Cisplatin-resistant A549 non-small cell lung cancer cells can be identified by increased mitochondrial mass and are sensitive to pemetrexed treatment

Gao, Yanyun; Dorn, Patrick; Liu, Shengchen; Deng, Haibin; Hall, Sean; Peng, Ren‐Wang; Schmid, Ralph A.; Marti, Thomas

doi:10.1186/s12935-019-1037-1

Cited by 25 publications

(23 citation statements)

References 43 publications

(57 reference statements)

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“…In detail, targeting mitochondrial energetics and metabolism overcame drug resistance in acute myeloid leukemia (AML) [ 15 , 16 ]. In lung cancer, high mitochondrial activity is related to chemotherapy resistance [ 17 , 18 ]. Thus, aberrant mitochondrial metabolism might prove to be the Achilles heel of chemotherapy-resistant cancer cells.…”

Section: Introductionmentioning

confidence: 99%

“…In replicating cancer cells, blocked thymidine synthesis leads to nucleotide pool imbalance, which subsequently leads to DNA replication errors and activation of the DNA damage response machinery, and, if not repaired, to cell death (reviewed in [ 28 ]). Indeed, we previously showed that blocking nucleotide synthesis by MTA treatment results in the accumulation of persistent DNA damage [ 18 , 29 ]. Further, we found that prolonged pretreatment with MTA enhances the anticancer efficacy of subsequent cisplatin treatment [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

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Chemotherapy-induced CDA expression renders resistant non-small cell lung cancer cells sensitive to 5′-deoxy-5-fluorocytidine (5′-DFCR)

Gao

Zens

et al. 2021

J Exp Clin Cancer Res

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Background Pemetrexed (MTA) plus cisplatin combination therapy is considered the standard of care for patients with advanced non-small-cell lung cancer (NSCLC). However, in advanced NSCLC, the 5-year survival rate is below 10%, mainly due to resistance to therapy. We have previously shown that the fraction of mesenchymal-like, chemotherapy-resistant paraclone cells increased after MTA and cisplatin combination therapy in the NSCLC cell line A549. Cytidine deaminase (CDA) and thymidine phosphorylase (TYMP) are key enzymes of the pyrimidine salvage pathway. 5′-deoxy-5-fluorocytidine (5′-DFCR) is a cytidine analogue (metabolite of capecitabine), which is converted by CDA and subsequently by TYMP into 5-fluorouracil, a chemotherapeutic agent frequently used to treat solid tumors. The aim of this study was to identify and exploit chemotherapy-induced metabolic adaptations to target resistant cancer cells. Methods Cell viability and colony formation assays were used to quantify the efficacy of MTA and cisplatin treatment in combination with schedule-dependent addition of 5′-DFCR on growth and survival of A549 paraclone cells and NSCLC cell lines. CDA and TYMP protein expression were monitored by Western blot. Finally, flow cytometry was used to analyze the EMT phenotype, DNA damage response activation and cell cycle distribution over time after treatment. CDA expression was measured by immunohistochemistry in tumor tissues of patients before and after neoadjuvant chemotherapy. Results We performed a small-scale screen of mitochondrial metabolism inhibitors, which revealed that 5′-DFCR selectively targets chemotherapy-resistant A549 paraclone cells characterized by high CDA and TYMP expression. In the cell line A549, CDA and TYMP expression was further increased by chemotherapy in a time-dependent manner, which was also observed in the KRAS-addicted NSCLC cell lines H358 and H411. The addition of 5′-DFCR on the second day after MTA and cisplatin combination therapy was the most efficient treatment to eradicate chemotherapy-resistant NSCLC cells. Moreover, recovery from treatment-induced DNA damage was delayed and accompanied by senescence induction and acquisition of a hybrid-EMT phenotype. In a subset of patient tumors, CDA expression was also increased after treatment with neoadjuvant chemotherapy. Conclusions Chemotherapy increases CDA and TYMP expression thereby rendering resistant lung cancer cells susceptible to subsequent 5′-DFCR treatment.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chemotherapy-induced CDA expression renders resistant non-small cell lung cancer cells sensitive to 5′-deoxy-5-fluorocytidine (5′-DFCR)

Gao

Zens

et al. 2021

J Exp Clin Cancer Res

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“…Stained cells were analyzed by flow cytometry (Attune cytometry, BD biosciences). Cisplatin 80 μM was used as a positive control [32,33].…”

