In-silico Approach to Target Cancer Cell DNA Repair Pathway

2019 ◽  
pp. 373-392
Author(s):  
Azra Yasmin ◽  
Zarrin Basharat ◽  
Naila Safdar
Keyword(s):  
Dna Repair ◽  
Cancer Cell ◽  
In Silico ◽  
Repair Pathway ◽  
Target Cancer

Synthetic lethality: exploiting the addiction of cancer to DNA repair

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6074-6082 ◽  
Author(s):  
Montaser Shaheen ◽  
Christopher Allen ◽  
Jac A. Nickoloff ◽  
Robert Hromas
Keyword(s):  
Dna Repair ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Synthetic Lethality ◽  
Double Strand Breaks ◽  
Repair Pathway ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Repair Pathways ◽  
Cancer Multiple

Abstract Because cancer at its origin must acquire permanent genomic mutations, it is by definition a disease of DNA repair. Yet for cancer cells to replicate their DNA and divide, which is the fundamental phenotype of cancer, multiple DNA repair pathways are required. This produces a paradox for the cancer cell, where its origin is at the same time its weakness. To overcome this difficulty, a cancer cell often becomes addicted to DNA repair pathways other than the one that led to its initial mutability. The best example of this is in breast or ovarian cancers with mutated BRCA1 or 2, essential components of a repair pathway for repairing DNA double-strand breaks. Because replicating DNA requires repair of DNA double-strand breaks, these cancers have become reliant on another DNA repair component, PARP1, for replication fork progression. The inhibition of PARP1 in these cells results in catastrophic double-strand breaks during replication, and ultimately cell death. The exploitation of the addiction of cancer cells to a DNA repair pathway is based on synthetic lethality and has wide applicability to the treatment of many types of malignancies, including those of hematologic origin. There is a large number of novel compounds in clinical trials that use this mechanism for their antineoplastic activity, making synthetic lethality one of the most important new concepts in recent drug development.

Promising Anticancer Therapeutics From Mushrooms: Current Findings and Future Perceptions

2020 ◽  
Vol 21 ◽  
Author(s):  
Mrunmaya Kumar Panda ◽  
Manish Paul ◽  
Sameer Kumar Singdevsachan ◽  
Kumananda Tayung ◽  
Swagat Kumar Das ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cancer Cell ◽  
In Silico ◽  
Present Review ◽  
Cancer Cell Proliferation ◽  
Research Papers ◽  
Medicinal Mushrooms ◽  
In Silico Studies ◽  
Anticancer Therapeutics ◽  
Ethnomedicinal Uses

Background: Nowadays medicines derived from natural sources have drawn much attention as potential therapeutic agents in the suppression and treatment of cancer because of their low toxicity and fewer side effects. Objective: The present review aims to assess the currently available knowledge on the ethnomedicinal uses and pharmacological activities of bioactive compounds obtained from medicinal mushrooms towards cancer treatment. Methods: Literature search has been conducted for the collection of research papers from universally accepted scientific databases. These research papers and published book chapters were scrutinized to retrieve information on ethnomedicinal uses of mushrooms, different factors involved in cancer cell proliferation, clinical and in silico pharmaceutical studies made for possible treatments of cancer using mushroom derived compounds. Overall 241 articles were retrieved and reviewed from the year of 1970 to 2020, out of which 98 relevant articles were finally considered for preparation of this review. Results: This review presents an update on the natural bioactive substances derived from medicinal mushrooms and their role in inhibiting the factors responsible for cancer cell proliferation. Along with it, the present review also provides information on the ethnomedicinal uses, solvents used for extraction of anticancer metabolites, clinical trials, and in silico studies that were undertaken towards anticancer drug development from medicinal mushrooms. Conclusion: The present review provides an extensive knowledge on various anticancer substances obtained from medicinal mushrooms, their biological actions and in silico drug designing approaches which could form a basis for the development of natural anticancer therapeutics.

