When Poisons Cure: The Case of Arsenic in Acute Promyelocytic Leukemia

Gurnari, Carmelo; Bellis, Eleonora De; Divona, Mariadomenica; Ottone, Tiziana; Lavorgna, Serena; Voso, Maria Teresa

doi:10.1159/000507805

Cited by 21 publications

(10 citation statements)

References 71 publications

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“…This oncogene, found in 98% of cases, causes the transcriptional repression of RARA -targeted genes and the destruction of PML nuclear bodies (PML-NBs), resulting in altered self-renewal, senescence mechanisms, and response to DNA damage ( 3 – 7 ). With the introduction of daunorubicin in 1973, all-trans-retinoic acid (ATRA) in 1988, arsenic trioxide (ATO) in 1997, and, eventually, the chemo-free ATRA+ATO approach in 2006, the disease changed from highly fatal to curable leukemia in most cases ( 6 , 8 – 14 ).…”

Section: Introductionmentioning

confidence: 99%

Atypical Rearrangements in APL-Like Acute Myeloid Leukemias: Molecular Characterization and Prognosis

et al. 2022

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Acute promyelocytic leukemia (APL) accounts for 10–15% of newly diagnosed acute myeloid leukemias (AML) and is typically caused by the fusion of promyelocytic leukemia with retinoic acid receptor α (RARA) gene. The prognosis is excellent, thanks to the all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) combination therapy. A small percentage of APLs (around 2%) is caused by atypical transcripts, most of which involve RARA or other members of retinoic acid receptors (RARB or RARG). The diagnosis of these forms is difficult, and clinical management is still a challenge for the physician due to variable response rates to ATRA and ATO. Herein we review variant APL cases reported in literature, including genetic landscape, incidence of coagulopathy and differentiation syndrome, frequent causes of morbidity and mortality in these patients, sensitivity to ATRA, ATO, and chemotherapy, and outcome. We also focus on non-RAR rearrangements, complex rearrangements (involving more than two chromosomes), and NPM1-mutated AML, an entity that can, in some cases, morphologically mimic APL.

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Section: Introductionmentioning

confidence: 99%

Atypical Rearrangements in APL-Like Acute Myeloid Leukemias: Molecular Characterization and Prognosis

et al. 2022

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“…T (15, 17) chromosome rearrangements lead to this malignant tumor. APL is characterized by representative promyelocytic leukemia protein/retinoic acid receptor a gene fusion and high invasiveness and infiltration in clinical practice [ 32 – 35 ]. The oncogenic protein produced by the fusion can antagonize myeloid differentiation and promote APL to initiate cell self-renewal, leading to abnormal development of promyelocytic bone marrow infiltration [ 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

Mineral medicine: from traditional drugs to multifunctional delivery systems

Zhong

et al. 2022

Chin Med

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Mineral drugs are an important constituent of traditional Chinese medicine (TCM). Taking minerals that contain heavy metals as drugs is a very national characteristic part of TCM. However, the safety and scientific nature of mineral drugs are controversial owing to their heavy metals and strong toxicity. In 2000, the Food and Drug Administration (FDA) authorized arsenic trioxide (ATO) as first-line therapy for acute promyelocytic leukemia. This makes the development and utilization of mineral drugs become a research hotspot. The development of nanomedicine has found a great prospect of mineral drugs in nano-delivery carriers. And that will hold promise to address the numerous biological barriers facing mineral drug formulations. However, the studies on mineral drugs in the delivery system are few at present. There is also a lack of a detailed description of mineral drug delivery systems. In this review, the advanced strategies of mineral drug delivery systems in tumor therapy are summarized. In addition, the therapeutic advantages and research progress of novel mineral drug delivery systems are also discussed. Here, we hope that this will provide a useful reference for the design and application of new mineral drug delivery systems. Graphical Abstract

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“…Moreover, PML-RARA interferes with the normal formation of PML-Nuclear Bodies (PML-NBs) leading to impaired stress response, decreased DNA damage repair and reduced cell propensity to undergo senescence and apoptosis (Gurnari et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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

Giansanti

Gabrieli

Prete

et al. 2021

J Pharmacol Exp Ther

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Arsenic trioxide (ATO) is an anticancer agent used for the treatment of acute promyelocytic leukemia (APL). However, 5-10% of patients fail to respond or experience disease relapse. Based on poly(ADP-ribose) polymerase 1 (PARP1) 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 5hydroxymethylcytosine (5hmC)-mediated DNA demethylation. ATO-sensitive andresistant 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 Cmax reported in patients, likely due to 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 non-overlapping 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.

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When Poisons Cure: The Case of Arsenic in Acute Promyelocytic Leukemia

Cited by 21 publications

References 71 publications

Atypical Rearrangements in APL-Like Acute Myeloid Leukemias: Molecular Characterization and Prognosis

Atypical Rearrangements in APL-Like Acute Myeloid Leukemias: Molecular Characterization and Prognosis

Mineral medicine: from traditional drugs to multifunctional delivery systems

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

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