Poly(ADP-Ribose) Polymerase (PARP) Inhibitors for Cancer Therapy: Advances, Challenges, and Future Directions

Biomolecules, Год журнала: 2024, Номер 14(10), С. 1269 - 1269

Опубликована: Окт. 9, 2024

Poly(ADP-ribose) polymerases (PARPs) are crucial nuclear proteins that play important roles in various cellular processes, including DNA repair, gene transcription, and cell death. Among the 17 identified PARP family members, PARP1 is most abundant enzyme, with approximately 1-2 million molecules per cell, acting primarily as a damage sensor. It has become promising biological target for anticancer drug studies. Enhanced expression present several types of tumors, such melanomas, lung cancers, breast correlating low survival outcomes resistance to treatment. inhibitors, especially newly developed third-generation inhibitors currently undergoing Phase II clinical trials, have shown efficacy agents both single drugs sensitizers chemo- radiotherapy. This review explores properties, characteristics, challenges discussing their development from first-generation compounds, more sustainable synthesis methods discovery new anti-cancer agents, mechanisms therapeutic action, potential targeting additional targets beyond catalytic active site proteins. Perspectives on green chemistry also discussed.

Язык: Английский

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Recent advances of nucleic acid-based cancer biomarkers and biosensors

Coordination Chemistry Reviews, Год журнала: 2023, Номер 497, С. 215456 - 215456

Опубликована: Сен. 26, 2023

Язык: Английский

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FSP1 inhibition enhances olaparib sensitivity in BRCA-proficient ovarian cancer patients via a nonferroptosis mechanism

Cell Death and Differentiation, Год журнала: 2024, Номер 31(4), С. 497 - 510

Опубликована: Фев. 19, 2024

Poly ADP-ribose polymerase inhibitors (PARPis) exhibit promising efficacy in patients with BRCA mutations or homologous repair deficiency (HRD) ovarian cancer (OC). However, less than 40% of have HRD, it is vital to expand the indications for PARPis BRCA-proficient patients. Ferroptosis suppressor protein 1 (FSP1) a key newly identified ferroptosis-protective mechanism that occurs parallel GPX4-mediated pathway and associated chemoresistance several cancers. Herein, FSP1 reported be negatively correlated prognosis OC Combination therapy comprising olaparib iFSP1 (a inhibitor) strongly inhibited tumour proliferation cell lines, patient-derived organoids (PDOs) xenograft mouse models. Surprisingly, synergistic killing effect could not reversed by ferroptosis inhibitors, indicating mechanisms other were responsible lethality. In addition, cotreatment was shown induce increased γH2A.X foci impair nonhomologous end joining (NHEJ) activity greater extent did any single drug. Mass spectrometry immunoprecipitation analyses revealed interacted Ku70, classical component recruited occupying double-strand breaks (DSBs) NHEJ process. inhibition decreased Ku70 PARylation, impaired subsequent DNA-PKcs recruitment Ku complex at DSB sites rescued restoring PARylation. These findings unprecedentedly reveal novel role DNA damage provide new insights into how sensitize PARPi treatment.

Язык: Английский

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Complexity of the Genetic Background of Oncogenesis in Ovarian Cancer—Genetic Instability and Clinical Implications

Cells, Год журнала: 2024, Номер 13(4), С. 345 - 345

Опубликована: Фев. 15, 2024

Ovarian cancer is a leading cause of death among women with gynecological cancers, and often diagnosed at advanced stages, to poor outcomes. This review explores genetic aspects high-grade serous, endometrioid, clear-cell ovarian carcinomas, emphasizing personalized treatment approaches. Specific mutations such as TP53 in serous BRAF/KRAS low-grade carcinomas highlight the need for tailored therapies. Varying mutation prevalence across subtypes, including BRCA1/2, PTEN, PIK3CA, CTNNB1, c-myc amplification, offers potential therapeutic targets. underscores TP53’s pivotal role advocates p53 immunohistochemical staining mutational analysis. BRCA1/2 mutations’ significance risk factors their relevance PARP inhibitor therapy are discussed, importance testing. also addresses paradoxical better prognosis linked KRAS BRAF cancer. ARID1A, PTEN alterations platinum resistance contribute landscape. Therapeutic strategies, like restoring WT function exploring PI3K/AKT/mTOR inhibitors, considered. The evolving understanding supports approaches based on individual tumor profiles. Ongoing research shows promise advancing treatments refining testing neoplastic diseases, Clinical screening tests can identify increased risk, guiding predictive risk-reducing surgery.