Fanconi Anemia DNA Repair Pathway as a New Mechanism to Exploit Cancer Drug Resistance

2020 ◽  
Vol 20 (9) ◽  
pp. 779-787
Author(s):  
Kajal Ghosal ◽  
Christian Agatemor ◽  
Richard I. Han ◽  
Amy T. Ku ◽  
Sabu Thomas ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Cancer Drug ◽  
Drug Resistant ◽  
Cancer Drugs ◽  
Repair Pathway ◽  
Cancer Drug Resistance ◽  
Anti Cancer ◽  
Cancerous Cells

Chemotherapy employs anti-cancer drugs to stop the growth of cancerous cells, but one common obstacle to the success is the development of chemoresistance, which leads to failure of the previously effective anti-cancer drugs. Resistance arises from different mechanistic pathways, and in this critical review, we focus on the Fanconi Anemia (FA) pathway in chemoresistance. This pathway has yet to be intensively researched by mainstream cancer researchers. This review aims to inspire a new thrust toward the contribution of the FA pathway to drug resistance in cancer. We believe an indepth understanding of this pathway will open new frontiers to effectively treat drug-resistant cancer.

scholarly journals Discovery of pyrano[2,3-d]pyrimidine-2,4-dione derivatives as novel PARP-1 inhibitors: design, synthesis and antitumor activity

RSC Advances ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 4454-4464
Author(s):  
Nour E. A. Abd El-sattar ◽  
Eman H. K. Badawy ◽  
Eman Z. Elrazaz ◽  
Nasser S. M. Ismail
Keyword(s):  
Cell Death ◽  
Dna Repair ◽  
Antitumor Activity ◽  
Cancer Cell ◽  
Cytotoxic Agents ◽  
Repair Mechanism ◽  
Design Synthesis ◽  
Parp 1

PARP-1 are involved in DNA repair damage and so PARP-1 inhibitors have been used as potentiators in combination with DNA damaging cytotoxic agents to compromise the cancer cell DNA repair mechanism, resulting in genomic dysfunction and cell death.

scholarly journals Modifications on the Tetrahydroquinoline Scaffold Targeting a Phenylalanine Cluster on GPER as Antiproliferative Compounds against Renal, Liver and Pancreatic Cancer Cells

2021 ◽  
Vol 14 (1) ◽  
pp. 49
Author(s):  
David Méndez-Luna ◽  
Loreley Araceli Morelos-Garnica ◽  
Juan Benjamín García-Vázquez ◽  
Martiniano Bello ◽  
Itzia Irene Padilla-Martínez ◽  
...  
Keyword(s):  
Binding Site ◽  
Cell Lines ◽  
Cancer Cell ◽  
Inhibitory Activity ◽  
In Silico ◽  
Cancer Cell Lines ◽  
Pancreatic Cancer Cells ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
New Compounds

The implementation of chemo- and bioinformatics tools is a crucial step in the design of structure-based drugs, enabling the identification of more specific and effective molecules against cancer without side effects. In this study, three new compounds were designed and synthesized with suitable absorption, distribution, metabolism, excretion and toxicity (ADME-tox) properties and high affinity for the G protein-coupled estrogen receptor (GPER) binding site by in silico methods, which correlated with the growth inhibitory activity tested in a cluster of cancer cell lines. Docking and molecular dynamics (MD) simulations accompanied by a molecular mechanics/generalized Born surface area (MMGBSA) approach yielded the binding modes and energetic features of the proposed compounds on GPER. These in silico studies showed that the compounds reached the GPER binding site, establishing interactions with a phenylalanine cluster (F206, F208 and F278) required for GPER molecular recognition of its agonist and antagonist ligands. Finally, a 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay showed growth inhibitory activity of compounds 4, 5 and 7 in three different cancer cell lines—MIA Paca-2, RCC4-VA and Hep G2—at micromolar concentrations. These new molecules with specific chemical modifications of the GPER pharmacophore open up the possibility of generating new compounds capable of reaching the GPER binding site with potential growth inhibitory activities against nonconventional GPER cell models.

scholarly journals The SRS2 suppressor of rad6 mutations of Saccharomyces cerevisiae acts by channeling DNA lesions into the RAD52 DNA repair pathway.

