Exploring the promising potential of induced pluripotent stem cells in cancer research and therapy

Molecular Cancer, Год журнала: 2023, Номер 22(1)

Опубликована: Ноя. 28, 2023

The advent of iPSCs has brought about a significant transformation in stem cell research, opening up promising avenues for advancing cancer treatment. formation is multifaceted process influenced by genetic, epigenetic, and environmental factors. offer distinctive platform investigating the origin cancer, paving way novel approaches to treatment, drug testing, tailored medical interventions. This review article will provide an overview science behind iPSCs, current limitations challenges iPSC-based therapy, ethical social implications, comparative analysis with other types also discuss applications tumorigenesis, future tumorigenesis highlight successful case studies utilizing research. conclusion summarize advancements made research importance continued investment iPSC unlock full potential these cells.

Язык: Английский

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Targeting ferroptosis in ovarian cancer: Novel strategies to overcome chemotherapy resistance

Life Sciences, Год журнала: 2024, Номер 349, С. 122720 - 122720

Опубликована: Май 16, 2024

This review investigates the role of ferroptosis in combating chemotherapy resistance ovarian cancer, with a focus on its underlying mechanisms and therapeutic implications.

Язык: Английский

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Double‐strand DNA break repair: molecular mechanisms and therapeutic targets

MedComm, Год журнала: 2023, Номер 4(5)

Опубликована: Окт. 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.

Язык: Английский

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Discovery of the Potent and Selective ATR Inhibitor Camonsertib (RP-3500)

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(4), С. 2349 - 2368

Опубликована: Фев. 1, 2024

ATR is a key kinase in the DNA-damage response (DDR) that synthetic lethal with several other DDR proteins, making it an attractive target for treatment of genetically selected solid tumors. Herein we describe discovery novel inhibitor guided by pharmacophore model to position hydrogen bond. Optimization was driven potency and selectivity over related mTOR, resulting identification camonsertib (RP-3500) high excellent ADME properties. Preclinical evaluation focused on impact myelosuppression, exploration intermittent dosing schedules allow recovery erythroid compartment mitigate anemia. Camonsertib currently undergoing clinical both as single agent combination talazoparib, olaparib, niraparib, lunresertib, or gemcitabine (NCT04497116, NCT04972110, NCT04855656). A preliminary recommended phase 2 dose monotherapy identified 160 mg QD given 3 days/week.

Язык: Английский

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Targeted inhibition of the ATR/CHK1 pathway overcomes resistance to olaparib and dysregulates DNA damage response protein expression in BRCA2MUT ovarian cancer cells

Scientific Reports, Год журнала: 2023, Номер 13(1)

Опубликована: Дек. 19, 2023

Olaparib is a PARP inhibitor (PARPi) approved for targeted treatment of ovarian cancer (OC). However, its efficacy impeded by the inevitable occurrence resistance. Here, we investigated whether cytotoxic activity olaparib could be synergistically enhanced in olaparib-resistant OC cells with BRCA2 reversion mutation addition inhibitors ATR/CHK1 pathway. Moreover, provide insights into alterations DNA damage response (DDR) pathway induced combination treatments. Antitumor alone or combined an ATR (ATRi, ceralasertib) CHK1 (CHK1i, MK-8776) was evaluated cell lines sensitive (PEO1, PEO4) and resistant (PEO1-OR) to olaparib. Antibody microarrays were used explore changes expression 27 DDR-related proteins. decrease viability clonogenic survival increase apoptosis mediated caspase-3/7 all cells. Combination treatments cumulative proteins mediating distinct repair pathways cycle control. In presence ATRi CHK1i, olaparib-induced upregulation determining fate after (PARP1, CHK1, c-Abl, Ku70, Ku80, MDM2, p21) abrogated PEO1-OR Overall, CHK1i effectively overcomes resistance PARPi exerting anti-proliferative effect BRCA2MUT alters These new molecular cellular might help improve therapies OC.

Язык: Английский

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MK-8776 and Olaparib Combination Acts Synergistically in Hepatocellular Carcinoma Cells, Demonstrating Lack of Adverse Effects on Liver Tissues in Ovarian Cancer PDX Model

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(2), С. 834 - 834

Опубликована: Янв. 20, 2025

Hepatocellular carcinoma (HCC) cells critically depend on PARP1 and CHK1 activation for survival. Combining the PARP inhibitor (PARPi) olaparib with a (MK-8776, CHK1i) produced synergistic effect, reducing cell viability inducing marked oxidative stress DNA damage, particularly in HepG2 cells. This dual treatment significantly increased apoptosis markers, including γH2AX caspase-3/7 activity. Both HCC lines exhibited heightened sensitivity to combined treatment. The effect of drugs expression proliferation markers an olaparib-resistant patient-derived xenograft (PDX) model ovarian cancer was also investigated. Ovarian tumors displayed reduced tissue growth, as reflected by drop marker Ki-67 levels response PARPi CHK1i. No changes were observed corresponding liver tissues using pCHK staining, which indicates absence metastases hepatotoxic effect. Thus, our results indicate that inhibition may prove be promising therapeutic approach primary well OC without risk metastases, especially patients tumor profiles.

