTRONE; TROPONIN I;

ADULT; ARTICLE; CARDIOTOXICITY; CONCENTRATION RESPONSE; DRUG CLEARANCE; DRUG INHIBITION; DRUG METABOLISM; DRUG OXIDATION; DRUG SAFETY; DRUG STRUCTURE; DRUG UPTAKE; FEMALE; HEART PROTECTION; HUMAN; HUMAN TISSUE; MAJOR CLINICAL STUDY; MALE; OXIDATION REDUCTION REACTION; PRIORITY JOURNAL; PROTEIN SECRETION;

AGED; ANTIBIOTICS, ANTINEOPLASTIC; BIOTRANSFORMATION; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; DOXORUBICIN; DRUG SYNERGISM; FEMALE; HEART; HUMANS; HYDROGEN PEROXIDE; ISOQUINOLINES; MALE; MITOXANTRONE; MOLECULAR STRUCTURE; MYOCARDIUM; OXIDATION-REDUCTION; SUPEROXIDES;

EID: 84872719512     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.112.200568     Document Type: Article

References (59)

1. Barry E, Alvarez JA, Scully RE, Miller TL, and Lipshultz SE (2007) Anthracyclineinduced cardiotoxicity: course, pathophysiology, prevention and management. Expert Opin Pharmacother 8:1039-10578.
2. Blanco JG, Sun CL, Landier W, Chen L, Esparza-Duran D, Leisenring W, Mays A, Friedman DL, Ginsberg JP, and Hudson MM, et al. (2012) Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes - a report from the Children's Oncology Group. J Clin Oncol 30: 1415-1421.
3. Blanz J, Mewes K, Ehninger G, Proksch B, Waidelich D, Greger B, and Zeller KP (1991) Evidence for oxidative activation of mitoxantrone in human, pig, and rat. Drug Metab Dispos 19:871-880.
4. Borchmann P, Schnell R, Knippertz R, Staak JO, Camboni GM, Bernareggi A, Hübel K, Staib P, Schulz A, and Diehl V, et al. (2001) Phase I study of BBR 2778, a new aza-anthracenedione, in advanced or refractory non-Hodgkin's lymphoma. Ann Oncol 12:661-667. (Pubitemid 32519919)
5. Braunwald E (2008) Biomarkers in heart failure. N Engl J Med 358:2148-2159.
6. Budde T, Haney J, Bien S, Schwebe M, Riad A, Tschöpe C, Staudt A, Jedlitschky G, Felix SB, and Kroemer HK, et al. (2011) Acute exposure to doxorubicin results in increased cardiac P-glycoprotein expression. J Pharm Sci 100:3951-39578.
7. Canal P, Attal M, Chatelut E, Guichard S, Huguet F, Muller C, Schlaifer D, Laurent G, Houin G, and Bugat R (1993) Plasma and cellular pharmacokinetics of mitoxantrone in high-dose chemotherapeutic regimen for refractory lymphomas. Cancer Res 53: 4850-4854. (Pubitemid 23326177)
8. Cardinale D and Sandri MT (2010) Role of biomarkers in chemotherapy-induced cardiotoxicity. Prog Cardiovasc Dis 53:121-129.
9. Cavalletti E, Crippa L, Mainardi P, Oggioni N, Cavagnoli R, Bellini O, and Sala F (2007) Pixantrone (BBR 2778) has reduced cardiotoxic potential in mice pretreated with doxorubicin: comparative studies against doxorubicin and mitoxantrone. Invest New Drugs 25:187-195. (Pubitemid 46774706)
10. Cell Therapeutics Inc (2010) Pixantrone (BBR 2778) versus other chemotherapeutic agents for third-line single agent treatment of patients with relapsed aggressive non-Hodgkin's lymphoma: A randomized, controlled, phase III comparative trial. CTI Study Report PIX301 PK.
