Synthetic plant hormones shut down DNA repair in cancer cells

(Georgetown University Medical Center) Two drugs that mimic a common plant hormone effectively cause DNA damage and turn off a major DNA repair mechanism, suggesting their potential use as an anti-cancer therapy.
Source: EurekAlert! - Cancer - Category: Cancer & Oncology Source Type: news

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Abstract WEE1 kinase regulates the G2-M cell-cycle checkpoint, a critical mechanism for DNA repair in cancer cells that can confer resistance to DNA-damaging agents. We previously reported a series of pyrazolopyrimidinones based on AZD1775, a known WEE1 inhibitor, as an initial investigation into the structural requirements for WEE1 inhibition. Our lead inhibitor demonstrated WEE1 inhibition in the same nanomolar range as AZD1775, and potentiated the effects of cisplatin in medulloblastoma cells, but had reduced single-agent cytotoxicity. These results prompted the development of a more comprehensive series of WEE...
Source: ChemMedChem - Category: Chemistry Authors: Tags: ChemMedChem Source Type: research
ConclusionsClinicopathological features and survival outcomes in the PBM-treated patients were similar to previously published data for conventional treatments in patients with advanced OSCC. In this study, prophylactic use of PBM therapy did not impact treatment outcomes of the primary cancer, recurrence or new primary tumors, or survival in advanced OSCC patients.
Source: Supportive Care in Cancer - Category: Cancer & Oncology Source Type: research
Seminal progress has been achieved in the development of cancer therapies targeting at different biological pathways or genomic alterations. In breast cancer, the rapid clinical development of PARPi which is selectively cytotoxic to BRCA1/2 mutated or DNA-damage repair deficient patients, has made it a field rich in opportunity [1,2,3]. Progress in determining the function of BRCA1 and BRCA2 suggests that these two genes are critically involved in leading high-fidelity repair by 'homologous recombination' (HR) [4,5].
Source: Cancer Treatment Reviews - Category: Cancer & Oncology Authors: Tags: Tumour Review Source Type: research
This study indicates that frailty and other age-related diseases could be prevented and significantly reduced in older adults. Getting our heart risk factors under control could lead to much healthier old ages. Unfortunately, the current obesity epidemic is moving the older population in the wrong direction, however our study underlines how even small reductions in risk are worthwhile." The study analysed data from more than 421,000 people aged 60-69 in both GP medical records and in the UK Biobank research study. Participants were followed up over ten years. The researchers analysed six factors that could impa...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Recent studies have shown that inactivation of (DNA mismatch repair gene) MMR could be exploited as a potential therapeutic tool in cancer therapy [1 –3]. MMR inactivation has shown to increase the mutational load of the cancer cells which in turn causes a sustained antigenic response against the neoantigens (additional mutations) leading to tumor inhibition. Although in-vitro and animal based in-vivo studies have shown the effectiveness of MMR inhibition (flow chart 1) [3] on halting the tumor progression, there are potential complications which could arise due to MMR inactivation.
Source: Medical Hypotheses - Category: Biomedical Science Authors: Source Type: research
CONCLUSION: NDRG1 is an important modulator linking DNA damage response and hypoxia-related cellular stress response during the development of drug resistance to cisplatin/CMNa in lung cancer. Targeting both NDRG1 and ERCC1 may be a viable strategy for overcoming drug resistance in cancer therapy, and has significant clinical implications. PMID: 29768183 [PubMed - as supplied by publisher]
Source: The International Journal of Biochemistry and Cell Biology - Category: Biochemistry Authors: Tags: Int J Biochem Cell Biol Source Type: research
Authors: Buoninfante OA, Pilzecker B, Aslam MA, Zavrakidis I, van der Wiel R, van de Ven M, van den Berk PCM, Jacobs H Abstract DNA damage tolerance (DDT) enables replication to continue in the presence of a damaged template and constitutes a key step in DNA interstrand crosslink repair. In this way DDT minimizes replication stress inflicted by a wide range of endogenous and exogenous agents, and provides a critical first line defense against alkylating and platinating chemotherapeutics. Effective DDT strongly depends on damage-induced, site-specific PCNA-ubiquitination at Lysine (K) 164 by the E2/E3 complex (RAD6/...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research
Abstract The E3 ubiquitin ligase HUWE1/Mule/ARF-BP1 plays an important role in diverse biological processes including DNA damage repair and apoptosis. Our previous study has shown that in response to DNA damage HUWE1 was downregulated in CUL4B-mediated ubiquitination and subsequent proteasomal degradation, and CUL4B-mediated regulation of HUWE1 is important for cell survival upon DNA damage. CUL4B is a core component of the CUL4B Ring ligase complexes containing ROC1, DDB1 and a DDB1-Cullin Associated Factors (DCAFs), the latter of which are DDB1-binding WD40 adaptors critical for substrate recognition and recruit...
Source: Biochemical and Biophysical Research communications - Category: Biochemistry Authors: Tags: Biochem Biophys Res Commun Source Type: research
In this study, eight new Torin2 analogs were designed and synthesized through multistep synthesis. All the synthesized compounds were characterized by NMR and mass analysis. The newly synthesized analogs were evaluated for their anti-cancer activity via CellTiter-Glo® assay. Additionally, compounds 13 and 14 also showed significant inhibition for ATR and mTOR substrates, i.e., p-Chk1 Ser 317 and p70 S6K Thr 389, respectively. Compounds 13 and 14 displayed promising anti-cancer activity with HCT-116 cell lines in the preliminary study. Further, a comparative model of ATR kinase was generated using the SWISS-MODEL server...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research
Abstract The DNA damage response (DDR) is a series of pathways and processes required to repair lesions to DNA. These pathways range from repairing strand breaks to the double helix, damaged bases formed after oxidation or deamination, inaccurate DNA replication resulting in mispaired base alignment, intrastrand crosslinks that trigger cell death, and a plethora of other genomic insults. The DDR is believed to be a critical component of radio and chemoresistance in many cancers as well, with the tumor's ability to repair therapy induced damage being an important tool used to survive traditional chemotherapeutic ag...
Source: DNA Repair - Category: Genetics & Stem Cells Authors: Tags: DNA Repair (Amst) Source Type: research
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