scholarly journals Lactate Upregulates the Expression of DNA Repair Genes, Causing Intrinsic Resistance of Cancer Cells to Cisplatin

2021 ◽  
Vol 27 ◽  
Author(s):  
Marzia Govoni ◽  
Valentina Rossi ◽  
Giuseppina Di Stefano ◽  
Marcella Manerba
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Cellular Response ◽  
Regulation Of Gene Expression ◽  
Dna Recombination ◽  
Chemotherapeutic Agents ◽  
Glycolytic Metabolism ◽  
Intrinsic Resistance ◽  
The Impact

Intrinsic or acquired drug resistance is one of the major problems compromising the success of antineoplastic treatments. Several evidences correlated some therapeutic failures with changes in cell metabolic asset and in line with these findings, hindering the glycolytic metabolism of cancer cells via lactate dehydrogenase (LDH) inhibition was found to overcome the resistance to chemotherapeutic agents. Lactate, the product of LDH reaction, was shown to be involved in epigenetic regulation of gene expression. The experiments described in this paper were aimed at highlighting a possible direct effect of lactate in modifying the response of cancer cells to a chemotherapeutic treatment. To discriminate between the effects potentially caused by glycolytic metabolism from those directly referable to lactate, we selected cancer cell lines able to grow in glucose deprived conditions and evaluated the impact of lactate on the cellular response to cisplatin-induced DNA damage. In lactate-exposed cells we observed a reduced efficacy of cisplatin, which was associated with reduced signatures of DNA damage, enhanced DNA recombination competence and increased expression of a panel of genes involved in DNA repair. The identified genes take part in mismatch and nucleotide excision repair pathways, which were found to contribute in restoring the cisplatin-induced DNA damage. The obtained results suggest that this metabolite could play a role in reducing the efficacy of antineoplastic treatments.

scholarly journals A ”Clickable” Probe for Active MGMT in Glioblastoma Demonstrates Two Discrete Populations of MGMT

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 453 ◽  
Author(s):  
Sudhir Raghavan ◽  
David S. Baskin ◽  
Martyn A. Sharpe
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Dna Adducts ◽  
Alkylating Agents ◽  
Chemotherapeutic Agents ◽  
Dna Alkylation ◽  
Methylated Dna ◽  
Methylguanine Methyltransferase ◽  
Discrete Populations

Various pathways can repair DNA alkylation by chemotherapeutic agents such as temozolomide (TMZ). The enzyme O6-methylguanine methyltransferase (MGMT) removes O6-methylated DNA adducts, leading to the failure of chemotherapy in resistant glioblastomas. Because of the anti-chemotherapeutic activities of MGMT previously described, estimating the levels of active MGMT in cancer cells can be a significant predictor of response to alkylating agents. Current methods to detect MGMT in cells are indirect, complicated, time-intensive, or utilize molecules that require complex and multistep chemistry synthesis. Our design simulates DNA repair by the transfer of a clickable propargyl group from O6-propargyl guanine to active MGMT and subsequent attachment of fluorescein-linked PEG linker via ”click chemistry.” Visualization of active MGMT levels reveals discrete active and inactive MGMT populations with biphasic kinetics for MGMT inactivation in response to TMZ-induced DNA damage.

scholarly journals DNA Damage and Its Cellular Response in Mother and Fetus Exposed to Hyperglycemic Environment

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Jusciele Brogin Moreli ◽  
Janine Hertzog Santos ◽  
Clarissa Ribeiro Rocha ◽  
Débora Cristina Damasceno ◽  
Glilciane Morceli ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Dna Repair ◽  
Cellular Response ◽  
Genetic Material ◽  
Endogenous Factors ◽  
Dna Repair Mechanisms ◽  
Scavenging Capacity ◽  
Repair Mechanisms ◽  
The Impact

