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 Databases and Bioinformatics Tools for the Study of DNA Repair

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Kaja Milanowska ◽  
Kristian Rother ◽  
Janusz M. Bujnicki
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Excision Repair ◽  
Uv Light ◽  
Dna Lesions ◽  
Environmental Chemicals ◽  
Nonhomologous End Joining ◽  
End Joining ◽  
Repair Mechanisms ◽  
Base Excision

DNA is continuously exposed to many different damaging agents such as environmental chemicals, UV light, ionizing radiation, and reactive cellular metabolites. DNA lesions can result in different phenotypical consequences ranging from a number of diseases, including cancer, to cellular malfunction, cell death, or aging. To counteract the deleterious effects of DNA damage, cells have developed various repair systems, including biochemical pathways responsible for the removal of single-strand lesions such as base excision repair (BER) and nucleotide excision repair (NER) or specialized polymerases temporarily taking over lesion-arrested DNA polymerases during the S phase in translesion synthesis (TLS). There are also other mechanisms of DNA repair such as homologous recombination repair (HRR), nonhomologous end-joining repair (NHEJ), or DNA damage response system (DDR). This paper reviews bioinformatics resources specialized in disseminating information about DNA repair pathways, proteins involved in repair mechanisms, damaging agents, and DNA lesions.

scholarly journals DNA Damage/Repair Management in Cancers

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1050 ◽  
Author(s):  
Jehad F. Alhmoud ◽  
John F. Woolley ◽  
Ala-Eddin Al Moustafa ◽  
Mohammed Imad Malki
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Repair ◽  
Critical Factor ◽  
Dna Lesions ◽  
Cancer Development ◽  
Dna Damaging Agents ◽  
Damage Repair ◽  
Repair Mechanisms ◽  
Dna Strand

DNA damage is well recognized as a critical factor in cancer development and progression. DNA lesions create an abnormal nucleotide or nucleotide fragment, causing a break in one or both chains of the DNA strand. When DNA damage occurs, the possibility of generated mutations increases. Genomic instability is one of the most important factors that lead to cancer development. DNA repair pathways perform the essential role of correcting the DNA lesions that occur from DNA damaging agents or carcinogens, thus maintaining genomic stability. Inefficient DNA repair is a critical driving force behind cancer establishment, progression and evolution. A thorough understanding of DNA repair mechanisms in cancer will allow for better therapeutic intervention. In this review we will discuss the relationship between DNA damage/repair mechanisms and cancer, and how we can target these pathways.

scholarly journals Quantitative Proteomics Identifies DNA Repair as a Novel Biological Function for Hepatocyte Nuclear Factor 4α in Colorectal Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 626 ◽  
Author(s):  
Jean-Philippe Babeu ◽  
Samuel D. Wilson ◽  
Élie Lambert ◽  
Dominique Lévesque ◽  
François-Michel Boisvert ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Transcription Factor ◽  
Cancer Cells ◽  
Quantitative Proteomics ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Colorectal Cancer Cells ◽  
Hepatocyte Nuclear Factor 4Α

Hepatocyte nuclear factor 4α (HNF4α) is a transcription factor that acts as a master regulator of genes for several endoderm-derived tissues, including the intestine, in which it plays a central role during development and tumorigenesis. To better define the mechanisms by which HNF4α can influence these processes, we identified proteins interacting with HNF4α using stable isotope labelling with amino acids in cell culture (SILAC)-based quantitative proteomics with either immunoprecipitation of green fluorescent protein (GFP) or with proximity-dependent purification by the biotin ligase BirA (BioID), both fused to HNF4α. Surprisingly, these analyses identified a significant enrichment of proteins characterized with a role in DNA repair, a so far unidentified biological feature of this transcription factor. Several of these proteins including PARP1, RAD50, and DNA-PKcs were confirmed to interact with HNF4α in colorectal cancer cell lines. Following DNA damage, HNF4α was able to increase cell viability in colorectal cancer cells. Overall, these observations identify a potential role for this transcription factor during the DNA damage response.

Alpinumisoflavone causes DNA damage in Colorectal Cancer Cells via blocking DNA repair mediated by RAD51

Life Sciences ◽  
2019 ◽  
Vol 216 ◽  
pp. 259-270 ◽  
Author(s):  
Dong Li ◽  
Xiaoyan Li ◽  
Genqu Li ◽  
Yan Meng ◽  
Yanghong Jin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Colorectal Cancer Cells

scholarly journals DNA Double Strand Break Repair Pathways in Response to Different Types of Ionizing Radiation

2021 ◽  
Vol 12 ◽  
Author(s):  
Gerarda van de Kamp ◽  
Tim Heemskerk ◽  
Roland Kanaar ◽  
Jeroen Essers
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Spatial Configuration ◽  
Strand Break ◽  
Dna Lesions ◽  
Particle Therapy ◽  
Photon Radiation ◽  
Particle Radiation ◽  
Dna Double Strand Break ◽  
Repair Mechanisms

The superior dose distribution of particle radiation compared to photon radiation makes it a promising therapy for the treatment of tumors. However, the cellular responses to particle therapy and especially the DNA damage response (DDR) is not well characterized. Compared to photons, particles are thought to induce more closely spaced DNA lesions instead of isolated lesions. How this different spatial configuration of the DNA damage directs DNA repair pathway usage, is subject of current investigations. In this review, we describe recent insights into induction of DNA damage by particle radiation and how this shapes DNA end processing and subsequent DNA repair mechanisms. Additionally, we give an overview of promising DDR targets to improve particle therapy.

