Methotrexate induces DNA damage and inhibits homologous recombination repair in choriocarcinoma cells

Xie, Lisha; Zhao, Tiancen; Cai, Jing; You, Suya; Wang, Zehua; Wu, Dong

doi:10.2147/ott.s116387

Cited by 28 publications

(20 citation statements)

References 31 publications

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“…DHFR catalyzes the reduction of dihydrofolate to tetrahydrofolate, which is indispensable for DNA synthesis. There is also evidence that MTX causes DNA damage in cancer cells, such as oxidative damage and DSBs [46]. Previously, we have shown that MTX induces DNA lesions (DSBs) and senescence in colon cancer cells [47].…”

Section: Discussionmentioning

confidence: 81%

Diversity of the Senescence Phenotype of Cancer Cells Treated with Chemotherapeutic Agents

Bojko

Czarnecka‐Herok

Charzyńska

et al. 2019

Cells

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It is acknowledged that cancer cells are able to undergo senescence in response to clinically used chemotherapeutics. Moreover, recent years have provided evidence that some drugs can selectively remove senescent cells. Therefore, it is essential to properly identify and characterize senescent cells, especially when it comes to cancer. Senescence was induced in various cancer cell lines (A549, SH-SY-5Y, HCT116, MDA-MB-231, and MCF-7) following treatment with doxorubicin, irinotecan, methotrexate, 5-fluorouracil, oxaliplatin, or paclitaxel. Treatment with tested chemotherapeutics resulted in upregulation of p21 and proliferation arrest without cytotoxicity. A comparative analysis with the use of common senescence markers (i.e., morphology, SA-β-galactosidase, granularity, secretory phenotype, and the level of double-stranded DNA damage) revealed a large diversity in response to the chemotherapeutics used. The strongest senescence inducers were doxorubicin, irinotecan, and methotrexate; paclitaxel had an intermediate effect and oxaliplatin and 5-fluorouracil did not induce senescence. In addition, different susceptibility of cancer cells to senescence was observed. A statistical analysis aimed at finding any relationship between the senescence markers applied did not show clear correlations. Moreover, increased SA-β-gal activity coupled with p21 expression proved not to be an unequivocal senescence marker. This points to a need to simultaneously analyze multiple markers, given their individual limitations.

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Section: Discussionmentioning

confidence: 81%

Diversity of the Senescence Phenotype of Cancer Cells Treated with Chemotherapeutic Agents

Bojko

Czarnecka‐Herok

Charzyńska

et al. 2019

Cells

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“…Methotrexate, the third component of the most common chemococktails, is an anti-metabolite folate analog that interferes with the synthesis of purine and pyrimidine bases and, therefore, DNA and RNA synthesis. Of note, the anticancer effect of methotrexate has also been reported to be due to DNA breakage [37]. Thus, it seems that the DNA damage response (DDR) might be the Achilles heel of osteosarcomas.…”

Section: Discussionmentioning

confidence: 99%

Targeting Nuclear NAD+ Synthesis Inhibits DNA Repair, Impairs Metabolic Adaptation and Increases Chemosensitivity of U-2OS Osteosarcoma Cells

Kiss

Ráduly

Regdon

et al. 2020

Cancers

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Osteosarcoma (OS) is the most common bone tumor in children and adolescents. Modern OS treatment, based on the combination of neoadjuvant chemotherapy (cisplatin + doxorubicin + methotrexate) with subsequent surgical removal of the primary tumor and metastases, has dramatically improved overall survival of OS patients. However, further research is needed to identify new therapeutic targets. Here we report that expression level of the nuclear NAD synthesis enzyme, nicotinamide mononucleotide adenylyltransferase-1 (NMNAT1), increases in U-2OS cells upon exposure to DNA damaging agents, suggesting the involvement of the enzyme in the DNA damage response. Moreover, genetic inactivation of NMNAT1 sensitizes U-2OS osteosarcoma cells to cisplatin, doxorubicin, or a combination of these two treatments. Increased cisplatin-induced cell death of NMNAT1−/− cells showed features of both apoptosis and necroptosis, as indicated by the protective effect of the caspase-3 inhibitor z-DEVD-FMK and the necroptosis inhibitor necrostatin-1. Activation of the DNA damage sensor enzyme poly(ADP-ribose) polymerase 1 (PARP1), a major consumer of NAD+ in the nucleus, was fully blocked by NMNAT1 inactivation, leading to increased DNA damage (phospho-H2AX foci). The PARP inhibitor, olaparib, sensitized wild type but not NMNAT1−/− cells to cisplatin-induced anti-clonogenic effects, suggesting that impaired PARP1 activity is important for chemosensitization. Cisplatin-induced cell death of NMNAT1−/− cells was also characterized by a marked drop in cellular ATP levels and impaired mitochondrial respiratory reserve capacity, highlighting the central role of compromised cellular bioenergetics in chemosensitization by NMNAT1 inactivation. Moreover, NMNAT1 cells also displayed markedly higher sensitivity to cisplatin when grown as spheroids in 3D culture. In summary, our work provides the first evidence that NMNAT1 is a promising therapeutic target for osteosarcoma and possibly other tumors as well.