Section: Active Caspase 3 Assaymentioning

confidence: 99%

Damage-associated molecular patterns (DAMPs) related to immunogenic cell death are differentially triggered by clinically relevant chemotherapeutics in lung adenocarcinoma cells

et al. 2020

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Background: Chemotherapeutics can stimulate immune antitumor response by inducing immunogenic cell death (ICD), which is activated by Damage-Associated Molecular Patterns (DAMPs) like the exposure of calreticulin (CRT) on the cell surface, the release of ATP and the secretion of High Mobility Group Box 1 (HMGB1). Methods: Here, we investigated the levels of ICD-associated DAMPs induced by chemotherapeutics commonly used in the clinical practice of non-small cell lung cancer (NSCLC) and the association of these DAMPs with apoptosis and autophagy. A549 human lung adenocarcinoma cells were treated with clinically relevant doses of cisplatin, carboplatin, etoposide, paclitaxel and gemcitabine. We assessed ICD-associated DAMPs, cell viability, apoptosis and autophagy in an integrated way. Results: Cisplatin and its combination with etoposide induced the highest levels of apoptosis, while etoposide was the less pro-apoptotic treatment. Cisplatin also induced the highest levels of ICD-associated DAMPs, which was not incremented by co-treatments. Etoposide induced the lower levels of ICD and the highest levels of autophagy, suggesting that the cytoprotective role of autophagy is dominant in relation to its pro-ICD role. High levels of CRT were associated with better prognosis in TCGA databank. In an integrative analysis we found a strong positive correlation between DAMPs and apoptosis, and a negative correlation between cell number and ICD-associated DAMPs as well as between autophagy and apoptosis markers. We also purpose a mathematical integration of ICDassociated DAMPs in an index (IndImunnog) that may represent with greater biological relevance this process. Cisplatin-treated cells showed the highest IndImmunog, while etoposide was the less immunogenic and the more pro-autophagic treatment.

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“…We utilized the well-established SRB cell viability assay [4,5] to determine the inhibitory effect of RO 48-8071 on drug-resistant colon, lung and pancreatic cells of aggressive nature [6][7][8][9][10][11][12]. The SRB assay quantitates protein content of surviving cells as an index of cell growth and viability, as described in our previous publications [1,2,13].…”

Section: Cell Viability Assaymentioning

confidence: 99%

Cholesterol biosynthesis inhibitor RO 48-8071 inhibits viability of aggressive cancer cells

Liang¹,

Zou²,

Hyder³

2020

Cancer Rep Rev

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Background: propen-1-ylamino)hexyl]oxy]phenyl]methanone) (RO) is a cholesterol lowering drug that targets oxidosqualene cyclase in the cholesterol biosynthesis pathway. We recently reported anti-cancer properties for RO in breast and prostate cancer cells. Methods:The present study describes that RO 48-8071 is also an effective agent against aggressive drug-resistant colon, pancreas and lung cancer cells. We examined whether RO could inhibit the growth of cancer cells in vitro using a well-established cell viability assay in a short time frame (24-48 h).Results: Treatment of 7 different aggressive cancer cell lines with RO for 48 h significantly reduced their viability (IC50 range 3.3 to 13.68 µM). Conclusion:As reported earlier, a long term-assay (5-7 days) showed that nM levels of RO also effectively reduced the viability of breast and prostate cancer cells, though this remains to be investigated for the cell lines reported here. RO warrants further investigation as an effective anti-cancer compound.

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Cisplatin-resistant A549 non-small cell lung cancer cells can be identified by increased mitochondrial mass and are sensitive to pemetrexed treatment

Cited by 25 publications

References 43 publications

Chemotherapy-induced CDA expression renders resistant non-small cell lung cancer cells sensitive to 5′-deoxy-5-fluorocytidine (5′-DFCR)

Chemotherapy-induced CDA expression renders resistant non-small cell lung cancer cells sensitive to 5′-deoxy-5-fluorocytidine (5′-DFCR)

Damage-associated molecular patterns (DAMPs) related to immunogenic cell death are differentially triggered by clinically relevant chemotherapeutics in lung adenocarcinoma cells

Cholesterol biosynthesis inhibitor RO 48-8071 inhibits viability of aggressive cancer cells

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