Article

Current treatment strategy of acute promyelocytic leukemia

Department of Hematology, Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
Frontiers of Medicine 12/2011; 5(4):341-7. DOI: 10.1007/s11684-011-0169-z
Source: PubMed

ABSTRACT

Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML). The prognosis of APL has changed from the worst among the AMLs to currently the best. The application of all-trans retinoic acid (ATRA) in the induction therapy of APL decreases the high mortality of newly diagnosed patients, thereby significantly improving the response rate. ATRA combined with anthracycline-based chemotherapy is the current standard treatment, and for high-risk patients, high doses cytarabine have a beneficial effect on relapse prevention. In recent years, the indications of arsenic trioxide (ATO) therapy for APL have been extended from the salvage therapy for relapse patients to the first-line treatment of de novo APL. The introduction of both ATRA and ATO represents great achievements in translational medicine. In this review article, we discuss the therapeutic strategies for this disease, including the initial approaches to newly diagnosed patients, prevention, and treatment of side effects and relapse to ensure the best and timely treatment for each newly diagnosed APL patient.

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    • "Arsenic trioxide (ATO) is currently FDA-approved for the treatment of acute promyelocytic leukemia (Mi, 2011). Despite the long history of human exposure to and usage of arsenic, the exact mechanisms by which arsenic exerts these biological effects remain obscure. "
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    ABSTRACT: The metalloid arsenic is a worldwide environmental toxicant, exposure to which is associated with many adverse outcomes. Arsenic is also an effective therapeutic agent in certain disease settings. Recently, arsenic was shown to regulate the activity of the Hedgehog (HH) signal transduction pathway, and this regulation of HH signaling was proposed to be responsible for a subset of arsenic's biological effects. Surprisingly, these separate reports proposed contradictory activities for arsenic, as either an agonist or antagonist of HH signaling. Here we provide in vitro and in vivo evidence that arsenic acts as a modulator of the activity of the HH effector protein GLI, activating or inhibiting GLI activity in a context-dependent manner. This arsenic induced modulation of HH signaling is observed in: 1) cultured cells, 2) colorectal cancer patients who have received arsenic based therapy, and 3) a mouse colorectal cancer xenograft model. Our results show that arsenic activates GLI signaling when the intrinsic GLI activity is low, but inhibits signaling in the presence of high-level GLI activity. Further, we show that this modulation occurs downstream of primary cilia, evidenced by experiments in SUFU-/- cells. Combining our findings with previous reports, we present an inclusive model in which arsenic plays dual roles in GLI signaling modulation: when GLIs are primarily in their repressor form, arsenic antagonizes their repression capacity, leading to low-level GLI activation, but when GLIs are primarily in their activator form, arsenic attenuates their activity.
    Full-text · Article · Nov 2015 · Molecular pharmacology
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    • "In this study, we report for the first time the effects of these natural compounds on ribonucleotide reductase (RR) metabolism in human HL-60 promyelocytic leukemia cells. Acute promyelocytic leukemia is a distinct subtype of acute myeloid leukemia and represents a relatively rare hematological disease, accounting for approximately 5–8% of all AML cases (Mi 2011). The balanced reciprocal translocation t(15;17) generates a PML (promyelocytic leukemia)-RARα (retinoic acid receptor alpha) fusion (onco)gene (Mi et al. 2012). "
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    ABSTRACT: Epigallocatechin gallate (EGCG), ellagic acid (EA) and rosmarinic acid (RA) are natural polyphenols exerting cancer chemopreventive effects. Ribonucleotide reductase (RR; EC 1.17.4.1) converts ribonucleoside diphosphates into deoxyribonucleoside diphosphates being essential for DNA replication, which is why the enzyme is considered an excellent target for anticancer therapy. EGCG, EA, and RA dose-dependently inhibited the growth of human HL-60 promyelocytic leukemia cells, exerted strong free radical scavenging potential, and significantly imbalanced nuclear deoxyribonucleoside triphosphate (dNTP) concentrations without distinctly affecting the protein levels of RR subunits (R1, R2, p53R2). Incorporation of (14)C-cytidine into nascent DNA of tumor cells was also significantly lowered, being equivalent to an inhibition of DNA synthesis. Consequently, treatment with EGCG and RA attenuated cells in the G0/G1 phase of the cell cycle, finally resulting in a pronounced induction of apoptosis. Sequential combination of EA and RA with the first-line antileukemic agent arabinofuranosylcytosine (AraC) synergistically potentiated the antiproliferative effect of AraC, whereas EGCG plus AraC yielded additive effects. Taken together, we show for the first time that EGCG, EA, and RA perturbed dNTP levels and inhibited cell proliferation in human HL-60 promyelocytic leukemia cells, with EGCG and RA causing a pronounced induction of apoptosis. Due to these effects and synergism with AraC, these food ingredients deserve further preclinical and in vivo testing as inhibitors of leukemic cell proliferation. Copyright © 2014 Elsevier GmbH. All rights reserved.
    Full-text · Article · Jan 2015 · Phytomedicine: international journal of phytotherapy and phytopharmacology
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    • "On the other hand, chronic exposure to low-levels of arsenic in drinking water is an emerging risk across different parts of the world, including North America (Figure 1) [4-7]. Paradoxically, arsenic (as arsenic trioxide, A2O3) is also used as therapeutic agent in the treatment of acute promyelocytic leukemia [8,9]. "
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    ABSTRACT: Arsenic is a well-known human carcinogen, which potentially affects ~160 million people worldwide via exposure to unsafe levels in drinking water. Lungs are one of the main target organs for arsenic-related carcinogenesis. These tumors exhibit particular features, such as squamous cell-type specificity and high incidence among never smokers. Arsenic-induced malignant transformation is mainly related to the biotransformation process intended for the metabolic clearing of the carcinogen, which results in specific genetic and epigenetic alterations that ultimately affect key pathways in lung carcinogenesis. Based on this, lung tumors induced by arsenic exposure could be considered an additional subtype of lung cancer, especially in the case of never-smokers, where arsenic is a known etiological agent. In this article, we review the current knowledge on the various mechanisms of arsenic carcinogenicity and the specific roles of this metalloid in signaling pathways leading to lung cancer.
    Full-text · Article · Mar 2013 · Molecular Cancer
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