Small molecule nitroalkenes inhibit RAD51-mediated homologous recombination and amplify triple-negative breast cancer cell killing by DNA-directed therapies DOI Open Access
Lisa Hong, Dennis Braden,

Yaoning Zhao

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 14, 2023

Nitro fatty acids (NO 2 -FAs) are endogenously generated lipid signaling mediators from metabolic and inflammatory reactions between conjugated diene nitric oxide or nitrite-derived reactive species. NO -FAs undergo reversible Michael addition with hyperreactive protein cysteine thiolates to induce posttranslational modifications that can impact function. Herein, we report a novel mechanism of action natural non-natural nitroalkenes structurally similar ( E ) 10-nitro-octadec-9-enoic acid (CP-6), recently de-risked by preclinical Investigational New Drug-enabling studies Phase 1 clinical trials found DNA damage in TNBC xenograft inhibiting homologous-recombination (HR)-mediated repair double-strand breaks (DSB). CP-6 specifically targets Cys319, essential RAD51-controlled HR-mediated DSB cells. A nitroalkene library screen identified two different nitroalkenes, [( 8-nitro- nonadec-7-enoic (CP-8)] dicarboxylate ester [dimethyl )nitro-oct-4-enedioate (CP- 23)] superior cells killing, synergism three inhibitors the poly ADP-ribose polymerase (PARP) γ-IR. CP-8 CP-23 effectively inhibited γ-IR-induced RAD51 foci formation HR GFP-reported assay but did not affect benign human epithelial cell cycle phases. In vivo, CP-23's efficacies diverged as only showed promising anticancer activities alone combined PARP inhibitor talazoparib an HR-proficient mouse model. As preliminary toxicology analysis also suggests safe, our data endorse molecule for treating cancers sensitive homologous recombination-mediated inhibitors.

Language: Английский

New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives DOI Creative Commons
Viola Previtali, Greta Bagnolini, Andrea Ciamarone

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(14), P. 11488 - 11521

Published: July 2, 2024

In recent years, synthetic lethality has been recognized as a solid paradigm for anticancer therapies. The discovery of growing number lethal targets led to significant expansion in the use lethality, far beyond poly(ADP-ribose) polymerase inhibitors used treat BRCA1/2-defective tumors. particular, molecular within DNA damage response have provided source that rapidly reached clinical trials. This Perspective focuses on most progress and their inhibitors, response, describing design associated therapeutic strategies. We will conclude by discussing current challenges new opportunities this promising field research, stimulate discussion medicinal chemistry community, allowing investigation reach its full potential.

Language: Английский

Citations

17
Small Molecules Targeting DNA Polymerase Theta (POLθ) as Promising Synthetic Lethal Agents for Precision Cancer Therapy DOI Creative Commons
Maria Chiara Pismataro, Andrea Astolfi, Maria Letizia Barreca

et al.

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(10), P. 6498 - 6522

Published: May 3, 2023

Synthetic lethality (SL) is an innovative strategy in targeted anticancer therapy that exploits tumor genetic vulnerabilities. This topic has come to the forefront recent years, as witnessed by increased number of publications since 2007. The first proof concept for effectiveness SL was provided approval poly(ADP-ribose)polymerase inhibitors, which exploit a interaction BRCA-deficient cells, although their use limited resistance. Searching additional interactions involving BRCA mutations, DNA polymerase theta (POLθ) emerged exciting target. review summarizes, time, POLθ and helicase inhibitors reported date. Compounds are described focusing on chemical structure biological activity. With aim enable further drug discovery efforts interrogating target, we propose plausible pharmacophore model POLθ-pol provide structural analysis known ligand binding sites.

Language: Английский

Citations

26
Double‐strand DNA break repair: molecular mechanisms and therapeutic targets DOI Creative Commons

Jinpeng Tan,

Xingyao Sun,

Hongling Zhao

et al.

MedComm, Journal Year: 2023, Volume and Issue: 4(5)

Published: Oct. 1, 2023

Abstract Double‐strand break (DSB), a significant DNA damage brought on by ionizing radiation, acts as an initiating signal in tumor radiotherapy, causing cancer cells death. The two primary pathways for DSB repair mammalian are nonhomologous end joining (NHEJ) and homologous recombination (HR), which cooperate compete with one another to achieve effective repair. mechanism depends numerous regulatory variables. recognition the recruitment of components, instance, depend MRE11–RAD50–NBS1 (MRN) complex Ku70/80 heterodimer/DNA–PKcs (DNA–PK) complex, whose control is crucial determining pathway choice efficiency HR NHEJ. In‐depth elucidation pathway's molecular mechanisms has greatly facilitated creation proteins or pathways‐specific inhibitors advance precise therapy boost effectiveness radiotherapy. architectures, roles, processes, target reviewed this article. strategy application also discussed based advancement targeted response proteins.