Genetics ◽  
1990 ◽  
Vol 124 (4) ◽  
pp. 817-831 ◽  
Author(s):  
R H Schiestl ◽  
S Prakash ◽  
L Prakash
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Repair ◽  
Gamma Ray ◽  
Dna Lesions ◽  
Recombinational Repair ◽  
Repair Pathway ◽  
Uv Mutagenesis ◽  
Uv Sensitivity ◽  
Suppressor Mutations ◽  
Induced Mutagenesis

Abstract rad6 mutants of Saccharomyces cerevisiae are defective in the repair of damaged DNA, DNA damage induced mutagenesis, and sporulation. In order to identify genes that can substitute for RAD6 function, we have isolated genomic suppressors of the UV sensitivity of rad6 deletion (rad6 delta) mutations and show that they also suppress the gamma-ray sensitivity but not the UV mutagenesis or sporulation defects of rad6. The suppressors show semidominance for suppression of UV sensitivity and dominance for suppression of gamma-ray sensitivity. The six suppressor mutations we isolated are all alleles of the same locus and are also allelic to a previously described suppressor of the rad6-1 nonsense mutation, SRS2. We show that suppression of rad6 delta is dependent on the RAD52 recombinational repair pathway since suppression is not observed in the rad6 delta SRS2 strain containing an additional mutation in either the RAD51, RAD52, RAD54, RAD55 or RAD57 genes. Possible mechanisms by which SRS2 may channel unrepaired DNA lesions into the RAD52 DNA repair pathway are discussed.

scholarly journals MiR223-3p promotes synthetic lethality in BRCA1-deficient cancers

2019 ◽  
Vol 116 (35) ◽  
pp. 17438-17443 ◽  
Author(s):  
Gayathri Srinivasan ◽  
Elizabeth A. Williamson ◽  
Kimi Kong ◽  
Aruna S. Jaiswal ◽  
Guangcun Huang ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cancer Cells ◽  
Synthetic Lethality ◽  
Negative Regulator ◽  
Nonhomologous End Joining ◽  
Chromosomal Translocations ◽  
Replication Forks ◽  
Repair Pathway ◽  
End Joining ◽  
Parp1 Inhibitors

Defects in DNA repair give rise to genomic instability, leading to neoplasia. Cancer cells defective in one DNA repair pathway can become reliant on remaining repair pathways for survival and proliferation. This attribute of cancer cells can be exploited therapeutically, by inhibiting the remaining repair pathway, a process termed synthetic lethality. This process underlies the mechanism of the Poly-ADP ribose polymerase-1 (PARP1) inhibitors in clinical use, which target BRCA1 deficient cancers, which is indispensable for homologous recombination (HR) DNA repair. HR is the major repair pathway for stressed replication forks, but when BRCA1 is deficient, stressed forks are repaired by back-up pathways such as alternative nonhomologous end-joining (aNHEJ). Unlike HR, aNHEJ is nonconservative, and can mediate chromosomal translocations. In this study we have found that miR223-3p decreases expression of PARP1, CtIP, and Pso4, each of which are aNHEJ components. In most cells, high levels of microRNA (miR) 223–3p repress aNHEJ, decreasing the risk of chromosomal translocations. Deletion of the miR223 locus in mice increases PARP1 levels in hematopoietic cells and enhances their risk of unprovoked chromosomal translocations. We also discovered that cancer cells deficient in BRCA1 or its obligate partner BRCA1-Associated Protein-1 (BAP1) routinely repress miR223-3p to permit repair of stressed replication forks via aNHEJ. Reconstituting the expression of miR223-3p in BRCA1- and BAP1-deficient cancer cells results in reduced repair of stressed replication forks and synthetic lethality. Thus, miR223-3p is a negative regulator of the aNHEJ DNA repair and represents a therapeutic pathway for BRCA1- or BAP1-deficient cancers.

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