Epigenetic modification enhances the cytotoxicity of busulfan and4-hydroperoxycyclophosphamide in AML cells

Valdez, Benigno C.; Tang, Xiaowen; Yang, Li; Murray, David; Liu, Yan; Popat, Uday; Champlin, Richard E.; Andersson, Börje S.

doi:10.1016/j.exphem.2018.08.002

Cited by 9 publications

(6 citation statements)

References 44 publications

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“…Similar effects were observed in leukemic blast cells isolated from peripheral blood of leukemia patients, suggesting a generally enhanced anticancer efficacy of the [Bu+4HC+ABT199] and [Bu+Flu+ABT199] combinations. The cytotoxicity of the two-drug combinations [Bu+4HC] and [Bu+Flu] is primarily mediated by drug-induced DNA damage resulting in CASPASE 3 activation, as we previously reported [17,41]. The synergistic potentiation of the effects of these two-drug combinations by ABT199/ venetoclax is partly due to CASPASE 3-mediated cleavages of MEK1/2 and MCL1.…”

Section: Discussionmentioning

confidence: 63%

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ABT199/venetoclax potentiates the cytotoxicity of alkylating agents and fludarabine in acute myeloid leukemia cells

et al. 2022

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The antineoplastic activity of pre-transplant regimens in hematopoietic stem cell transplantation (HSCT) is a critical factor for acute myeloid leukemia (AML) patients. There is an urgent need to identify novel approaches without jeopardizing patient safety. We hypothesized that combination of drugs with different mechanisms of action would provide better cytotoxicity. We, therefore, determined the synergistic cytotoxicity of various combinations of the alkylating agents busulfan (Bu) and 4-hydroperoxycyclophosphamide (4HC), the nucleoside analog fludarabine (Flu) and the BCL2 inhibitor ABT199/venetoclax in AML cells. [Bu+4HC] and [Bu+Flu] inhibited cell proliferation and activated apoptosis; addition of ABT199 to either combinations significantly increased these effects with combination indexes < 1. Apoptosis is suggested by cleavages of PARP1 and CASPASE 3, DNA fragmentation, increased reactive oxygen species, decreased mitochondrial membrane potential, and increased proapoptotic proteins in the cytoplasm. A similar enhancement of apoptosis was observed in patient-derived cell samples. ABT199/venetocalx upregulated anti-apoptotic MCL1 as a compensatory mechanism but addition of [Bu+4HC] or [Bu+Flu] negated this effect by CASPASE 3-mediated cleavage of MEK1/2 and its substrate MCL1. CASPASE 3 caused cleavage of pro-survival β-CATENIN, which likely contributed to the activation of stress signaling pathways involving SAPK/JNK and AMPK. The observed synergistic cytotoxicity was associated with an inhibition of pro-survival pathways involving STAT1, STAT5 and PI3K. These findings will be useful in designing clinical trials using these drug combinations as pre-transplant conditioning regimens for AML patients.

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Section: Discussionmentioning

confidence: 63%

“…The cytotoxicity of drugs alone or in combination was determined as previously described using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay [17]. Cell proliferation was determined relative to control cells exposed to solvent alone.…”

Section: Drug Cytotoxicity Assaysmentioning

confidence: 99%

ABT199/venetoclax potentiates the cytotoxicity of alkylating agents and fludarabine in acute myeloid leukemia cells

et al. 2022

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“…They explained this sensitizing effect may owing to the molecular interactions between DNA alkylation and epigenetic modification events. Therefore, we can speculate that transplantation with a Dec-containing preconditioning regimen may further increase the depth of remission by chemotherapy synergy ( 37 ) and enhance the GVL effect ( 18 , 38 – 40 ) on the basis of Dec sensitization, which needs to be confirmed by further studies.…”

Section: Discussionmentioning

confidence: 97%

Allogeneic haematopoietic stem cell transplantation with decitabine-containing preconditioning regimen in TP53-mutant myelodysplastic syndromes: A case study

et al. 2022

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Myelodysplastic syndrome (MDS) with TP53 mutations has a poor prognosis after transplantation, and novel therapeutic means are urgently needed. Decitabine (Dec) monotherapy has demonstrated improved overall response rates in MDS and acute myeloid leukaemia, although these responses were not durable. This study aimed to preliminary evaluate the efficacy of a Dec-containing allogeneic haematopoietic stem cell transplantation (allo-HSCT) preconditioning regimen in TP53-mutant MDS. Nine patients with TP53-mutant myelodysplastic syndromes received the decitabine-containing preconditioning regimen and subsequent myeloablative allo-HCT between April 2013 and September 2021 in different centres. At a median follow-up of 42 months (range, 5 to 61 months), the overall survival (OS) was 89% (8/9), progression-free survival (PFS) was 89% (8/9), and relapse incidence was 11.1%. The incidence of severe acute (grade III-IV) graft-versus-host disease (GVHD) was 22.2% (2/9) and that of chronic moderate-to-severe GVHD was 11.1% (1/9). The 1-year GVHD-free/relapse-free survival (GRFS) was 56% (5/9). In conclusion, we found real-world clinical data that supports the use of a Dec-containing preconditioning regimen before allo-HSCT for possible improved outcomes in TP53-mutant MDS patients; there is therefore an urgent call for an in-depth exploration of the involved mechanism to confirm these preliminary findings.

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“…It had been reported that DAC can upregulate tumor-specific antigens ( 7 ), increase the expansion of cytotoxic immune cells including CAR-T cells ( 7 ), prevent T-cell exhaustion ( 15 ), induce cell death through DNA damage-mediated G2/M or S phase arrest ( 16 ) and inhibit GVHD and enhancement of graft-versus-leukemia/lymphoma (GVL) effects after allo-HSCT ( 6 ). In our previous study, we found that additional DAC application may improve the outcome of CAR-T therapy in a high-risk population of R/R acute leukemia patients with TP53 alterations.…”

Section: Discussionmentioning

confidence: 99%

Decitabine-primed tandem CD19/CD22 CAR-T therapy in relapsed/refractory diffuse large B-cell lymphoma patients

Zou

Wang

et al. 2022

Front. Immunol.

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Chimeric antigen receptor T cell (CAR-T) therapy has emerged as highly effective in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but only about 40% patients have achieved sustained responses. Here, we conducted a phase II clinical trial testing efficacy and toxicities of CAR-T therapy in R/R non-Hodgkin’s lymphoma patients (NCT03196830). Among enrolled patients, 33 R/R DLBCL patients pretreated with DFC (decitabine, fludarabine plus cyclophosphamide) lymphodepletion chemotherapy and infused with tandem CD19-CD22 based CAR-T cells were drawn out for efficacy and toxicities of CAR-T therapy evaluation. With a median follow-up of 10.9(0.6-29.0) months, the best overall response and complete remission (CR) rates were 90.9% and 63.6%, respectively. The median progression-free survival (PFS) was 10.2 months and overall survival (OS) was undefined. The 2-year OS and PFS rates were 54.3% and 47.2%, respectively. No severe grade 4 cytokine release syndrome (CRS) was observed and grade 3 CRS was observed in only 7 patients; 3 patients developed mild immune effect or cell-associated neurotoxic syndrome. All toxicities were transient and reversible and no CAR-T-related mortality. Further subgroup analysis showed that achieving CR was an independent prognostic factor associated with favorable PFS and OS. The 2-year OS and PFS for patients who achieved CR within 3 months (undefined versus undefined P=0.021 and undefined versus undefined P=0.036) or during the follow-up period were significantly longer than those who did not (undefined versus 4.6 months P < 0.0001 and undefined versus 2.0months P<0.001). While severe CRS was also an independent prognostic factor but associated with inferior PFS and OS. The 2-year OS and PFS for patients with grade 3 CRS were significantly shorter than those with grade 0-2 CRS (4.1 months versus undefined P<0.0001 and 1.7 months versus undefined P=0.0002). This study indicated that CD19/CD22 dual-targeted CAR-T therapy under a decitabine-containing lymphodepletion regimen may be a safe, potent effective approach to R/R DLBCL patients.

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Epigenetic modification enhances the cytotoxicity of busulfan and4-hydroperoxycyclophosphamide in AML cells

Cited by 9 publications

References 44 publications

ABT199/venetoclax potentiates the cytotoxicity of alkylating agents and fludarabine in acute myeloid leukemia cells

ABT199/venetoclax potentiates the cytotoxicity of alkylating agents and fludarabine in acute myeloid leukemia cells

Allogeneic haematopoietic stem cell transplantation with decitabine-containing preconditioning regimen in TP53-mutant myelodysplastic syndromes: A case study

Decitabine-primed tandem CD19/CD22 CAR-T therapy in relapsed/refractory diffuse large B-cell lymphoma patients

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