Language: Английский

Citations

22
Small molecule nitroalkenes inhibit RAD51-mediated homologous recombination and amplify triple-negative breast cancer cell killing by DNA-directed therapies DOI Creative Commons
Lisa Hong, Dennis Braden,

Yaoning Zhao

et al.

Redox Biology, Journal Year: 2023, Volume and Issue: 66, P. 102856 - 102856

Published: Aug. 19, 2023

Nitro fatty acids (NO2-FAs) are endogenously generated lipid signaling mediators from metabolic and inflammatory reactions between conjugated diene nitric oxide or nitrite-derived reactive species. NO2-FAs undergo reversible Michael addition with hyperreactive protein cysteine thiolates to induce posttranslational modifications that can impact function. Herein, we report a novel mechanism of action natural non-natural nitroalkenes structurally similar (E) 10-nitro-octadec-9-enoic acid (CP-6), recently de-risked by preclinical Investigational New Drug-enabling studies Phase 1 2 clinical trials found DNA damage in TNBC xenograft inhibiting homologous-recombination (HR)-mediated repair double-strand breaks (DSB). CP-6 specifically targets Cys319, essential RAD51-controlled HR-mediated DSB cells. A nitroalkene library screen identified two different nitroalkenes, [(E) 8-nitro-nonadec-7-enoic (CP-8)] dicarboxylate ester [dimethyl (E)nitro-oct-4-enedioate (CP-23)] superior cells killing, synergism three inhibitors the poly ADP-ribose polymerase (PARP) γ-IR. CP-8 CP-23 effectively inhibited γ-IR-induced RAD51 foci formation HR GFP-reported assay but did not affect benign human epithelial cell cycle phases. In vivo, CP-23's efficacies diverged as only showed promising anticancer activities alone combined PARP inhibitor talazoparib an HR-proficient mouse model. As preliminary toxicology analysis also suggests safe, our data endorse molecule for treating cancers sensitive homologous recombination-mediated inhibitors.

Language: Английский

Citations

5
AZD-7648, a DNA-PK Inhibitor, Induces DNA Damage, Apoptosis, and Cell Cycle Arrest in Chronic and Acute Myeloid Leukemia Cells DOI Open Access
Beatriz Lapa, Maria Inês Costa, Diana Figueiredo

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(20), P. 15331 - 15331

Published: Oct. 18, 2023

The non-homologous end joining pathway is vital for repairing DNA double-strand breaks (DSB), with DNA-dependent protein kinase (DNA-PK) playing a critical role. Altered damage response (DDR) in chronic (CML) and acute myeloid leukemia (AML) offers potential therapeutic opportunities. We studied the of AZD-7648 (DNA-PK inhibitor) CML AML cell lines. This study used two (K-562 LAMA-84) five (HEL, HL-60, KG-1, NB-4, THP-1) DDR gene mutations were obtained from COSMIC database. copy number methylation profile evaluated using MS-MLPA genes, telomere length qPCR. p53 expression was assessed Western Blot, chromosomal through cytokinesis-block micronucleus assay, γH2AX levels DSB repair kinetics flow cytometry. Cell density viability analyzed trypan blue assay after treatment concentrations ranging 10 to 200 µM. death, cycle distribution, proliferation rate cells displayed different baseline damage, expressions, mutations, genetic/epigenetic changes, expression. Only HEL inefficient repair. LAMA-84, HEL, KG-1 most sensitive AZD-7648, whereas HL-60 K-562 showed lower effect on viability. Besides reduction proliferation, induced apoptosis, arrest, damage. In conclusion, these results suggest that holds promise as therapy leukemias, however, variations drug sensitivity among tested lines, thus supporting further investigation identify specific factors influencing this DNA-PK inhibitor.

Language: Английский

Citations

5
Cold snapshots of DNA repair: Cryo-EM structures of DNA-PKcs and NHEJ machinery DOI Creative Commons
Himani Amin, Sayma Zahid, Chloe M. Hall

et al.