The increased production of reactive oxygen species (ROS) plays a key role in pathogenesis of diabetic complications. ROS are generated by exogenous and endogenous factors such as during hyperglycemia. When ROS production exceeds the detoxification and scavenging capacity of the cell, oxidative stress ensues. Oxidative stress induces DNA damage and when DNA damage exceeds the cellular capacity to repair it, the accumulation of errors can overwhelm the cell resulting in cell death or fixation of genome mutations that can be transmitted to future cell generations. These mutations can lead to and/or play a role in cancer development. This review aims at (i) understanding the types and consequences of DNA damage during hyperglycemic pregnancy; (ii) identifying the biological role of DNA repair during pregnancy, and (iii) proposing clinical interventions to maintain genome integrity. While hyperglycemia can damage the maternal genetic material, the impact of hyperglycemia on fetal cells is still unclear. DNA repair mechanisms may be important to prevent the deleterious effects of hyperglycemia both in mother and in fetus DNA and, as such, prevent the development of diseases in adulthood. Hence, in clinical practice, maternal glycemic control may represent an important point of intervention to prevent the deleterious effects of maternal hyperglycemia to DNA.

scholarly journals Platinum Complexes in Colorectal Cancer and Other Solid Tumors

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2073
Author(s):  
Beate Köberle ◽  
Sarah Schoch
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Cisplatin Resistance ◽  
Platinum Complexes ◽  
Dna Lesions ◽  
Dna Damage Signaling ◽  
Repair Mechanisms ◽  
P53 Inactivation

Cisplatin is one of the most commonly used drugs for the treatment of various solid neoplasms, including testicular, lung, ovarian, head and neck, and bladder cancers. Unfortunately, the therapeutic efficacy of cisplatin against colorectal cancer is poor. Various mechanisms appear to contribute to cisplatin resistance in cancer cells, including reduced drug accumulation, enhanced drug detoxification, modulation of DNA repair mechanisms, and finally alterations in cisplatin DNA damage signaling preventing apoptosis in cancer cells. Regarding colorectal cancer, defects in mismatch repair and altered p53-mediated DNA damage signaling are the main factors controlling the resistance phenotype. In particular, p53 inactivation appears to be associated with chemoresistance and poor prognosis. To overcome resistance in cancers, several strategies can be envisaged. Improved cisplatin analogues, which retain activity in resistant cancer, might be applied. Targeting p53-mediated DNA damage signaling provides another therapeutic strategy to circumvent cisplatin resistance. This review provides an overview on the DNA repair pathways involved in the processing of cisplatin damage and will describe signal transduction from cisplatin DNA lesions, with special attention given to colorectal cancer cells. Furthermore, examples for improved platinum compounds and biochemical modulators of cisplatin DNA damage signaling will be presented in the context of colon cancer therapy.

scholarly journals Veliparib Is an Effective Radiosensitizing Agent in a Preclinical Model of Medulloblastoma

2021 ◽  
Vol 8 ◽  
Author(s):  
Jessica Buck ◽  
Patrick J. C. Dyer ◽  
Hilary Hii ◽  
Brooke Carline ◽  
Mani Kuchibhotla ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Combination Therapy ◽  
Cellular Response ◽  
Molecular Subtype ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Parp Inhibition ◽  
Preclinical Model ◽  
Radiation Induced

Medulloblastoma is the most common malignant childhood brain tumor, and 5-year overall survival rates are as low as 40% depending on molecular subtype, with new therapies critically important. As radiotherapy and chemotherapy act through the induction of DNA damage, the sensitization of cancer cells through the inhibition of DNA damage repair pathways is a potential therapeutic strategy. The poly-(ADP-ribose) polymerase (PARP) inhibitor veliparib was assessed for its ability to augment the cellular response to radiation-induced DNA damage in human medulloblastoma cells. DNA repair following irradiation was assessed using the alkaline comet assay, with veliparib inhibiting the rate of DNA repair. Veliparib treatment also increased the number of γH2AX foci in cells treated with radiation, and analysis of downstream pathways indicated persistent activation of the DNA damage response pathway. Clonogenicity assays demonstrated that veliparib effectively inhibited the colony-forming capacity of medulloblastoma cells, both as a single agent and in combination with irradiation. These data were then validated in vivo using an orthotopic implant model of medulloblastoma. Mice harboring intracranial D425 medulloblastoma xenografts were treated with vehicle, veliparib, 18 Gy multifractionated craniospinal irradiation (CSI), or veliparib combined with 18 Gy CSI. Animals treated with combination therapy exhibited reduced tumor growth rates concomitant with increased intra-tumoral apoptosis observed by immunohistochemistry. Kaplan–Meier analyses revealed a statistically significant increase in survival with combination therapy compared to CSI alone. In summary, PARP inhibition enhanced radiation-induced cytotoxicity of medulloblastoma cells; thus, veliparib or other brain-penetrant PARP inhibitors are potential radiosensitizing agents for the treatment of medulloblastoma.

scholarly journals Advances and perspectives of PARP inhibitors

2019 ◽  
Vol 8 (1) ◽  
Author(s):  
Ming Yi ◽  
Bing Dong ◽  
Shuang Qin ◽  
Qian Chu ◽  
Kongming Wu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Genome Instability ◽  
Single Gene ◽  
High Sensitivity ◽  
Lethal Effect ◽  
Single Strand Break ◽  
Synthetic Lethal ◽  
Increased Risk

Abstract DNA damage repair deficiency leads to the increased risk of genome instability and oncogenic transformation. In the meanwhile, this deficiency could be exploited for cancer treatment by inducing excessive genome instability and catastrophic DNA damage. Continuous DNA replication in cancer cells leads to higher demand of DNA repair components. Due to the oncogenic loss of some DNA repair effectors (e.g. BRCA) and incomplete DNA repair repertoire, some cancer cells are addicted to certain DNA repair pathways such as Poly (ADP-ribose) polymerase (PARP)-related single-strand break repair pathway. The interaction between BRCA and PARP is a form of synthetic lethal effect which means the simultaneously functional loss of two genes lead to cell death, while defect in any single gene has a slight effect on cell viability. Based on synthetic lethal theory, Poly (ADP-ribose) polymerase inhibitor (PARPi) was developed aiming to selectively target cancer cells harboring BRCA1/2 mutations. Recently, a growing body of evidence indicated that a broader population of patients could benefit from PARPi therapy far beyond those with germline BRCA1/2 mutated tumors. Numerous biomarkers including homologous recombination deficiency and high level of replication pressure also herald high sensitivity to PARPi treatment. Besides, a series of studies indicated that PARPi-involved combination therapy such as PARPi with additional chemotherapy therapy, immune checkpoint inhibitor, as well as targeted agent had a great advantage in overcoming PARPi resistance and enhancing PARPi efficacy. In this review, we summarized the advances of PARPi in clinical application. Besides, we highlighted multiple promising PARPi-based combination strategies in preclinical and clinical studies.

scholarly journals WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1258 ◽  
Author(s):  
Kamila Burdova ◽  
Radka Storchova ◽  
Matous Palek ◽  
Libor Macurek
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Genotoxic Stress ◽  
Parp Inhibitors ◽  
Cell Cycle Checkpoint ◽  
Dna Lesion ◽  
Cycle Checkpoint ◽  
G2 Cells

Genotoxic stress triggers a combined action of DNA repair and cell cycle checkpoint pathways. Protein phosphatase 2C delta (referred to as WIP1) is involved in timely inactivation of DNA damage response by suppressing function of p53 and other targets at chromatin. Here we show that WIP1 promotes DNA repair through homologous recombination. Loss or inhibition of WIP1 delayed disappearance of the ionizing radiation-induced 53BP1 foci in S/G2 cells and promoted cell death. We identify breast cancer associated protein 1 (BRCA1) as interactor and substrate of WIP1 and demonstrate that WIP1 activity is needed for correct dynamics of BRCA1 recruitment to chromatin flanking the DNA lesion. In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1. Finally, we report that inhibition of WIP1 allowed accumulation of DNA damage in S/G2 cells and increased sensitivity of cancer cells to a poly-(ADP-ribose) polymerase inhibitor olaparib. We propose that inhibition of WIP1 may increase sensitivity of BRCA1-proficient cancer cells to olaparib.

scholarly journals Inhibition of AKT-Signaling Sensitizes Soft Tissue Sarcomas (STS) and Gastrointestinal Stromal Tumors (GIST) to Doxorubicin via Targeting of Homology-Mediated DNA Repair

