<i>PACSIN2</i>as a modulator of autophagy and mercaptopurine cytotoxicity: mechanisms in lymphoid and intestinal cells

Zudeh, Giulia; Franca, Raffaella; Lucafò, Marianna; Bonten, Erik; Bramuzzo, Matteo; Sgarra, Riccardo; Lagatolla, Cristina; Franzin, Martina; Evans, William E.; Decorti, Giuliana; Stocco, Gabriele

doi:10.26508/lsa.202201610

Cited by 3 publications

(3 citation statements)

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“…15,16 ITPA degrades TITP into TIMP, regenerating an intermediate of reaction required for the synthesis of TGN; PACSIN2 is a protein involved in the regulation of cell cytoskeleton, intracellular trafficking and signaling, and autophagy. 17,18 MTX is conjugated intracellularly to polyglutamates and thus remains trapped inside the cells. As an antifolate, MTX inhibits several folate-dependent enzymes whose function is central to thymidylate and de novo purine biosynthesis and in one-carbon metabolism, affecting amino acid metabolism, and mitochondrial protein synthesis.…”

Section: Articlementioning

confidence: 99%

“…Additional single nucleotide polymorphisms (SNPs) in the inosine triphosphate pyro‐phosphatase ( ITPA ) and in the protein kinase C and casein kinase substrate in neurons 2 ( PACSIN2 ) genes are under investigation for their contribution to MP efficacy and safety 15,16 . ITPA degrades TITP into TIMP, regenerating an intermediate of reaction required for the synthesis of TGN; PACSIN2 is a protein involved in the regulation of cell cytoskeleton, intracellular trafficking and signaling, and autophagy 17,18 . MTX is conjugated intracellularly to polyglutamates and thus remains trapped inside the cells.…”

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confidence: 99%

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Impact of Mercaptopurine Metabolites on Disease Outcome in the AIEOP‐BFM ALL 2009 Protocol for Acute Lymphoblastic Leukemia

Franca

Stocco

Kiren

et al. 2023

Clin Pharma and Therapeutics

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In the maintenance phase of AIEOP‐BFM acute lymphoblastic leukemia (ALL) 2009 protocol, mercaptopurine (MP) is given at the planned dose of 50 mg/m2/day; however, dose adjustments are routinely performed to target patients’ white blood cells to the optimal range of 2000‐3000 cells/μl. ALL pediatric patients (n=290, age: median (1st‐3rd quartile): 4.8 (3.0‐8.1) years; male: 56.9%) were enrolled mainly in four medium‐large Italian pediatric hospitals; 14.1% of patients relapsed after a median (1st‐3rd quartile) follow‐up time of 4.43 (3.82‐5.46) years from maintenance beginning. MP metabolites (thionucleotide (TGN) and methyl‐derivatives (MMPN)) were measured in the erythrocytes of 387 blood samples of 200 patients by HPLC‐UV. SNPs (rs1800462, rs1800460 and rs1142345 in TPMT gene, rs116855232 in NUDT15, rs1127354, rs7270101, rs6051702 in ITPA and rs2413739 in PACSIN2) were characterized by Taqman SNP genotyping assays. Cox proportional hazard models did not show an impact TGN levels and variability on relapse. In contrast, after multivariate analysis, relapse hazard ratio (HR) increased in ALL children of the intermediate risk arm compared to those in standard risk arm (3.44, 95% confidence interval (CI), 1.31‐9.05, p= 0.012), and in carriers of the PACSIN2 rs2413739 T allele compared to those with the CC genotype (heterozygotes CT: HR, 2.32; 95% CI, 0.90‐5.97; p=0.081; homozygous TT: HR, 4.14; 95% CI, 1.54‐11.11; p=0.005). Future studies are needed to confirm the lack of impact of TGN levels and variability on relapse in the AIEOP‐BFM ALL trials, and to clarify the mechanism of PACSIN2 rs2413739 on outcome.

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Section: Articlementioning

confidence: 99%

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confidence: 99%

Impact of Mercaptopurine Metabolites on Disease Outcome in the AIEOP‐BFM ALL 2009 Protocol for Acute Lymphoblastic Leukemia

Franca

Stocco

Kiren

et al. 2023

Clin Pharma and Therapeutics

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“…Intestinal ADRs can result in malabsorption, mucosal damage, hemorrhagic phenomena, or alterations in the motility (Srisajjakul et al, 2022). To manage intestinal ADRs, many scientists developed in‐vitro models based on immortalized intestinal cell lines like Caco‐2 (Volpe, 2011; Voss et al, 2021), or LS‐180 (Zudeh et al, 2023); nonetheless, such models do not represent the genetic differences existing between different patients. In this regard, iPSC‐derived intestinal cells and organoids can help to overcome these issues.…”

Section: Ipscs and Drug‐induced Toxicitiesmentioning

confidence: 99%

iPSCs as a groundbreaking tool for the study of adverse drug reactions: A new avenue for personalized therapy

Rispoli,

Scandiuzzi Piovesan,

Decorti

et al. 2023

WIREs Mechanisms of Disease

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Induced pluripotent stem cells (iPSCs), obtained by reprogramming different somatic cell types, represent a promising tool for the study of drug toxicities, especially in the context of personalized medicine. Indeed, these cells retain the same genetic heritage of the donor, allowing the development of personalized models. In addition, they represent a useful tool for the study of adverse drug reactions (ADRs) in special populations, such as pediatric patients, which are often poorly represented in clinical trials due to ethical issues. Particularly, iPSCs can be differentiated into any tissue of the human body, following several protocols which use different stimuli to induce specific differentiation processes. Differentiated cells also maintain the genetic heritage of the donor, and therefore are suitable for personalized pharmacological studies; moreover, iPSC‐derived differentiated cells are a valuable tool for the investigation of the mechanisms underlying the physiological differentiation processes. iPSCs‐derived organoids represent another important tool for the study of ADRs. Precisely, organoids are in vitro 3D models which better represent the native organ, both from a structural and a functional point of view. Moreover, in the same way as iPSC‐derived 2D models, iPSC‐derived organoids are appropriate personalized models since they retain the genetic heritage of the donor. In comparison to other in vitro models, iPSC‐derived organoids present advantages in terms of versatility, patient‐specificity, and ethical issues. This review aims to provide an updated report of the employment of iPSCs, and 2D and 3D models derived from these, for the study of ADRs.This article is categorized under: Cancer > Stem Cells and Development

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Transcriptome analysis reveals involvement of thiopurine S-methyltransferase in oxidation-reduction processes

Šmid,

Štajdohar,

Milek

et al. 2024

European Journal of Pharmaceutical Sciences

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PACSIN2as a modulator of autophagy and mercaptopurine cytotoxicity: mechanisms in lymphoid and intestinal cells

Cited by 3 publications

References 83 publications

Impact of Mercaptopurine Metabolites on Disease Outcome in the AIEOP‐BFM ALL 2009 Protocol for Acute Lymphoblastic Leukemia

Impact of Mercaptopurine Metabolites on Disease Outcome in the AIEOP‐BFM ALL 2009 Protocol for Acute Lymphoblastic Leukemia

iPSCs as a groundbreaking tool for the study of adverse drug reactions: A new avenue for personalized therapy

Transcriptome analysis reveals involvement of thiopurine S-methyltransferase in oxidation-reduction processes

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