Usnic Acid Inhibits Proliferation and Migration through ATM Mediated DNA Damage Response in RKO Colorectal Cancer Cell

2020 ◽  
Vol 21 ◽  
Author(s):  
Wenbing Wu ◽  
Hui Gou ◽  
Jingying Dong ◽  
Xiaolong Yang ◽  
Yanan Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Dna Damage ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Usnic Acid ◽  
Chemotherapeutic Drugs ◽  
Dna Damage Signaling ◽  
And Migration ◽  
Proliferation And Migration

Background: Usnic acid (UA), also known as lichenol, has been reported to have inhibitory effects on a variety of cancer cells, but its specific mechanism remained to be elucidated. Tumor chemotherapy drugs, especially DNA damage chemotherapeutic drugs target Chromosomal DNA, but their spontaneous and acquired drug resistance are also an urgent problem to be solved. Therefore, drug combination research has become the focus of researchers. Methods: Here, we evaluated the tumor-suppressing molecular mechanism of UA in colorectal cancer cells RKO from the perspective of ATM-mediated DNA damage signaling pathway through H2O2 simulating DNA damage chemotherapeutic drugs. CCK8 cell proliferation assay was used to determine the inhibition of RKO cells by hydrogen peroxide and UA alone or in combination, and wound healing assay was applied to determine the effect of the drug on cell migration. Results: Transfected cells with miRNA18a-5p mimics and inhibitors, MDC and DCFH-DA staining for the measurement of autophagy and ROS, cell cycle and apoptosis were detected by flow cytometry, expressions of microRNA and mRNA were determined by fluorescence quantitative PCR, and protein by Western blot. Discussion: We found that UA can up-regulate ATM via miR-18a to activate DNA damage signaling pathway and inhibit the proliferation and migration of RKO cells in a concentration-dependent manner. Conclusion: At the same time, DNA damage responses including cell cycle, autophagy, apoptosis and ROS levels are also regulated by UA respectively. Therefore, UA combined with DNA damage chemotherapeutic drugs may be an effective treatment for cancer.

scholarly journals In Silico Investigation of the Biological Implications of Complex DNA Damage with Emphasis in Cancer Radiotherapy through a Systems Biology Approach

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7602
Author(s):  
Athanasia Pavlopoulou ◽  
Seyedehsadaf Asfa ◽  
Evangelos Gioukakis ◽  
Ifigeneia V. Mavragani ◽  
Zacharenia Nikitaki ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Systems Biology ◽  
In Silico ◽  
Apoptotic Cell ◽  
Normal Function ◽  
Dna Lesions ◽  
Cancer Pathways ◽  
Repair Mechanisms ◽  
Effects Of Radiation

Different types of DNA lesions forming in close vicinity, create clusters of damaged sites termed as “clustered/complex DNA damage” and they are considered to be a major challenge for DNA repair mechanisms resulting in significant repair delays and induction of genomic instability. Upon detection of DNA damage, the corresponding DNA damage response and repair (DDR/R) mechanisms are activated. The inability of cells to process clustered DNA lesions efficiently has a great impact on the normal function and survival of cells. If complex lesions are left unrepaired or misrepaired, they can lead to mutations and if persistent, they may lead to apoptotic cell death. In this in silico study, and through rigorous data mining, we have identified human genes that are activated upon complex DNA damage induction like in the case of ionizing radiation (IR) and beyond the standard DNA repair pathways, and are also involved in cancer pathways, by employing stringent bioinformatics and systems biology methodologies. Given that IR can cause repair resistant lesions within a short DNA segment (a few nm), thereby augmenting the hazardous and toxic effects of radiation, we also investigated the possible implication of the most biologically important of those genes in comorbid non-neoplastic diseases through network integration, as well as their potential for predicting survival in cancer patients.

scholarly journals RAD52 as a Potential Target for Synthetic Lethality-Based Anticancer Therapies

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1561 ◽  
Author(s):  
Toma ◽  
Sullivan-Reed ◽  
Śliwiński ◽  
Skorski
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Synthetic Lethality ◽  
Lethal Effect ◽  
Drug Induced ◽  
Synthetic Lethal ◽  
Repair Mechanisms ◽  
Cancer Tumor

