Aspirin overcomes cisplatin resistance in lung cancer by inhibiting cancer cell stemness

Zhao, Maoyuan; Wang, Ting; Hui, Zhouguang

doi:10.1111/1759-7714.13619

Cited by 15 publications

(8 citation statements)

References 37 publications

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“…Main functions of NADPH rely on variety of dehydrogenases [ 55 , 56 ]. We prove that decreased NADPH oxidase-mediated ROS may account for cisplatin resistance of NSCLC based on a published dataset [ 57 ]. Besides the maintenance of NADPH, the glutathione metabolism system is also dysregulated after APR-246 treatment.…”

Section: Discussionmentioning

confidence: 68%

Aberrant ROS Served as an Acquired Vulnerability of Cisplatin-Resistant Lung Cancer

Qian

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Lung cancer has become a global health issue in recent decades. Approximately 80-85% of cases are non-small-cell lung cancer (NSCLC). Despite the high rate of resistance, cisplatin-base chemotherapy is still the main treatment for NSCLC patients. Thus, overcoming cisplatin resistance is urgently needed in NSCLC therapy. In this study, we identify NADPH metabolism and reactive oxygen species (ROS) levels as the main causes accounting for cisplatin resistance. Based on a small panel consisting of common chemotherapy drugs or compounds, APR-246 is proved to be an effective compound targeting cisplatin-resistant NSCLC cells. APR-246 specially inhibits proliferation and colony formation of cisplatin-resistant cells. In details, APR-246 can significantly cause G0/G1 accumulation and S phase arrest of cisplatin resistant cells and gives rise to severe mitochondria dysfunction as well as elevated apoptosis. Further study proves that it is the aberrant ROS levels as well as NRF2/SLC7A11/GSH axis dysfunction accounting for the specific antitumor effects of APR-246. Scavenging ROS with N-acetylcysteine (NAC) disrupts the inhibitory effect of APR-246 on cisplatin-resistant cells. Mechanistically, NRF2 is specifically degraded by the proteasome following its own ubiquitylation in APR-246-treated cisplatin-resistant cells, which in turn decreases NRF2/SLC7A11/GSH axis activity. Our study provides new insights into the biology driving cisplatin resistance of lung cancer and highlights APR-246 as a potential therapeutic reagent for overcoming cisplatin resistance.

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Section: Discussionmentioning

confidence: 68%

Aberrant ROS Served as an Acquired Vulnerability of Cisplatin-Resistant Lung Cancer

Qian

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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show abstract

“…Main functions of NADPH are served by a variety of dehydrogenases (48,49). We prove that decreased NADPH oxidase-mediated ROS may account for cisplatin resistance of NSCLC based on a published dataset (50). Besides to maintenance of NADPH, the glutathione metabolism system is also dysregulated after APR-246 treatment.…”

Section: Discussionmentioning

confidence: 68%

Aberrant ROS Served as an Acquired Vulnerability of Cisplatin-resistant Lung Cancer

Qian¹,

Ji²,

Zhang³

et al. 2021

Preprint

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BackgroundLung cancer has become a global health issue in recent decades. Despite of high rate of resistance, cisplatin-base chemotherapy is still the main treatment of lung cancer patients who are not suitable for TKI-based targeted therapy and immunotherapy. Thus, overcoming cisplatin resistance is urgently needed.MethodsA small panel is established to screen chemicals and compounds overcoming cisplatin resistance. Survival fractions as well as proliferation are determined by MTT assay. Colony formation assay, JC-1 assay, EdU assay, ROS assay as well as apoptosis and cell cycle assay are performed to verify vitalities of different groups. Quantifications of NADP+/NADPH and GSH/GSSG are carried out according to standard protocols. Xenograft model is generated to evaluate the in vivo role of APR-246.ResultsIn this study, we identify NADPH metabolism and reactive oxygen species (ROS) levels as the main cause accounting for cisplatin resistance of H460. Based on a small panel consisting common chemotherapy drugs and compounds, APR-246 is proved an effective compound specifically inhibiting proliferation and colony formation of cisplatin resistant H460 (H460-Cis) cells. APR-246 significantly causes G0/G1 accumulation and S phase inhibition of H460-Cis cells. Besides, APR-246 can obviously lead to severe mitochondria dysfunction as well as elevated apoptosis by altering apoptosis-related protein expressions in H460-Cis cells. Further study proves that it is the aberrant ROS levels as well as NRF2/SLC7A11/GSH axis dysfunction accounting for the specific anti-tumor effects of APR-246. Mechanistically, NRF2 is specifically ubiquitylated degraded in APR-246 treated H460-Cis cells, which in turn decrease NRF2/SLC7A11/GSH axis activity.ConclusionOur study uncovered new insights into the biology driving cisplatin resistance of lung cancer and highlights potentials of APR-246 as future therapeutic agents again cisplatin resistance.