Progress in Biophysics and Molecular Biology, Journal Year: 2023, Volume and Issue: 186, P. 1 - 13

Published: Nov. 28, 2023

The proteins and protein assemblies involved in DNA repair have been the focus of a multitude structural studies for past few decades. Historically, structures these complexes resolved by X-ray crystallography. However, more recently with advancements cryo-electron microscopy (cryo-EM) ranging from optimising methodology sample preparation to development improved electron detectors, has shifted crystallography cryo-EM. This methodological transition allowed determination larger, complex pathways subsequently led deeper understanding mechanisms utilised fascinating molecular machines. Here, we review some key that gained study non-homologous end joining (NHEJ) use cryo-EM, on composed DNA-PKcs Ku70/80 (Ku) various methodologies obtain structures.

Language: Английский

Citations

5
Potential clinical treatment prospects behind the molecular mechanism of alternative lengthening of telomeres (ALT) DOI Creative Commons

Haolu Sun,

Guijuan Chen,

Baochang Guo

et al.

Journal of Cancer, Journal Year: 2023, Volume and Issue: 14(3), P. 417 - 433

Published: Jan. 1, 2023

Normal somatic cells inevitably experience replicative stress and senescence during proliferation.Somatic cell carcinogenesis can be prevented in part by limiting the reproduction of damaged or old removing them from cycle [1, 2].However, Cancer must overcome issues replication pressure as well preserve telomere length order to achieve immortality, contrast normal [1,2].Although telomerase accounts for bulk lengthening methods human cancer cells, there is a non-negligible portion pathways that depend on alternative telomeres (ALT) [3].For selection novel possible therapeutic targets ALT-related disorders, thorough understanding molecular biology these diseases crucial [4].The roles ALT, typical ALT tumor traits, pathophysiology mechanisms such adrenocortical carcinoma (ACC), are all summarized this work.Additionally, research compiles many its hypothetically viable but unproven treatment it (ALT-associated PML bodies (APB), etc.).This review intended contribute much development research, while also trying provide partial information prospective investigations associated diseases.

Language: Английский

Citations

4
Exploring the Role of Seven Key Genes in Breast Cancer: Insights from In Silico and In Vitro Analyses DOI Creative Commons
Devashish Mehta, Jignesh Prajapati, Vinal Upadhyay

et al.

Gene Expression, Journal Year: 2024, Volume and Issue: 000(000), P. 000 - 000

Published: Jan. 2, 2024

Background and objectivesBreast cancer remains a significant global health concern, warranting further exploration into its genetic basis potential therapeutic targets. This study aimed to elucidate the associations of seven pivotal genes with breast discern their role in disease prognosis.

Language: Английский

Citations

1
Impact of Optimized Ku–DNA Binding Inhibitors on the Cellular and In Vivo DNA Damage Response DOI Open Access
Pamela L. Mendoza-Munoz,

Narva Deshwar Kushwaha,

Dineshsinha Chauhan

et al.

Cancers, Journal Year: 2024, Volume and Issue: 16(19), P. 3286 - 3286

Published: Sept. 26, 2024

: DNA-dependent protein kinase (DNA-PK) is a validated cancer therapeutic target involved in DNA damage response (DDR) and non-homologous end-joining (NHEJ) repair of double-strand breaks (DSBs). Ku serves as sensor DSBs by binding to ends activating DNA-PK. Inhibition DNA-PK common strategy block DSB improve efficacy ionizing radiation (IR) therapy radiomimetic drug therapies. We have previously developed Ku-DNA inhibitors (Ku-DBis) that vitro cellular NHEJ activity, abrogate autophosphorylation, potentiate sensitivity IR.

Language: Английский

Citations

1
A Cell System-Assisted Strategy for Evaluating the Natural Antioxidant-Induced Double-Stranded DNA Break (DSB) Style DOI Open Access

Yuduki Someya,

Sakine Kobayashi,

Kazuya Toriumi

et al.

Genes, Journal Year: 2023, Volume and Issue: 14(2), P. 420 - 420

Published: Feb. 6, 2023

Natural antioxidants derived from plants exert various physiological effects, including antitumor effects. However, the molecular mechanisms of each natural antioxidant have not yet been fully elucidated. Identifying targets with properties in vitro is costly and time-consuming, results thus obtained may reliably reflect vivo conditions. Therefore, to enhance understanding regarding effects antioxidants, we focused on DNA, one anticancer drugs, evaluated whether e.g., sulforaphane, resveratrol, quercetin, kaempferol, genistein, which induce DNA damage using gene-knockout cell lines human Nalm-6 HeLa cells pretreated DNA-dependent protein kinase inhibitor NU7026. Our suggested that sulforaphane induces single-strand breaks or strand crosslinks quercetin double-strand breaks. In contrast, resveratrol showed ability cytotoxic other than damage. also kaempferol genistein via unknown mechanisms. Taken together, use this evaluation system facilitates analysis antioxidants.

Language: Английский

Citations

3