Poly(ADP-Ribose) Polymerase Inhibitors for Arsenic Trioxide-Resistant Acute Promyelocytic Leukemia: Synergistic In Vitro Antitumor Effects with Hypomethylating Agents or High-Dose Vitamin C.

Autor:	Giansanti M; Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy (M.G., A.D.G., S.P.P., T.K., G.G., I.F.); Department of Physiology and Pharmacology 'V. Erspamer,' Sapienza University of Rome, Rome, Italy (M.G.); Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy (T.O., M.D., M.T.V.); Unit of Neuro-Oncohematology, Santa Lucia Foundation-IRCCS, Rome, Italy (T.O., M.T.V.); and IRCCS San Raffaele Pisana, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy (F.C.)., De Gabrieli A; Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy (M.G., A.D.G., S.P.P., T.K., G.G., I.F.); Department of Physiology and Pharmacology 'V. Erspamer,' Sapienza University of Rome, Rome, Italy (M.G.); Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy (T.O., M.D., M.T.V.); Unit of Neuro-Oncohematology, Santa Lucia Foundation-IRCCS, Rome, Italy (T.O., M.T.V.); and IRCCS San Raffaele Pisana, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy (F.C.)., Prete SP; Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy (M.G., A.D.G., S.P.P., T.K., G.G., I.F.); Department of Physiology and Pharmacology 'V. Erspamer,' Sapienza University of Rome, Rome, Italy (M.G.); Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy (T.O., M.D., M.T.V.); Unit of Neuro-Oncohematology, Santa Lucia Foundation-IRCCS, Rome, Italy (T.O., M.T.V.); and IRCCS San Raffaele Pisana, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy (F.C.)., Ottone T; Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy (M.G., A.D.G., S.P.P., T.K., G.G., I.F.); Department of Physiology and Pharmacology 'V. Erspamer,' Sapienza University of Rome, Rome, Italy (M.G.); Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy (T.O., M.D., M.T.V.); Unit of Neuro-Oncohematology, Santa Lucia Foundation-IRCCS, Rome, Italy (T.O., M.T.V.); and IRCCS San Raffaele Pisana, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy (F.C.)., Divona MD; Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy (M.G., A.D.G., S.P.P., T.K., G.G., I.F.); Department of Physiology and Pharmacology 'V. Erspamer,' Sapienza University of Rome, Rome, Italy (M.G.); Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy (T.O., M.D., M.T.V.); Unit of Neuro-Oncohematology, Santa Lucia Foundation-IRCCS, Rome, Italy (T.O., M.T.V.); and IRCCS San Raffaele Pisana, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy (F.C.)., Karimi T; Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy (M.G., A.D.G., S.P.P., T.K., G.G., I.F.); Department of Physiology and Pharmacology 'V. Erspamer,' Sapienza University of Rome, Rome, Italy (M.G.); Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy (T.O., M.D., M.T.V.); Unit of Neuro-Oncohematology, Santa Lucia Foundation-IRCCS, Rome, Italy (T.O., M.T.V.); and IRCCS San Raffaele Pisana, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy (F.C.)., Ciccarone F; Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy (M.G., A.D.G., S.P.P., T.K., G.G., I.F.); Department of Physiology and Pharmacology 'V. Erspamer,' Sapienza University of Rome, Rome, Italy (M.G.); Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy (T.O., M.D., M.T.V.); Unit of Neuro-Oncohematology, Santa Lucia Foundation-IRCCS, Rome, Italy (T.O., M.T.V.); and IRCCS San Raffaele Pisana, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy (F.C.)