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“…32) In addition, research has shown that PCNA participate in DNA replication. 33) Therefore, the increase of PCNA synthesis may initiate the reproduction of DNA, resulting in cell growth. The result of our study suggested that PTE decreased the expression level of PCNA, indicating that PTE inhibited the reproduction of DNA, ultimately leading to the inhibition of proliferation in RCC cells.…”

Section: Discussionmentioning

confidence: 99%

“…Similar results were observed in colon cancer cells treated with inhibitors of thymidylate synthase and in imatinib-resistant chronic myeloid leukemia cells. 34) Rad51 has become a potential anti-tumor target for chemotherapy. Our study showed that PTE decreased Rad51 in RCC cells, demonstrating that PTE-induced inhibition on Rad51 may result in failure of repaired DNA double strand breaks, contributing to the growth retardation in RCC cells.…”

Section: Discussionmentioning

confidence: 99%

Pterostilbene Inhibits Human Renal Cell Carcinoma Cells Growth and Induces DNA Damage

Zhao

Luo

et al. 2020

Biological & Pharmaceutical Bulletin

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Pterostilbene (PTE) has inhibitory effect on a wide array of tumors. However, the therapeutic potential of PTE in renal cancer cells and the underlying mechanisms have not been evaluated. In this study, the aim is to demonstrate the growth inhibitory and the underlying mechanisms of PTE on human renal cell carcinoma (RCC) cells in vitro. By cell viability, cell morphology and colony formation assays, we found that PTE significantly suppressed the proliferation of RCC cells, while had little toxicity to the normal renal cell line HK-2. Flow cytometry assay revealed that PTE potently induced the apoptosis of RCC cells in a concentration-dependent manner, which was also testified by up-regulation of the pro-apoptosis-related protein (Cyto C, Bad, Bak, Bax, Cleaved-caspase 3, Cleaved-caspase 9, Cleaved-poly(ADP-ribose)polymerase (PARP)) and down-regulation of the anti-apoptosis-related protein Bcl-2. Moreover, cell cycle being arrested in S phase and down-regulation of p-Akt and p-extracellular signal-regulated kinase (ERK)1/2 were observed following treatment with PTE in RCC cells, indicating that PTE exerted remarkable anti-tumor activity in RCC cells possibly via cell cycle arrest and inactivation of Akt and ERK1/2 signaling pathways. Immunofluorescence analysis of γH2AX and detecting the expression levels of γH2AX, proliferating cell nuclear antigen (PCNA) and Rad51 by Western blot showed that PTE induced the DNA damages response in RCC cells. Taken together, the results of the present study demonstrated that PTE was a potential preventive and therapeutic agent for human renal cell carcinoma.

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Methotrexate induces DNA damage and inhibits homologous recombination repair in choriocarcinoma cells

Cited by 28 publications

References 31 publications

Diversity of the Senescence Phenotype of Cancer Cells Treated with Chemotherapeutic Agents

Diversity of the Senescence Phenotype of Cancer Cells Treated with Chemotherapeutic Agents

Targeting Nuclear NAD+ Synthesis Inhibits DNA Repair, Impairs Metabolic Adaptation and Increases Chemosensitivity of U-2OS Osteosarcoma Cells

Pterostilbene Inhibits Human Renal Cell Carcinoma Cells Growth and Induces DNA Damage

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