3 research outputs found
The Neuroprotective Role of Nimodipine and nNOS Inhibitor Against Bortezomib-Induced Cell Death in Schwann Cells
Objective. The study was conducted to assess the neuroprotective role of Nimodipine (Nim) and nNOS inhibitor (nNi) against bortezomib (BTZ)-induced cell death in Schwann cells (RT4-D6P2T). Background. Schwann cells (SC) are myelinating cells, known to maintain the integrity and regeneration of neurons in the peripheral nervous system (PNS). Our study was designed to determine the molecular mechanisms involved in the use of neuroprotective agents against bortezomib-induced damage in SC. Methods. In our study, the cell viability of BTZ-treated cells was measured after 24, 48, and 72 h of treatments, followed by neuroprotective studies with Nim and nNi. Reactive oxygen species (ROS) and mitochondrial membrane potential (Δψm) were assessed using DCFDA and JC-1 staining method. Western blot analysis was conducted for measuring phospho-epidermal growth factor receptor (pEGFR), myelin basic protein (MBP), Protein kinase B (AKT) and phospho-Protein kinase B (pAKT) protein levels. Results. BTZ (1 µM) treatment was able to significantly reduce the cell viability after 24 h treatment compared to untreated controls. In addition, pre-treatment with Nim (10 µM) and nNi (1 µM) demonstrated significant upregulation of pAKT levels in BTZ-treated cells, while a significant decrease in MBP expression levels was observed. Interestingly, marginal decrease was observed in Nim and nNi pre-treated cells. Conclusion. Our results indicate that the neuroprotective role of Nim and nNi may be due to upregulation of pAKT and related pathways. Grants. This study was funded by the PFRDG grant 334818 and the financial support from the Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida
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3039 – OXIDIZED 5-METHYLCYTOSINE MODULATES SYNTHETIC LETHALITY TO POLY-ADP-RIBOSE POLYMERASE INHIBITORS IN ACUTE MYELOID LEUKEMIA
TET2 haploinsufficiency is a driving event in myeloid cancers and associated with a worse prognosis in patients with AML. Enhancing residual TET2 activity using vitamin C increases oxidized 5-methylcytosine (oxi-mC) formation and promotes active DNA demethylation via base-excision repair (BER) that slows leukemia progression. We utilized genetic and compound library screening approaches to identify rational combination treatment strategies to improve the use of vitamin C as an adjuvant therapy for AML. In addition to increasing the efficacy of multiple FDA approved drugs, vitamin C treatment with poly-ADP-ribose polymerase inhibitors (PARPi) elicited a strong synergistic effect at blocking AML self-renewal in murine and human models. AML cells treated with a combination of vitamin C and PARPi in vitro led to reduced replating capacity in colony-forming assays, reduced viability in liquid culture, and increased survival upon treatment in vivo. These phenotypes were associated with increased p21 expression, cell-cycle stalling in S-phase and differentiation of AML cells toward a more mature myeloid phenotype. Furthermore, we show that vitamin C-mediated TET activation combined with PARPi causes an enrichment of chromatin-bound PARP1 protein specifically at 5-formylcytosine (5fC) oxi-mCs, and an enrichment for yH2AX at these sites in addition to its accumulation during mid-S phase. This work provides the first proof of PARP1 as a direct reader of 5fC, and enrichment of 5fC at sites marked by yH2AX. The generation of BER-inducing oxi-mCs imparts a novel therapeutic potential of PARPi, which are currently in clinical trial to determine their therapeutic efficacy for AML. Given the majority of AML subtypes maintain residual TET2 expression, vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant to improve treatment outcome
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Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia
TET2 haploinsufficiency is a driving event in myeloid cancers and is associated with a worse prognosis in patients with acute myeloid leukemia (AML). Enhancing residual TET2 activity using vitamin C increases oxidized 5-methylcytosine (mC) formation and promotes active DNA demethylation via base excision repair (BER), which slows leukemia progression. We utilize genetic and compound library screening approaches to identify rational combination treatment strategies to improve use of vitamin C as an adjuvant therapy for AML. In addition to increasing the efficacy of several US Food and Drug Administration (FDA)-approved drugs, vitamin C treatment with poly-ADP-ribosyl polymerase inhibitors (PARPis) elicits a strong synergistic effect to block AML self-renewal in murine and human AML models. Vitamin-C-mediated TET activation combined with PARPis causes enrichment of chromatin-bound PARP1 at oxidized mCs and γH2AX accumulation during mid-S phase, leading to cell cycle stalling and differentiation. Given that most AML subtypes maintain residual TET2 expression, vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant.
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•Vitamin C synergizes with PARPis, causing S phase stalling and AML differentiation•Combination treatment efficacy is dependent on TET2 expression in AML•PARPi treatment with vitamin C causes 5fC accumulation in the genome of AML cells•PARPi treatment with vitamin C enriches for PARP1 binding and γH2AX at 5fC sites
Vitamin C treatment can slow the progression of AML by enhancing TET2 activity but is not curative as a single agent therapy. Using genetic and compound screening approaches, Brabson et al. identify a rational combination treatment strategy where vitamin C enhances the therapeutic efficacy of PARPis for AML treatment