11. Seattle, WA. Cell Therapeutics Inc (2012) Pixantrone dimaleate (BBR 2778). Investigator Brochure Version 12.
12. Seattle, WA. Chance B, Sies H, and Boveris A (1979) Hydroperoxide metabolism in mammalian organs. Physiol Rev 59:527-605. (Pubitemid 9236599)
13. Chou KM, Krapcho AP, Horn D, and Hacker M (2002) Characterization of anthracenediones and their photoaffinity analogs. Biochem Pharmacol 63:1143-1147. (Pubitemid 34267030)
14. Colombo R, Carotti A, Catto M, Racchi M, Lanni C, Verga L, Caccialanza G, and De Lorenzi E (2009) CE can identify small molecules that selectively target soluble oligomers of amyloid beta protein and display antifibrillogenic activity. Electrophoresis 30:1418-1429.
15. Deng S, Kruger A, Kleschyov AL, Kalinowski L, Daiber A, and Wojnowski L (2007) Gp91phox-containing NAD(P)H oxidase increases superoxide formation by doxorubicin and NADPH. Free Radic Biol Med 42:466-473. (Pubitemid 46162116)
16. Doroshow JH (1983) Anthracycline antibiotic-stimulated superoxide, hydrogen peroxide, and hydroxyl radical production by NADH dehydrogenase. Cancer Res 43: 4543-4551. (Pubitemid 13014179)
17. Evison BJ, Bilardi RA, Chiu FC, Pezzoni G, Phillips DR, and Cutts SM (2009) CpG methylation potentiates pixantrone and doxorubicin-induced DNA damage and is a marker of drug sensitivity. Nucleic Acids Res 37:6355-6370.
18. Faulds D, Balfour JA, Chrisp P, and Langtry HD (1991) Mitoxantrone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the chemotherapy of cancer. Drugs 41:400-449. (Pubitemid 21920736)
19. Flens MJ, Zaman GJ, van der Valk P, Izquierdo MA, Schroeijers AB, Scheffer GL, van der Groep P, de Haas M, Meijer CJ, and Scheper RJ (1996) Tissue distribution of the multidrug resistance protein. Am J Pathol 148:1237-1247. (Pubitemid 26111082)
20. Gardner PR (2002) Aconitase: sensitive target and measure of superoxide. Methods Enzymol 349:9-23. (Pubitemid 34229489)
21. Gewirtz DA (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57:727-741. (Pubitemid 29094544)
22. Gianni L, Viganò L, Locatelli A, Capri G, Giani A, Tarenzi E, and Bonadonna G (1997) Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer. J Clin Oncol 15:1906-1915. (Pubitemid 27209520)
23. Herbrecht R, MacDonald D, Weissinger F, Wilhelm M, Holladay C, Dang NH, Holman P, Cernohous P, Singer J, and van der Jagt RH (2011) CPOP-R versus CHOP-R as first-line therapy for diffuse large B-cell lymphoma (DLBCL): A phase 2, randomized, open-label, multicenter study. Blood 118:1605A.
24. Kalabus JL, Sanborn CC, Jamil RG, Cheng Q, and Blanco JG (2010) Expression of the anthracycline-metabolizing enzyme carbonyl reductase 1 in hearts from donors with Down syndrome. Drug Metab Dispos 38:2096-2099.
25. Kalyanaraman B, Darley-Usmar V, Davies KJ, Dennery PA, Forman HJ, Grisham MB, Mann GE, Moore K, Roberts LJ, 2nd, and Ischiropoulos H (2012) Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations. Free Radic Biol Med 52:1-6.
26. Lameh J, Chuang RY, Israel M, and Chuang LF (1989) Nucleoside uptake and membrane fluidity studies on N-trifluoroacetyladriamycin-14-O-hemiadipatetreated human leukemia and lymphoma cells. Cancer Res 49:2905-29078.
27. LeBel CP, Ischiropoulos H, and Bondy SC (1992) Evaluation of the probe 29,79- dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem Res Toxicol 5:227-231.
