Dataset Information

All-trans retinoic acid enhances the cytotoxic effect of decitabine on myelodysplastic syndromes and acute myeloid leukaemia by activating the RARα-Nrf2 complex.

ABSTRACT:

Background

Decitabine (DAC) is used as the first-line therapy in patients with higher-risk myelodysplastic syndromes (HR-MDS) and elderly acute myeloid leukaemia (AML) patients unsuitable for intensive chemotherapy. However, the clinical outcomes of patients treated with DAC as a monotherapy are far from satisfactory. Adding all-trans retinoic acid (ATRA) to DAC reportedly benefitted MDS and elderly AML patients. However, the underlying mechanisms remain unclear and need further explorations from laboratory experiments.

Methods

We used MDS and AML cell lines and primary cells to evaluate the combined effects of DAC and ATRA as well as the underlying mechanisms. We used the MOLM-13-luciferase murine xenograft model to verify the enhanced cytotoxic effect of the drug combination.

Results

The combination treatment reduced the viability of MDS/AML cells in vitro, delayed leukaemia progress, and extended survival in murine xenograft models compared to non- and mono-drug treated models. DAC application as a single agent induced Nrf2 activation and downstream antioxidative response, and restrained reactive oxygen species (ROS) generation, thus leading to DAC resistance. The addition of ATRA blocked Nrf2 activation by activating the RARα-Nrf2 complex, leading to ROS accumulation and ROS-dependent cytotoxicity.

Conclusions

These results demonstrate that combining DAC and ATRA has potential for the clinical treatment of HR-MDS/AML and merits further exploration.

SUBMITTER: Wang L

PROVIDER: S-EPMC9938271 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

All-trans retinoic acid enhances the cytotoxic effect of decitabine on myelodysplastic syndromes and acute myeloid leukaemia by activating the RARα-Nrf2 complex.

Wang Lu L Zhang Qi Q Ye Li L Ye Xingnong X Yang Wenli W Zhang Hua H Zhou Xinping X Ren Yanling Y Ma Liya L Zhang Xiang X Mei Chen C Xu Gaixiang G Li Kongfei K Luo Yingwan Y Jiang Lingxu L Lin Peipei P Zhu Shuanghong S Lang Wei W Wang Yuxia Y Shen Chuying C Han Yueyuan Y Liu Xiaozhen X Yang Haiyang H Lu Chenxi C Sun Jie J Jin Jie J Tong Hongyan H

British journal of cancer 20221208 4

<h4>Background</h4>Decitabine (DAC) is used as the first-line therapy in patients with higher-risk myelodysplastic syndromes (HR-MDS) and elderly acute myeloid leukaemia (AML) patients unsuitable for intensive chemotherapy. However, the clinical outcomes of patients treated with DAC as a monotherapy are far from satisfactory. Adding all-trans retinoic acid (ATRA) to DAC reportedly benefitted MDS and elderly AML patients. However, the underlying mechanisms remain unclear and need further explorat ...[more]

PMID: 36482192

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Project description:BackgroundThe molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear.MethodsWe enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols.ResultsOf the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles.ConclusionsPatients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).

Project description:IntroductionThe objective of this study was to evaluate the efficacy and safety of decitabine in Chinese patients with myelodysplastic syndrome (MDS).MethodsPatients (≥18 years) who had a de novo or secondary MDS diagnosis according to French-American-British classification and an International Prognostic Scoring System score ≥0.5 were enrolled and randomized (1:1) to one of two decitabine regimens: 3-day treatment (3-h intravenous infusion of 15 mg/m(2) given every 8 h for three consecutive days/cycle/6 weeks) or 5-day treatment (1-h intravenous infusion of 20 mg/m(2) once daily on days 1-5/cycle/4 weeks). After a minimum of 30 patients were assigned to 3-day schedule, the remaining were assigned to the 5-day schedule. The primary efficacy endpoint was the overall response rate (ORR). Secondary outcome measures included hematologic improvement (HI), cytogenetic response rate, the time to acute myeloid leukemia (AML) progression, and overall survival (OS).ResultsIn total, 132 of 135 enrolled patients (3-day treatment, n = 36; 5-day treatment, n = 99) discontinued treatment (major reasons included patient withdrawal/lack of efficacy, n = 48; adverse events, n = 23; and disease progression, n = 22). During the study, 35 of 132 (26.5%) patients from the intent-to-treat (ITT) group achieved significant (P < 0.001) ORR [3-day group (n = 10, 29.4%), P = 0.003; 5-day group (n = 25, 25.5%), P < 0.001]. The HI rate was similar between the 3-day (47.1%) and 5-day groups (48.0%). Cytogenetic response was achieved in 20 of the 30 (66.7%) patients who had a baseline cytogenetic abnormality. Fifty-three (40.2%) AML transformations or deaths occurred and the median AML-free survival time was 23.8 months for all patients from the ITT set; 24-month OS rate was 48.9%. Adverse events of myelosuppression-related disorders (85.6%) and infections (43.2%) were commonly reported.ConclusionDecitabine treatment was efficacious in Chinese patients with MDS with its safety profile comparable to the global studies of decitabine conducted to date.FundingXian-Janssen Pharmaceutical Ltd. China (a company of Johnson & Johnson).Trial registrationClinicalTrials.gov identifier, NCT01751867.

Dataset Information

All-trans retinoic acid enhances the cytotoxic effect of decitabine on myelodysplastic syndromes and acute myeloid leukaemia by activating the RARα-Nrf2 complex.

Background

Methods

Results

Conclusions

Publications

All-trans retinoic acid enhances the cytotoxic effect of decitabine on myelodysplastic syndromes and acute myeloid leukaemia by activating the RARα-Nrf2 complex.

Similar Datasets

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