., Voso MT; Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy (M.G., A.D.G., S.P.P., T.K., G.G., I.F.); Department of Physiology and Pharmacology 'V. Erspamer,' Sapienza University of Rome, Rome, Italy (M.G.); Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy (T.O., M.D., M.T.V.); Unit of Neuro-Oncohematology, Santa Lucia Foundation-IRCCS, Rome, Italy (T.O., M.T.V.); and IRCCS San Raffaele Pisana, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy (F.C.) faraoni@med.uniroma2.it graziani@uniroma2.it Voso@med.uniroma2.it., Graziani G; Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy (M.G., A.D.G., S.P.P., T.K., G.G., I.F.); Department of Physiology and Pharmacology 'V. Erspamer,' Sapienza University of Rome, Rome, Italy (M.G.); Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy (T.O., M.D., M.T.V.); Unit of Neuro-Oncohematology, Santa Lucia Foundation-IRCCS, Rome, Italy (T.O., M.T.V.); and IRCCS San Raffaele Pisana, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy (F.C.) faraoni@med.uniroma2.it graziani@uniroma2.it Voso@med.uniroma2.it., Faraoni I; Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy (M.G., A.D.G., S.P.P., T.K., G.G., I.F.); Department of Physiology and Pharmacology 'V. Erspamer,' Sapienza University of Rome, Rome, Italy (M.G.); Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy (T.O., M.D., M.T.V.); Unit of Neuro-Oncohematology, Santa Lucia Foundation-IRCCS, Rome, Italy (T.O., M.T.V.); and IRCCS San Raffaele Pisana, Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy (F.C.) faraoni@med.uniroma2.it graziani@uniroma2.it Voso@med.uniroma2.it.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2021 Jun; Vol. 377 (3), pp. 385-397. Date of Electronic Publication: 2021 Apr 05.
DOI:	10.1124/jpet.121.000537
Abstrakt:	Arsenic trioxide (ATO) is an anticancer agent used for the treatment ofacute promyelocytic leukemia (APL). However, 5%-10% of patients fail to respond or experience disease relapse. Based on poly(ADP-ribose) polymerase (PARP) 1 involvement in the processing of DNA demethylation, here we have tested the in vitro susceptibility of ATO-resistant clones (derived from the human APL cell line NB4) to PARP inhibitors (PARPi) in combination with hypomethylating agents (azacitidine and decitabine) or high-dose vitamin C (ascorbate), which induces 5-hydroxymethylcytosine (5hmC)-mediated DNA demethylation. ATO-sensitive and -resistant APL cell clones were generated and initially analyzed for their susceptibility to five clinically used PARPi (olaparib, niraparib, rucaparib, veliparib, and talazoparib). The obtained PARPi IC 50 values were far below (olaparib and niraparib), within the range (talazoparib), or above (rucaparib and veliparib) the C max reported in patients, likely as a result of differences in the mechanisms of their cytotoxic activity. ATO-resistant APL cells were also susceptible to clinically relevant concentrations of azacitidine and decitabine and to high-dose ascorbate. Interestingly, the combination of these agents with olaparib, niraparib, or talazoparib resulted in synergistic antitumor activity. In combination with ascorbate, PARPi increased the ascorbate-mediated induction of 5hmC, which likely resulted in stalled DNA repair and cytotoxicity. Talazoparib was the most effective PARPi in synergizing with ascorbate, in accordance with its marked ability to trap PARP1 at damaged DNA. These findings suggest that ATO and PARPi have nonoverlapping resistance mechanisms and support further investigation on PARPi combination with hypomethylating agents or high-dose ascorbate for relapsed/ATO-refractory APL, especially in frail patients. SIGNIFICANCE STATEMENT: This study found that poly(ADP-ribose) inhibitors (PARPi) show activity as single agents against human acute promyelocytic leukemia cells resistant to arsenic trioxide at clinically relevant concentrations. Furthermore, PARPi enhance the in vitro efficacy of azacitidine, decitabine, and high-dose vitamin C, all agents that alter DNA methylation. In combination with vitamin C, PARPi increase the levels of 5-hydroxymethylcytosine, likely as a result of altered processing of the oxidized intermediates associated with DNA demethylation. (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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