Язык: Английский

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BRCA genetic testing and counseling in breast cancer: how do we meet our patients’ needs?

npj Breast Cancer, Год журнала: 2024, Номер 10(1)

Опубликована: Сен. 5, 2024

Язык: Английский

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Mutations in homologous recombination repair genes in patients with metastatic endometrial cancer: association with clinical characteristics and prognosis

Journal of Gynecologic Oncology, Год журнала: 2025, Номер 36

Опубликована: Янв. 1, 2025

To evaluate the mutation rates of homologous recombination repair (HRR) genes and impact these mutations on clinical characteristics metastatic endometrial cancer (EC). Somatic DNA from 895 patients with EC in Memorial Sloan Kettering-Metastatic Events Tropisms cohort was assessed for 10 HRR (BRCA1, BRCA2, ATM, BARD1, BRIP1, PALB2, RAD51C, RAD51D, CHEK2, CDK12). The correlation between status evaluated. were detected 106 (11.8%) EC. Compared nonmutation carriers, a greater proportion carriers had endometrioid carcinoma (76.4% vs. 50.3%, p<0.001). Regarding TCGA classification, proportions POLE-ultramutated (POLEmut) mismatch repair-deficient (dMMR) subtypes significantly among than noncarriers (20.8% 0.4%, p<0.001; 34.9% 11.9%, p<0.001, respectively). lower frequency TP53 (25.5% 54.1%, Fewer intra-abdominal lung metastases (41.5% 54.2%, p=0.014; 19.8% 30.3%, p=0.026, did not affect overall survival are 11.8% noncarriers, have higher carcinoma, POLEmut, dMMR subtypes, unique patterns. However, prognoses similar regardless status.

Язык: Английский

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Common Drug-Drug and Drug-Food Interactions in Antineoplastic Agents: A short update review

Hacettepe University Journal of the Faculty of Pharmacy, Год журнала: 2025, Номер 45(1), С. 92 - 105

Опубликована: Март 1, 2025

Cancer treatment regimens often combine chemotherapeutics, supportive therapies, and medications for comorbidities, increasing the risk of drug-drug (DDIs) drug-food interactions (DFIs). These can alter pharmacokinetics pharmacodynamics anticancer agents, potentially leading to failure, severe adverse events, or hospitalization. Elderly patients, polypharmacy, narrow therapeutic index many chemotherapeutics further compound these challenges. This review explores mechanisms underlying DDIs DFIs, focusing on absorption, metabolism, transport protein modulation—key processes influencing drug bioavailability toxicity in oncology. Clinically relevant examples are provided illustrate interactions. The underscores critical role pharmacy services identifying, preventing, managing interactions, offering actionable strategies enhance patient safety efficacy. By addressing healthcare providers mitigate risks, improve outcomes, quality life cancer patients.

Язык: Английский

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Overview of Roles of Novel Components in the Regulation of DNA Damage Repair in BRCA1-Deficient Cancers: An Update

DNA, Год журнала: 2025, Номер 5(2), С. 17 - 17

Опубликована: Апрель 1, 2025

Cancers that arise from germline mutations of breast cancer associated gene 1 (BRCA1), which is a crucial player in homologous recombination (HR) DNA repair, are vulnerable to DNA-damaging agents such as platinum and PARP inhibitors (PARPis). Increasing evidence suggests BRCA1 an essential driver all phases the cell cycle, thereby maintaining orderly steps during cycle progression. Specifically, loss activity causes S-phase, G2/M, spindle checkpoints, centrosome duplication be dysregulated, blocking proliferation inducing apoptosis. In vertebrates, HR genes and/or BRCA2 lethal, since prerequisite for genome integrity. Thus, cells utilize alternative repair pathways non-homologous end joining (NHEJ) cope with function. this review, we attempt update discuss how these novel components regulating damage (DDR) BRCA1-deficient cancers.

Язык: Английский

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Olaparib Combined with Anti-PD1 Enhances Immunotherapy of Gastric Cancer Via NF-κB/c-Myc/PD-L1 Signaling

Digestive Diseases and Sciences, Год журнала: 2025, