Augmenting chemotherapy with low-dose decitabine through an immune-independent mechanism

Gutierrez, Wade R.; Scherer, Amanda; Rytlewski, Jeffrey D.; Laverty, Emily A.; Sheehan, Alexa P.; McGivney, Gavin R.; Brockman, Qierra R.; Knepper-Adrian, Vickie; Roughton, Grace A.; Quelle, Dawn E.; Gordon, David; Monga, Varun; Dodd, Rebecca D.

doi:10.1172/jci.insight.159419

Cited by 4 publications

(1 citation statement)

References 64 publications

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“…Combining busulfan, melphalan, GEM and DAC inhibited lymphoma cell growth. Additionally, a recent study demonstrated that the combination of DAC and GEM inhibited osteosarcoma cell proliferation and retarded tumor growth (Gutierrez et al, 2022). We studied DAC and GEM's in vitro antiproliferative effects on NK92MI.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effect and related mechanism of decitabine combined with gemcitabine on proliferation of NK/T cell lymphoma cells

Lin

Liu²,

Hui³

et al. 2023

Front. Pharmacol.

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Background: EBV-associated lymphoma is a neoplasm with a poor prognosis, highly aggressive, and progressive rapidly. There is no standard clinical treatment protocol. Decitabine and gemcitabine are known to have anticancer properties against cells of various cancer, respectively. However, the effect of the combination medication on NK/T cell lymphoma cells and potential mechanisms have not been thoroughly investigated.Methods: Human NK/T cell lymphoma cells NK92MI were treated with decitabine and gemcitabine alone or in combination. Experiments, including the Cell Counting Kit-8 and flow cytometry, were performed to investigate how the combination of decitabine and gemcitabine affects the biological behavior of NK92MI cells in vitro. mRNA sequencing, RT-PCR, and western blotting were used to detect changes in the related signal pathway, mRNA, and protein expressions.Results: Decitabine and gemcitabine significantly inhibited the viability and proliferation of NK92MI cells in a dose-dependent manner. The combination index was less than 1 after treating with two drugs, which was a significant synergistic effect. The decitabine concentration with the best synergistic effect was 4.046 µM, and the gemcitabine concentration was 0.005 µM. Flow cytometry showed that combining two drugs could significantly promote apoptosis and arrest the cell cycle at the S phase. In the combined DAC and GEM group, caspase3 protein levels were higher than in either group alone or the control group. The transcriptome sequence, KEGG, and PPI analysis showed that the differential genes after combined treatment were mainly enriched in signal pathways related to cell proliferation, adhesion, and migration compared with using alone and control groups. Based on the sequencing results, we further investigated the role of DAC and GEM in ferroptosis-related signaling molecules using RT-PCR and Western blot techniques. RT-PCR and western blotting showed that the expression levels of HMOX1 and EBV cleavage gene BRLF1 were higher in the group with combined DAC and GEM than in the group alone and the control group, while the protein and mRNA expression levels of SLC7A11 were lower than the others. In addition, the GPX4 protein expression level in the combination group was lower than in the drug-alone and control groups. In addition, the combination treatment increased the ROS level of NK92MI cells.Conclusion: Our current findings suggested that decitabine had an inhibitory effect on the proliferation of NK92MI cells when co-treated with gemcitabine. This combination may increase the expression of ferroptosis-related signaling molecules, thus inhibiting the proliferation of NK92MI cells. It also promoted apoptosis in NK/T cell lymphoma. For patients with NK/T cell lymphoma, this novel combination may provide clinical benefits.

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Section: Discussionmentioning

confidence: 99%

Inhibitory effect and related mechanism of decitabine combined with gemcitabine on proliferation of NK/T cell lymphoma cells

Lin

Liu²,

Hui³

et al. 2023

Front. Pharmacol.

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Epigenetic therapy: Research progress of decitabine in the treatment of solid tumors

Ye,

Jiang,

Zheng

et al. 2024

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Rewriting nuclear epigenetic scripts in mitochondrial diseases as a strategy for heteroplasmy control

Pérez,

Colombo,

Real

et al. 2024

Preprint

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Mitochondrial diseases, caused by mutations in either nuclear or mitochondrial DNA (mtDNA), currently have limited treatment options. For mtDNA mutations, reducing mutant-to-wild-type mtDNA ratio (heteroplasmy shift) is a promising therapeutic option, though current approaches face significant challenges. Previous research has shown that severe mitochondrial dysfunction triggers an adaptive nuclear epigenetic response, characterized by changes in DNA methylation, which does not occur or is less important when mitochondrial impairment is subtle. Building on this, we hypothesized that targeting nuclear DNA methylation could selectively compromise cells with high levels of mutant mtDNA, favor ones with lower mutant load and thereby reduce overall heteroplasmy. Using cybrid models harboring two disease-causing mtDNA mutations, m.13513G>A and m.8344A>G, at varying heteroplasmy levels, we discovered that both the mutation type and load distinctly shape the nuclear DNA methylome. We found this methylation pattern to be critical for the survival of high-heteroplasmy cells but not for the low-heteroplasmy ones. Consequently, by disrupting this epigenetic programming with FDA approved DNA methylation inhibitors we managed to selectively impact high-heteroplasmy cybrids and reduce heteroplasmy. These findings were validated in both cultured cells and an in vivo xenograft model. Our study reveals a previously unrecognized role for nuclear DNA methylation in regulating cell survival in the context of mitochondrial heteroplasmy. This insight not only advances our understanding of mitochondrial-nuclear interactions but also introduces epigenetic modulation as a possible therapeutic avenue for mitochondrial diseases.

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Augmenting chemotherapy with low-dose decitabine through an immune-independent mechanism

Cited by 4 publications

References 64 publications

Inhibitory effect and related mechanism of decitabine combined with gemcitabine on proliferation of NK/T cell lymphoma cells

Inhibitory effect and related mechanism of decitabine combined with gemcitabine on proliferation of NK/T cell lymphoma cells

Epigenetic therapy: Research progress of decitabine in the treatment of solid tumors

Rewriting nuclear epigenetic scripts in mitochondrial diseases as a strategy for heteroplasmy control

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