Alterations in DNA repair systems play a key role in the induction and progression of cancer. Tumor-specific defects in DNA repair mechanisms and activation of alternative repair routes create the opportunity to employ a phenomenon called “synthetic lethality” to eliminate cancer cells. Targeting the backup pathways may amplify endogenous and drug-induced DNA damage and lead to specific eradication of cancer cells. So far, the synthetic lethal interaction between BRCA1/2 and PARP1 has been successfully applied as an anticancer treatment. Although PARP1 constitutes a promising target in the treatment of tumors harboring deficiencies in BRCA1/2—mediated homologous recombination (HR), some tumor cells survive, resulting in disease relapse. It has been suggested that alternative RAD52-mediated HR can protect BRCA1/2-deficient cells from the accumulation of DNA damage and the synthetic lethal effect of PARPi. Thus, simultaneous inhibition of RAD52 and PARP1 might result in a robust dual synthetic lethality, effectively eradicating BRCA1/2-deficient tumor cells. In this review, we will discuss the role of RAD52 and its potential application in synthetic lethality-based anticancer therapies.

scholarly journals DNA Damage: From Threat to Treatment

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1665 ◽  
Author(s):  
Antonio Carusillo ◽  
Claudio Mussolino
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genetic Information ◽  
Dna Lesions ◽  
Interstrand Crosslinks ◽  
Dna Repair Mechanisms ◽  
Abasic Sites ◽  
Damage Sensing ◽  
Repair Mechanisms ◽  
Complete Failure

DNA is the source of genetic information, and preserving its integrity is essential in order to sustain life. The genome is continuously threatened by different types of DNA lesions, such as abasic sites, mismatches, interstrand crosslinks, or single-stranded and double-stranded breaks. As a consequence, cells have evolved specialized DNA damage response (DDR) mechanisms to sustain genome integrity. By orchestrating multilayer signaling cascades specific for the type of lesion that occurred, the DDR ensures that genetic information is preserved overtime. In the last decades, DNA repair mechanisms have been thoroughly investigated to untangle these complex networks of pathways and processes. As a result, key factors have been identified that control and coordinate DDR circuits in time and space. In the first part of this review, we describe the critical processes encompassing DNA damage sensing and resolution. In the second part, we illustrate the consequences of partial or complete failure of the DNA repair machinery. Lastly, we will report examples in which this knowledge has been instrumental to develop novel therapies based on genome editing technologies, such as CRISPR-Cas.

scholarly journals Alkannin-Induced Oxidative DNA Damage Synergizes With PARP Inhibition to Cause Cancer-Specific Cytotoxicity

2020 ◽  
Vol 11 ◽  
Author(s):  
Mingxin Chang ◽  
Hongge Wang ◽  
Jiajing Niu ◽  
Yan Song ◽  
Zhihua Zou
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Oxidative Dna Damage ◽  
Parp Inhibitor ◽  
Antioxidant Systems ◽  
Synergistic Cytotoxicity ◽  
Colorectal Cancer Cells

Background: Oncogenic transformation is associated with elevated oxidative stress that promotes tumor progression but also renders cancer cells vulnerable to further oxidative insult. Agents that stimulate ROS generation or suppress antioxidant systems can drive oxidative pressure to toxic levels selectively in tumor cells, resulting in oxidative DNA damage to endanger cancer cell survival. However, DNA damage response signaling protects cancer cells by activating DNA repair and genome maintenance mechanisms. In this study, we investigated the synergistic effects of combining the pro-oxidative natural naphthoquinone alkannin with inhibition of DNA repair by PARP inhibitors.Methods and Results: The results showed that sublethal doses of alkannin induced ROS elevation and oxidative DNA damage in colorectal cancer but not normal colon epithelial cells. Blocking DNA repair with the PARP inhibitor olaparib markedly synergized with alkannin to yield synergistic cytotoxicity in colorectal cancer cells at nontoxic doses of both drugs. Synergy between alkannin and olaparib resulted from interrupted repair of alkannin-induced oxidative DNA damage and PARP-trapping, as it was significantly attenuated by NAC or by OGG1 inhibition and the non-trapping PARP inhibitor veliparib did not yield synergism. Mechanistically, the combination of alkannin and olaparib caused intense replication stress and DNA strand breaks in colorectal cancer cells, leading to apoptotic cancer cell death after G2 arrest. Consequently, coadministration of alkannin and olaparib induced significant regression of tumor xenografts in vivo, while each agent alone had no effect.Conclusion: These studies clearly show that combining alkannin and olaparib can result in synergistic cancer cell lethality at nontoxic doses of the drugs. The combination exploits a cancer vulnerability driven by the intrinsic oxidative pressure in most cancer cells and hence provides a promising strategy to develop broad-spectrum anticancer therapeutics.

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