Oxidative stress in chronic lymphocytic leukemia: still a matter of debate

D’Arena, Giovanni; Seneca, Elisa; Migliaccio, Ilaria; Feo, Vincenzo De; Giudice, Aldo; Rocca, Francesco La; Coccia, Mario; Calapai, Gioacchino; Festa, Agostino; Caraglia, Michele; Musto, Pellegrino; Iorio, Eugenio Luigi; Ruggieri, Vitalba

doi:10.1080/10428194.2018.1509317

Cited by 15 publications

(25 citation statements)

References 80 publications

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“…Indeed, targeting intracellular redox homeostasis by increasing ROS levels in cancer cells is a promising treatment approach [ 15 ]. CLL B-cells were shown to produce abnormally large amounts of ROS and to have impaired antioxidant defenses [ 24 , 27 , 53 ]. Hence, these cells are vulnerable to molecules that perturb redox homeostasis [ 46 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown that the CLL microenvironment (including bone marrow MSCs) not only provides survival cues [ 30 , 57 ] but also protects against oxidative stress by modulating the expression of genes involved in redox homeostasis and by increasing glutathione synthesis [ 24 , 45 , 46 ]. However, our present results show that AA was able to induce CLL B-cell death and thus overcome the anti-apoptotic protection provided by primary bone marrow MSCs.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, some CLL patients suffer from vitamin C deficiency (hypovitaminosis C), which is correlated with more aggressive disease [ 23 ]. Given that CLL B-cells are known to be sensitive to oxidative stress mediated by H 2 O 2 [ 24 – 27 ], we hypothesized that a redox-inducing agent like AA might effectively kill leukemic cells and synergize with CLL treatments. Here, we performed a comprehensive study of the in vitro effect of 250 μM AA on primary highly purified CLL B-cells and two cell lines.…”

Section: Introductionmentioning

confidence: 99%

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Ascorbic acid (vitamin C) synergistically enhances the therapeutic effect of targeted therapy in chronic lymphocytic leukemia

Darwiche

Gomila

Ouled-Haddou

et al. 2020

J Exp Clin Cancer Res

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Background Novel, less toxic, cost-effective and safe therapeutic strategies are needed to improve treatment of chronic lymphocytic leukemia (CLL). Ascorbic acid (AA, vitamin C) has shown a potential anti-cancer therapeutic activity in several cancers. However, the anti-cancer effects of ascorbic acid on CLL B-cells have not been extensively studied. We aimed in this study to evaluate the in vitro therapeutic activity using clinically relevant conditions. Methods Primary CLL B-cells and two CLL cell lines were exposed to a dose that is clinically achievable by AA oral administration (250 μM), and cell death and potential mechanisms were assessed. The role of the protective CLL microenvironment was studied. Synergistic interaction between AA and CLL approved drugs (Ibrutinib, Idelalisib and Venetoclax) was also evaluated. Results Ascorbic acid is cytotoxic for CLL B-cells at low dose (250 μM) but spares healthy B-cells. Ascorbic-acid-induced cytotoxicity involved pro-oxidant damage through the generation of reactive oxygen species in the extracellular media and in CLL cells, and induced caspase-dependent apoptosis. We also found that AA treatment overcame the supportive survival effect provided by microenvironment including bone marrow mesenchymal stem cells, T-cell cues (CD40L + IL-4), cytokines and hypoxia. Our data suggest that resistance to AA could be mediated by the expression of the enzyme catalase in some CLL samples and by the glucose metabolite pyruvate. We also demonstrated that AA synergistically potentiates the cytotoxicity of targeted therapies used in or being developed for CLL. Conclusion These preclinical results point to AA as an adjuvant therapy with potential to further improve CLL treatments in combination with targeted therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ascorbic acid (vitamin C) synergistically enhances the therapeutic effect of targeted therapy in chronic lymphocytic leukemia

Darwiche

Gomila

Ouled-Haddou

et al. 2020

J Exp Clin Cancer Res

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“…In addition to enhanced ROS generation, the oxidative stress in B-cell malignancies results from diminished capacity of antioxidant systems ( 24 ). Indeed, decreased activity of SOD2 and catalase (CAT) has been reported in CLL and DLBCL patients compared to healthy individuals ( 16 , 25 ).…”

Section: Intrinsic and Extrinsic Sources Of Ros In B-cells Malignancimentioning

confidence: 99%

cROSsing the Line: Between Beneficial and Harmful Effects of Reactive Oxygen Species in B-Cell Malignancies

