MER1, a novel organic arsenic derivative, has potent PML-RARα- independent cytotoxic activity against leukemia cells
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Arsenic trioxide (ATO) is an inorganic arsenic derivative that is highly effective against PML-RARα-positive leukemia but much less against other hematological malignancies. We synthesized an organic arsenic derivative (OAD), S-dimethylarsino-thiosuccinic acid (MER1), which offers a superior toxicity profile and comparable in vitro activity relative to ATO. In Swiss Webster mice, maximally-tolerated cumulative dose of MER1 when given IV for 5 days was 100 mg/kg/d. We demonstrated that MER1 induced apoptosis and dose- and time-dependent inhibition of survival and growth in a panel of myeloid leukemia cell lines. Unlike ATO, this activity was independent of PML-RARα status and was not associated with induction of myeloid maturation. In NB4 and HL60 cells, MER1 and ATO induced caspase activation and dissipation of mitochondrial transmembrane potential. At the same time, MER1 induced generation of reactive oxygen species (ROS) and cell cycle arrest in G2/M phase and proved to be more potent than ATO at inducing apoptosis. ROS generation and intracellular glutathione levels were key modulators of MER1-induced cytotoxicity as evidenced by abrogation of apoptosis in myeloid leukemia cell lines pretreated with the disulfide bond-reducing agent dithiothreitol or the radical scavenger N-acetyl-L-cysteine. Collectively, these data indicate that MER1 induces apoptosis in PML-RARα-positive and -negative myeloid leukemia cells by enhancing oxidative stress. This agent, therefore, combines low in vivo toxicity with formidable in vitro pro-apoptotic ROS-mediated activity, and may represent a novel OAD suitable for clinical development against a variety of hematological malignancies.
KeywordsMER1 Organic arsenic derivatives PML-RARα Acute myeloid leukemia
Robert A. Welch Foundation sponsored work done by RAZ.
- 3.Shao W, Fanelli M, Ferrara FF, Riccioni R, Rosenauer A, Davison K, Lamph WW, Waxman S, Pelicci PG, Lo Coco F et al (1998) Arsenic trioxide as an inducer of apoptosis and loss of PML/RAR alpha protein in acute promyelocytic leukemia cells. J Natl Cancer Inst 90(2):124–133. doi: 10.1093/jnci/90.2.124 CrossRefPubMedGoogle Scholar
- 4.Chen GQ, Zhu J, Shi XG, Ni JH, Zhong HJ, Si GY, Jin XL, Tang W, Li XS, Xong SM et al (1996) In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia: As2O3 induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RAR alpha/PML. Blood 88(3):1052–1061PubMedGoogle Scholar
- 5.Soignet SL, Maslak P, Wang ZG, Jhanwar S, Calleja E, Dardashti LJ, Corso D, DeBlasio A, Gabrilove J, Scheinberg DA et al (1998) Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 339(19):1341–1348. doi: 10.1056/NEJM199811053391901 CrossRefPubMedGoogle Scholar
- 11.Verstovsek S, Duzkale, H, Orsolic, N et al (2002) S-dimethylarsino-thiosuccinic acid, an organic arsenic derivative, is comparable in in vitro antileukemic activity to arsenic trioxide but possesses significantly less toxicity. Blood 100(11):(abstr 4614)Google Scholar
- 15.Grignani F, Ferrucci PF, Testa U, Talamo G, Fagioli M, Alcalay M, Mencarelli A, Peschle C, Nicoletti I et al (1993) The acute promyelocytic leukemia-specific PML-RAR alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell 74(3):423–431. doi: 10.1016/0092-8674(93)80044-F CrossRefPubMedGoogle Scholar
- 16.Pan J, Quintas-Cardama A, Kantarjian HM, Akin C, Manshouri T, Lamb P, Cortes JE, Tefferi A, Giles FJ, Verstovsek S (2007) EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation. Blood 109(1):315–322. doi: 10.1182/blood-2006-04-013805 CrossRefPubMedGoogle Scholar
- 19.Rego EM, He LZ, Warrell RP Jr, Wang ZG, Pandolfi PP (2000) Retinoic acid (RA) and As2O3 treatment in transgenic models of acute promyelocytic leukemia (APL) unravel the distinct nature of the leukemogenic process induced by the PML-RARalpha and PLZF-RARalpha oncoproteins. Proc Natl Acad Sci USA 97(18):10173–10178. doi: 10.1073/pnas.180290497 CrossRefPubMedGoogle Scholar
- 21.Park JW, Choi YJ, Jang MA, Baek SH, Lim JH, Passaniti T, Kwon TK (2001) Arsenic trioxide induces G2/M growth arrest and apoptosis after caspase-3 activation and bcl-2 phosphorylation in promonocytic U937 cells. Biochem Biophys Res Commun 286(4):726–734. doi: 10.1006/bbrc.2001.5416 CrossRefPubMedGoogle Scholar