2020 ◽  
Vol 21 (22) ◽  
pp. 8842
Author(s):  
Sergei Boichuk ◽  
Firuza Bikinieva ◽  
Ilmira Nurgatina ◽  
Pavel Dunaev ◽  
Elena Valeeva ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Soft Tissue ◽  
Gastrointestinal Stromal Tumors ◽  
Topoisomerase Ii ◽  
Soft Tissue Sarcomas ◽  
Akt Signaling ◽  
Chemotherapeutic Agents ◽  
Tail Moment ◽  
Stromal Tumors

Activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway is well documented for a broad spectrum of human malignancies supporting their growth and progression. Accumulating evidence has also implicated AKT as a potent modulator of anti-cancer therapies via regulation of DNA damage response and repair (DDR) induced by certain chemotherapeutic agents and ionizing radiation (IR). In the present study, we examined the role of AKT signaling in regulating of Rad51 turnover and cytotoxic effects of topoisomerase II inhibitor, doxorubicin (Dox) in soft tissue sarcomas (STS) and gastrointestinal stromal tumors (GIST) in vitro. Blocking of AKT signaling (MK-2206) enhanced cytotoxic and pro-apoptotic effects of Dox in vast majority of STS and GIST cell lines. The phosphorylated form of Akt co-immunoprecipitates with Rad51 after Dox-induced DNA damage, whereas Akt inhibition interrupts this interaction and decreases Rad51 protein level by enhancing protein instability via proteasome-dependent degradation. Inhibition of Akt signaling in Dox-treated cells was associated with the increased number of γ-H2AX-positive cells, decrease of Rad51 foci formation and its colocalization with γ-H2AX foci, thereby revealing unsuccessful DDR events. This was also in consistency with an increase of tail moment (TM) and olive tail moment (OTM) in Dox-treated GIST and STS cells cultured in presence of Akt inhibitor after Dox washout. Altogether, our data illustrates that inhibition of AKT signaling is STS and GIST might potentiate the cytotoxic effect of topoisomerase II inhibitors via attenuating the homology-mediated DNA repair.

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

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1501 ◽  
Author(s):  
Agnieszka Bojko ◽  
Joanna Czarnecka-Herok ◽  
Agata Charzynska ◽  
Michal Dabrowski ◽  
Ewa Sikora
Keyword(s):  
Dna Damage ◽  
Comparative Analysis ◽  
Cancer Cells ◽  
Chemotherapeutic Agents ◽  
Double Stranded Dna ◽  
Secretory Phenotype ◽  
Paclitaxel Treatment ◽  
Senescence Phenotype ◽  
Mcf 7 ◽  
Intermediate Effect

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.

scholarly journals Overview of Human Intervention Studies Evaluating the Impact of the Mediterranean Diet on Markers of DNA Damage

Nutrients ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 391 ◽  
Author(s):  
Cristian Del Bo' ◽  
Mirko Marino ◽  
Daniela Martini ◽  
Massimiliano Tucci ◽  
Salvatore Ciappellano ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Telomere Length ◽  
Mediterranean Diet ◽  
Intervention Studies ◽  
Human Intervention ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
The Mediterranean ◽  
The Impact

The Mediterranean diet (MD) is characterized by high consumption of fruits, vegetables, cereals, potatoes, poultry, beans, nuts, lean fish, dairy products, small quantities of red meat, moderate alcohol consumption, and olive oil. Most of these foods are rich sources of bioactive compounds which may play a role in the protection of oxidative stress including DNA damage. The present review provides a summary of the evidence deriving from human intervention studies aimed at evaluating the impact of Mediterranean diet on markers of DNA damage, DNA repair, and telomere length. The few results available show a general protective effect of MD alone, or in combination with bioactive-rich foods, on DNA damage. In particular, the studies reported a reduction in the levels of 8-hydroxy-2′–deoxyguanosine and a modulation of DNA repair gene expression and telomere length. In conclusion, despite the limited literature available, the results obtained seem to support the beneficial effects of MD dietary pattern in the protection against DNA damage susceptibility. However, further well-controlled interventions are desirable in order to confirm the results obtained and provide evidence-based conclusions.

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