Oxidative Stress and Response to Thymidylate Synthase-Targeted Antimetabolites

Özer, Ufuk; Barbour, Karen W.; Clinton, Sarah A.; Berger, Franklin G.

doi:10.1124/mol.115.099614

Cited by 23 publications

(12 citation statements)

References 36 publications

(81 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, the inhibition of TS by TS inhibitors has also been shown to increase the intracellular level of ROS. 43 To explore whether pemetrexed-mediated TS inhibition could increase the intracellular level of ROS and result in the activation of NF-κB signaling pathway, we detected intracellular levels of ROS in CL1-5 and CL141 cells on the inhibition of TS. As expected, we found that intracellular levels of ROS were significantly elevated on inhibition of TS by either pemetrexed or TS knockdown ( figure 6A, B ).…”

Section: Resultsmentioning

confidence: 99%

Antimetabolite pemetrexed primes a favorable tumor microenvironment for immune checkpoint blockade therapy

Lin

Chang

et al. 2020

J Immunother Cancer

View full text Add to dashboard Cite

BackgroundThe immune checkpoint blockade (ICB) targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) has been proved beneficial for numerous types of cancers, including non-small-cell lung cancer (NSCLC). However, a significant number of patients with NSCLC still fail to respond to ICB due to unfavorable tumor microenvironment. To improve the efficacy, the immune-chemotherapy combination with pemetrexed, cis/carboplatin and pembrolizumab (anti-PD-1) has been recently approved as first-line treatment in advanced NSCLCs. While chemotherapeutic agents exert beneficial effects, the underlying antitumor mechanism(s) remains unclear.MethodsPemetrexed, cisplatin and other chemotherapeutic agents were tested for the potential to induce PD-L1 expression in NSCLC cells by immunoblotting and flow cytometry. The ability to prime the tumor immune microenvironment was then determined by NSCLC/T cell coculture systems and syngeneic mouse models. Subpopulations of NSCLC cells responding differently to pemetrexed were selected and subjected to RNA-sequencing analysis. The key signaling pathways were identified and validated in vitro and in vivo.ResultsPemetrexed induced the transcriptional activation of PD-L1 (encoded by CD274) by inactivating thymidylate synthase (TS) in NSCLC cells and, in turn, activating T-lymphocytes when combined with the anti-PD-1/PD-L1 therapy. Nuclear factor κB (NF-κB) signaling was activated by intracellular reactive oxygen species (ROSs) that were elevated by pemetrexed-mediated TS inactivation. The TS−ROS−NF-κB regulatory axis actively involves in pemetrexed-induced PD-L1 upregulation, whereas when pemetrexed fails to induce PD-L1 expression in NSCLC cells, NF-κB signaling is unregulated. In syngeneic mouse models, the combinatory treatment of pemetrexed with anti-PD-L1 antibody created a more favorable tumor microenvironment for the inhibition of tumor growth.ConclusionsOur findings reveal novel mechanisms showing that pemetrexed upregulates PD-L1 expression and primes a favorable microenvironment for ICB, which provides a mechanistic basis for the combinatory chemoimmunotherapy in NSCLC treatment.

show abstract

Section: Resultsmentioning

confidence: 99%

Antimetabolite pemetrexed primes a favorable tumor microenvironment for immune checkpoint blockade therapy

Lin

Chang

et al. 2020

J Immunother Cancer

View full text Add to dashboard Cite

show abstract

“…For these genes, a second hit did not lead to further downregulation, indicating that there is likely a threshold for their permanent downregulation. TYMS downregulation has been found to increase oxidative stress production as well as activate protective pathways in multiple cancer lines (Ozer et al 2015 ; Xu et al 2017 ) but has not been extensively studied in neurons.…”