2020

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B-cell malignancies are a heterogeneous group of hematological neoplasms derived from cells at different stages of B-cell development. Recent studies revealed that dysregulated redox metabolism is one of the factors contributing to the pathogenesis and progression of B-cell malignancies. Elevated levels of oxidative stress markers usually correlate with the advanced stage of various B-cell malignancies. In the complex tumor microenvironment, reactive oxygen species affect not only malignant cells but also bystander cells, including immune cells. Importantly, malignant cells, due to genetic dysregulation, are able to adapt to the increased demands for energy and reducing equivalents via metabolic reprogramming and upregulation of antioxidants. The immune cells, however, are more sensitive to oxidative imbalance. This may cause their dysfunction, leading to immune evasion and tumor progression. On the other hand, the already imbalanced redox homeostasis renders malignant B-cells particularly sensitive to further elevation of reactive oxygen species. Indeed, targeting antioxidant systems has already presented anti-leukemic efficacy in preclinical models. Moreover, the prooxidant treatment that triggers immunogenic cell death has been utilized to generate autologous anti-leukemic vaccines. In this article, we review novel research on the dual role of the reactive oxygen species in B-cell malignancies. We highlight the mechanisms of maintaining redox homeostasis by malignant B-cells along with the antioxidant shield provided by the microenvironment. We summarize current findings regarding therapeutic targeting of redox metabolism in B-cell malignancies. We also discuss how the oxidative stress affects antitumor immune response and how excessive reactive oxygens species influence anticancer prooxidant treatments and immunotherapies.

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“…3 Por meio desse método, um aumento do EO foi demonstrado em várias condições patológicas: insuficiência cardíaca, infarto agudo do miocárdio, hipertensão arterial, doença arterial periférica, insuficiência renal, eclâmpsia, artrite reumatoide, osteoartrite do joelho, fibrose pulmonar, leucemia linfática crônica, hipotireoidismo, hipopituitarismo, diabetes, dislipidemia, hiperuricemia, síndrome metabólica, obesidade, bem como em situações fisiológicas (envelhecimento, ciclo menstrual, menopausa, exercício estéril). [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] Dada a confiabilidade do teste d-ROMs e a falta de informação em sujeitos com tendinopatias, o objetivo do presente estudo foi avaliar o status do EO em jogadores profissionais de futebol de elite com e sem características ultrassonográficas de dano tendinoso.…”

Section: Introductionunclassified

Estresse oxidativo e características ultrassonográficas do tendão anormal em jogadores de futebol de elite (um estudo piloto)

Abate

Carlo

Cocco³

et al. 2021

Rev Bras Ortop (Sao Paulo)

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Resumo Objetivo Dados experimentais ultrassonográficos sugerem que o estresse oxidativo desempenha um papel importante na patogênese das tendinopatias. No entanto, essa hipótese permanece especulativa em humanos, dado que faltam dados clínicos para comprová-la. Recentemente, uma nova metodologia permitiu quantificar o estresse oxidativo in vivo medindo a concentração de hidroperóxidos de compostos orgânicos, que tem sido utilizada como um marcador relacionado ao estresse oxidativo em várias condições patológicas e fisiológicas. Dada a confiabilidade desse teste e a falta de informação em sujeitos com tendinopatias, o objetivo do presente estudo foi avaliar o status de estresse oxidativo em jogadores profissionais de elite com e sem características ultrassonográficas de dano tendinoso. Métodos Em 73 jogadores de elite foram avaliados parâmetros metabólicos e o estresse oxidativo foi medido por meio de um teste específico (expresso como unidades U-Carr). Por isso, foi realizada uma avaliação ultrassonográfica dos tendões de Aquiles e patelar. Resultados Não foram observadas relações significativas entre parâmetros metabólicos e biomarcadores de estresse oxidativo. Os tendões de Aquiles e patelar mostraram um padrão ecográfico normal em 58 atletas, e anormalidades ultrassonográficas em 15. Os atletas com alterações, em comparação com aqueles com quadro normal, apresentaram níveis significativamente mais elevados de U-Carr (p = 0,000), índice de massa corporal (IMC) (p = 0,03) e eram mais velhos (p = 0,005). A diferença nos valores de U-Carr entre os sujeitos permaneceu significativa também após ajuste por idade e IMC. Conclusão Os resultados deste estudo corroboram a hipótese de que as substâncias oxidativas, também aumentadas a nível sistêmico e não apenas a nível local, podem favorecer danos no tendão. Nível de Evidência IV (estudo piloto).

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Oxidative stress in chronic lymphocytic leukemia: still a matter of debate

Cited by 15 publications

References 80 publications

Ascorbic acid (vitamin C) synergistically enhances the therapeutic effect of targeted therapy in chronic lymphocytic leukemia

Ascorbic acid (vitamin C) synergistically enhances the therapeutic effect of targeted therapy in chronic lymphocytic leukemia

cROSsing the Line: Between Beneficial and Harmful Effects of Reactive Oxygen Species in B-Cell Malignancies

Estresse oxidativo e características ultrassonográficas do tendão anormal em jogadores de futebol de elite (um estudo piloto)

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