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“…Further experiments in vitro showed that ASA with 4-OHT could significantly inhibit the proliferation of tamoxifen resistance cells. Studies on the reversal of drug resistance of other tumors by ASA showed that cisplatin plus ASA significantly reduced the survival rate of cisplatin-resistant tumor cells, and ASA could inhibit the expression of tumor cell-related proteins, such as ALDH1, CD44, CD133, and P53 [34,35]. ASA reduced the growth and invasion of pancreatic ductal adenocarcinoma and significantly enhanced the therapeutic effect of gemcitabine.…”

Section: Discussionmentioning

confidence: 99%

Research on Clinical Effectiveness of Aspirin for Treating Breast Cancer and Cell Protein Biomarkers on Aspirin Treatment in Drug-Resistant Estrogen Receptor-Positive Breast Cancer Cells

Cui¹,

Li²,

Pang³

et al. 2022

Oncologie

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Background: Aspirin (ASA) has been reported to have an antitumor effect but the role of ASA in the prevention and treatment of breast cancer (BC) is still controversial. This study aimed to identify clinical effectiveness of ASA in the treatment of BC and explore the antitumor target proteins of ASA that may be involved in overcoming tamoxifen resistance in estrogen receptor (ER)-positive BC cells. Materials and Methods: Randomized controlled trials (RCTs) of ASA in the treatment of BC were queried from the databases, including PubMed, Web of Science, Cochrane Library, WanFang, and Chinese National Knowledge Infrastructure. According to the quality standard recommended in the Newcastle-Ottawa Scale (NOS), the outcome indexes were analyzed by RevMan 5.3 and Stata 12.0 software. Cell culture experiments were performed to explore the effect of tamoxifen combined with ASA on the proliferation of ER-positive BC cell lines MCF-7 and MCF-7/TAM. Cell cytotoxicity was determined by the 3-(4, 5-di-2-yl)-2, 5-ditetrazolium bromide (MTT) assay. A quantitative proteomic analysis was conducted between the control and experimental groups to identify differentially expressed proteins (DEPs). Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used for bioinformatic analysis of DEPs. The protein expression in patients of ER-positive BC was analyzed by immunochemistry (IHC). Results: Nine RCTs including 162,381 patients were selected for this study. The meta-analysis revealed that daily ASA use, as compared with its non-use, was associated with a decreased risk of BC death: relative risk (RR) = 0.83%, 95% CI [0.73, 0.94], Z = 2.89, P = 0.004 (P < 0.05). Cell culture experiments showed that tamoxifen combined with ASA can drastically inhibit the cell growth of MCF-7 and MCF-7/TAM cells more than the administration of tamoxifen alone (P < 0.05). Fifty-seven DEPs were up-regulated, while eighty-five DEPs were down-regulated in MCF-7/TAM cells after the ASA combination treatment. Several GO terms were significantly enriched, such as neutrophil degranulation, retinal metabolic process, sterol biosynthetic process, and prostaglandin metabolic process. KEGG pathway enrichment analysis also verified three associated pathways including metabolic pathways, chemical carcinogenesis-reactive oxygen species, and biosynthesis of amino acids. In ER-positive BC patients with Ki67 > 20%, the positive expression of one significantly DEP MYC was much higher than in BC patients with Ki67 ≤ 20% (40.91% vs. 12.50%, P < 0.05). There was no significant difference in MYC protein expression among the other subgroups (P > 0.05). Conclusions: Our results show that ASA has a clinical value in the treatment of BC. ASA could overcome tamoxifen resistance in ER-positive BC cells through some key proteins, which may be potential therapeutic targets for patients with tamoxifen resistance.

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Aspirin overcomes cisplatin resistance in lung cancer by inhibiting cancer cell stemness

Cited by 15 publications

References 37 publications

Aberrant ROS Served as an Acquired Vulnerability of Cisplatin-Resistant Lung Cancer

Aberrant ROS Served as an Acquired Vulnerability of Cisplatin-Resistant Lung Cancer

Aberrant ROS Served as an Acquired Vulnerability of Cisplatin-resistant Lung Cancer

Research on Clinical Effectiveness of Aspirin for Treating Breast Cancer and Cell Protein Biomarkers on Aspirin Treatment in Drug-Resistant Estrogen Receptor-Positive Breast Cancer Cells

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Aspirin overcomes cisplatin resistance in lung cancer by inhibiting cancer cell stemness

Cited by 15 publications

References 37 publications

Aberrant ROS Served as an Acquired Vulnerability of Cisplatin-Resistant Lung Cancer

Aberrant ROS Served as an Acquired Vulnerability of Cisplatin-Resistant Lung Cancer

Aberrant ROS&nbsp;Served as an Acquired Vulnerability of Cisplatin-resistant Lung Cancer

Research on Clinical Effectiveness of Aspirin for Treating Breast Cancer and Cell Protein Biomarkers on Aspirin Treatment in Drug-Resistant Estrogen Receptor-Positive Breast Cancer Cells

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Aberrant ROS Served as an Acquired Vulnerability of Cisplatin-resistant Lung Cancer