Язык: Английский

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Natural pentacyclic triterpenoid from Pristimerin sensitizes p53-deficient tumor to PARP inhibitor by ubiquitination of Chk1

Pharmacological Research, Год журнала: 2024, Номер 201, С. 107091 - 107091

Опубликована: Фев. 4, 2024

Inhibition of checkpoint kinase 1 (Chk1) has shown to overcome resistance poly (ADP-ribose) polymerase (PARP) inhibitors and expand the clinical utility PARP in a broad range human cancers. Pristimerin, naturally occurring pentacyclic triterpenoid, been focus intensive studies for its anticancer potential. However, it is not yet known whether low dose pristimerin can be combined with by targeting Chk1 signaling pathway. In this study, we investigated efficacy, safety molecular mechanisms synergistic effect produced combination olaparib TP53-deficient BRCA-proficient cell models. As result, an increased expression was correlated TP53 mutation, preferentially sensitized p53-defective cells olaparib. The resulted more pronounced abrogation DNA synthesis induction double-strand breaks (DSBs). Moreover, disrupted constitutional levels DSB repair activities. Mechanistically, promoted K48-linked polyubiquitination proteasomal degradation while affecting domain activity. Importantly, combinatorial therapy led higher rate tumor growth inhibition without apparent hematological toxicities. addition, suppressed olaparib-induced upregulation enhanced marker γΗ2ΑΧ vivo. Taken together, observed induce deficiency, which may application cancers harboring mutations. Thus, inhibitor-based therapy.

Язык: Английский

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Tabersonine Enhances Olaparib Sensitivity through FHL1-Mediated Epithelial–Mesenchymal Transition in an Ovarian Tumor

Journal of Natural Products, Год журнала: 2024, Номер 87(4), С. 837 - 848

Опубликована: Фев. 28, 2024

Ovarian cancer (OVC) is one of the most aggressive gynecological malignancies worldwide. Although olaparib treatment has shown favorable outcomes against OVC, its effectiveness remains limited in some OVC patients. Investigating new strategies to improve therapeutic efficacy imperative. Our study identified tabersonine, a natural indole alkaloid, for potential increase chemosensitivity OVC. The combined and tabersonine synergistically inhibited cell proliferation cells suppressed tumor growth A2780 xenografts. effectively epithelial–mesenchymal transition (EMT) by altering expression E-cadherin, N-cadherin, vimentin induced DNA damage responses. Integrating quantitative proteomics, FHL1 was as regulator modulate EMT after treatment. Increased treatment, while downregulation reversed inhibitory effects on mediating EMT. In vivo findings further reflected that significantly metastasis through upregulation FHL1. reveal role improving sensitivity FHL1-mediated EMT, suggesting holds promise future application

Язык: Английский

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RNA-binding protein THUMPD2 inhibits proliferation and promotes metastasis in epithelial ovarian cancer

Heliyon, Год журнала: 2024, Номер 10(13), С. e33201 - e33201

Опубликована: Июнь 25, 2024

Ovarian cancer (OC) is a common and lethal gynaecological malignancy. RNA-binding proteins (RBPs) play crucial role in governing RNA metabolism have been implicated the development progression of diverse types. Slight alterations RBPs' expression or activity can induce substantial modifications regulatory network. THUMPD2, as member RBP family, was found to differential ovarian cancer, with mechanism has not studied yet. In this study, THUMPD2 protein be weakly expressed early (I + II) stages OC (P = 0.013), low rate 78.6 %, highly late (III IV) 0.009), high 84.8 %. The shRNA-mediated knockdown OVCAR3 SKOV3 cells resulted increased cell proliferation but inhibited metastasis, whereas overexpression had opposite effect. suppressed tumour growth vivo. Conversely, promoted growth. Furthermore, we identified potential target genes pathways using GO KEGG analyses, which were related centrosome, microtubules, cycle, extracellular matrix. We demonstrated that stage metastasis. Our findings reveal dual function suggest may serve therapeutic for treatment OC.

Язык: Английский

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Modulatory Potential of Poly (ADP‐Ribose) Polymerase 1 (PARP1) in BRCA‐Mutated Tumors

European Journal of Cancer Care, Год журнала: 2024, Номер 2024(1)

Опубликована: Янв. 1, 2024

Poly (ADP‐ribose) polymerase 1 is a versatile enzyme that deeply involved in diverse cellular processes. It exerts influence on pivotal activities such as DNA repair, transcriptional regulation, and cell death. PARP1 crucial due to its susceptibility posttranslational modifications, each of which has distinct roles shaping functionality interactions with other proteins. Among these the addition ADP‐ribose an acetyl group lysine residues enhance engagement while ubiquitination cleavage are degradation PARP1. modification been exploited cancer treatment, particularly context breast ovarian cancers marked by BRCA1 BRCA2 mutations. However, resistance inhibitors selective confer functions remain elusive. The present review endeavors detail extent shedding light their profound implications at remains challenge, often drives treatment failure. effectiveness relies specific level. This trial registered NCT04550104 , NCT06120491 NCT05367440 NCT05797168 NCT04644068 NCT05573724 NCT05489211 NCT05938270 NCT02264678 .

Язык: Английский

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