Section: Discussionmentioning

confidence: 99%

Toxicity, recovery, and resilience in a 3D dopaminergic neuronal in vitro model exposed to rotenone

et al. 2018

View full text Add to dashboard Cite

To date, most in vitro toxicity testing has focused on acute effects of compounds at high concentrations. This testing strategy does not reflect real-life exposures, which might contribute to long-term disease outcome. We used a 3D-human dopaminergic in vitro LUHMES cell line model to determine whether effects of short-term rotenone exposure (100 nM, 24 h) are permanent or reversible. A decrease in complex I activity, ATP, mitochondrial diameter, and neurite outgrowth were observed acutely. After compound removal, complex I activity was still inhibited; however, ATP levels were increased, cells were electrically active and aggregates restored neurite outgrowth integrity and mitochondrial morphology. We identified significant transcriptomic changes after 24 h which were not present 7 days after wash-out. Our results suggest that testing short-term exposures in vitro may capture many acute effects which cells can overcome, missing adaptive processes, and long-term mechanisms. In addition, to study cellular resilience, cells were re-exposed to rotenone after wash-out and recovery period. Pre-exposed cells maintained higher metabolic activity than controls and presented a different expression pattern in genes previously shown to be altered by rotenone. NEF2L2, ATF4, and EAAC1 were downregulated upon single hit on day 14, but unchanged in pre-exposed aggregates. DAT and CASP3 were only altered after re-exposure to rotenone, while TYMS and MLF1IP were downregulated in both single-exposed and pre-exposed aggregates. In summary, our study shows that a human cell-based 3D model can be used to assess cellular adaptation, resilience, and long-term mechanisms relevant to neurodegenerative research.Electronic supplementary materialThe online version of this article (10.1007/s00204-018-2250-8) contains supplementary material, which is available to authorized users.

show abstract

“…In particular, chemotherapy drugs are responsible for an excessive production of radical oxygen species (ROS) and inflammatory mediators that trigger pathological mechanisms of cell damage, altering the normal physiological parameters of the cells [ 18 , 19 ]. In particular, ROS levels are also increased after 5-FU treatment and its induction is also critical to promote both inflammation and drug-mediated apoptotic cell death [ 20 ]. Therefore, inhibiting or limiting ROS production and inflammation may help in the treatment of dermatitis in cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Protective Effect of Pomegranate on Oxidative Stress and Inflammatory Response Induced by 5-Fluorouracil in Human Keratinocytes

et al. 2021

View full text Add to dashboard Cite

5-Fluorouracil (5-FU) is a pyrimidine analogue used as an antineoplastic agent to treat multiple solid tumors. Despite its use and efficacy, it also has important side effects in healthy cells, including skin reactions, related to its pro-oxidant and pro-inflammatory potential. Although there are numerous remedies for chemotherapy-induced skin reactions, the efficacy of these treatments remains limited. In this study we focused on the effects of pomegranate (Punica granatum L.) juice extract (PPJE) on the oxidative and inflammatory state in 5-FU-treated human skin keratinocytes (HaCaT). The obtained results showed that PPJE significantly inhibited reactive oxygen species release and increased the cellular antioxidant response, as indicated by the increased expression of cytoprotective enzymes, such as heme oxygenase-1 and NAD(P)H dehydrogenase [quinone] 1. In these experimental conditions, PPJE also inhibited nitrotyrosine formation and 5-FU-induced inflammatory response, as indicated by the reduced cytokine level release. Moreover, PPJE inhibited nuclear translocation of p65-NF-κB, a key factor regulating the inflammatory response. In 5-FU-treated HaCaT cells PPJE also inhibited apoptosis and promoted wound repair. These results suggest a potential use of PPJE as an adjuvant in the treatment of the oxidative and inflammatory state that characterizes chemotherapy-induced skin side effects.

show abstract

Oxidative Stress and Response to Thymidylate Synthase-Targeted Antimetabolites

Cited by 23 publications

References 36 publications

Antimetabolite pemetrexed primes a favorable tumor microenvironment for immune checkpoint blockade therapy

Antimetabolite pemetrexed primes a favorable tumor microenvironment for immune checkpoint blockade therapy

Toxicity, recovery, and resilience in a 3D dopaminergic neuronal in vitro model exposed to rotenone

Protective Effect of Pomegranate on Oxidative Stress and Inflammatory Response Induced by 5-Fluorouracil in Human Keratinocytes

Contact Info

Product

Resources

About