28. Lebrecht D and Walker UA (2007) Role of mtDNA lesions in anthracycline cardiotoxicity. Cardiovasc Toxicol 7:108-113. (Pubitemid 47339856)
29. Meissner K, Jedlitschky G, Meyer zu Schwabedissen H, Dazert P, Eckel L, Vogelgesang S, Warzok RW, Böhm M, Lehmann C, and Wendt M, et al. (2004) Modulation of multidrug resistance P-glycoprotein 1 (ABCB1) expression in human heart by hereditary polymorphisms. Pharmacogenetics 14:381-385. (Pubitemid 38813692)
30. Menna P, Salvatorelli E, and Minotti G (2008) Cardiotoxicity of antitumor drugs. Chem Res Toxicol 21:978-989.
31. Minotti G, Menna P, Salvatorelli E, Cairo G, and Gianni L (2004a) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185-229. (Pubitemid 38720829)
32. Minotti G, Recalcati S, Menna P, Salvatorelli E, Corna G, and Cairo G (2004b) Doxorubicin cardiotoxicity and the control of iron metabolism: quinone-dependent and independent mechanisms. Methods Enzymol 378:340-361.
33. Minotti G, Salvatorelli E, and Menna P (2010) Pharmacological foundations of cardiooncology. J Pharmacol Exp Ther 334:2-78.
34. Mordente A, Minotti G, Martorana GE, Silvestrini A, Giardina B, and Meucci E (2003) Anthracycline secondary alcohol metabolite formation in human or rabbit heart: biochemical aspects and pharmacologic implications. Biochem Pharmacol 66:989-9978.
35. Motzer RJ, Lyn P, Fischer P, Lianes P, Ngo RL, Cordon-Cardo C, and O'Brien JP (1995) Phase I/II trial of dexverapamil plus vinblastine for patients with advanced renal cell carcinoma. J Clin Oncol 13:1958-1965.
36. Mushlin PS, Cusack BJ, Boucek RJ, Jr., Andrejuk T, Li X, and Olson RD (1993) Timerelated increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function. Br J Pharmacol 110: 975-982. (Pubitemid 24005228)
37. Nguyen B and Gutierrez PL (1990) Mechanism(s) for the metabolism of mitoxantrone: electron spin resonance and electrochemical studies. Chem Biol Interact 74:139-162. (Pubitemid 20106142)
38. Osby E, Hagberg H, Kvaløy S, Teerenhovi L, Anderson H, Cavallin-Stahl E, Holte H, Myhre J, Pertovaara H, and Björkholm M; Nordic Lymphoma Group (2003) CHOP is superior to CNOP in elderly patients with aggressive lymphoma while outcome is unaffected by filgrastim treatment: results of a Nordic Lymphoma Group randomized trial. Blood 101:3840-38478.
39. Pettengell R, Coiffier B, Narayanan G, de Mendoza FH, Digumarti R, Gomez H, Zinzani PL, Schiller G, Rizzieri D, and Boland G, et al. (2012) Pixantrone dimaleate versus other chemotherapeutic agents as a single-agent salvage treatment in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: a phase 3, multicentre, open-label, randomised trial. Lancet Oncol 13:696-706.
40. Powis G (1989) Free radical formation by antitumor quinones. Free Radic Biol Med 6: 63-101. (Pubitemid 19032733)
41. Regev R and Eytan GD (1997) Flip-flop of doxorubicin across erythrocyte and lipid membranes. Biochem Pharmacol 54:1151-11578.
42. Reszka KJ, Matuszak Z, and Chignell CF (1997) Lactoperoxidase-catalyzed oxidation of the anticancer agent mitoxantrone by nitrogen dioxide (NO2.) radicals. Chem Res Toxicol 10:1325-1330. (Pubitemid 28018919)
43. Reszka KJ, Sallans L, Macha S, Brown K, McGraw DW, Kovacic MB, and Britigan BE (2011) Airway peroxidases catalyze nitration of the b2-agonist salbutamol and decrease its pharmacological activity. J Pharmacol Exp Ther 336:440-449.
44. Rota C, Fann YC, and Mason RP (1999) Phenoxyl free radical formation during the oxidation of the fluorescent dye 29,79-dichlorofluorescein by horseradish peroxidase. Possible consequences for oxidative stress measurements. J Biol Chem 274: 28161-281678.
45. Salvatorelli E, Guarnieri S, Menna P, Liberi G, Calafiore AM, Mariggiò MA, Mordente A, Gianni L, and Minotti G (2006a) Defective one- or two-electron reduction of the anticancer anthracycline epirubicin in human heart. Relative importance of vesicular sequestration and impaired efficiency of electron addition. J Biol Chem 281:10990-11001. (Pubitemid 43855522)
46. Salvatorelli E, Menna P, Cascegna S, Liberi G, Calafiore AM, Gianni L, and Minotti G (2006b) Paclitaxel and docetaxel stimulation of doxorubicinol formation in the human heart: implications for cardiotoxicity of doxorubicin-taxane chemotherapies. J Pharmacol Exp Ther 318:424-433.
47. Salvatorelli E, Menna P, Gianni L, and Minotti G (2007) Defective taxane stimulation of epirubicinol formation in the human heart: insight into the cardiac tolerability of epirubicin-taxane chemotherapies. J Pharmacol Exp Ther 320:790-800. (Pubitemid 46147961)
48. Salvatorelli E, Menna P, Lusini M, Covino E, and Minotti G (2009) Doxorubicinolone formation and efflux: a salvage pathway against epirubicin accumulation in human heart. J Pharmacol Exp Ther 329:175-184.
49. Salvatorelli E, Menna P, Gonzalez Paz O, Surapaneni S, Aukerman SL, Chello M, Covino E, Sung V, and Minotti G (2012a) Pharmacokinetic characterization of amrubicin cardiac safety in an ex vivo human myocardial strip model. II. Amrubicin shows metabolic advantages over doxorubicin and epirubicin. J Pharmacol Exp Ther 341:474-483.
50. Salvatorelli E, Menna P, Surapaneni S, Aukerman SL, Chello M, Covino E, Sung V, and Minotti G (2012b) Pharmacokinetic characterization of amrubicin cardiac safety in an ex vivo human myocardial strip model. I. Amrubicin accumulates to a lower level than doxorubicin or epirubicin. J Pharmacol Exp Ther 341: 464-473.
51. Slupe A, Williams B, Larson C, Lee LM, Primbs T, Bruesch AJ, Bjorklund C, Warner DL, Peloquin J, and Shadle SE, et al. (2005) Reduction of 13-deoxydoxorubicin and daunorubicinol anthraquinones by human carbonyl reductase. Cardiovasc Toxicol 5:365-376. (Pubitemid 43021259)
52. Sonneveld P, de Ridder M, van der Lelie H, Nieuwenhuis K, Schouten H, Mulder A, van Reijswoud I, Hop W, and Lowenberg B (1995) Comparison of doxorubicin and mitoxantrone in the treatment of elderly patients with advanced diffuse non- Hodgkin's lymphoma using CHOP versus CNOP chemotherapy. J Clin Oncol 13: 2530-2539.
53. Stewart DJ, Grewaal D, Green RM, Mikhael N, Goel R, Montpetit VA, and Redmond MD (1993) Concentrations of doxorubicin and its metabolites in human autopsy heart and other tissues. Anticancer Res 13 (6A):1945-1952. (Pubitemid 24036310)
54. Stoscheck CM (1990) Quantitation of protein. Methods Enzymol 182:50-678.
55. Swain SM, Whaley FS, and Ewer MS (2003) Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 97: 2869-2879. (Pubitemid 36605157)
56. Vásquez-Vivar J, Martasek P, HoggN, MastersBS, PritchardKA, Jr., andKalyanaraman B (1997) Endothelial nitric oxide synthase-dependent superoxide generation from adriamycin. Biochemistry 36:11293-11297. (Pubitemid 27408610)
57. Vellonen K-S, Honkakoski P, and Urtti A (2004) Substrates and inhibitors of efflux proteins interfere with the MTT assay in cells and may lead to underestimation of drug toxicity. Eur J Pharm Sci 23:181-1878.
58. Warner E, Hedley D, Andrulis I, Myers R, Trudeau M, Warr D, Pritchard KI, Blackstein M, Goss PE, and Franssen E, et al. (1998) Phase II study of dexverapamil plus anthracycline in patients with metastatic breast cancer who have progressed on the same anthracycline regimen. Clin Cancer Res 4:1451-1457. (Pubitemid 28265228)
59. Whitaker G, Lillquist A, Pasas SA, O'Connor R, Regan F, Lunte CE, and Smyth MR (2008) CE-LIF method for the separation of anthracyclines: application to protein binding analysis in plasma using ultrafiltration. J Sep Sci 31:1828-1833.\ (Pubitemid 351911746)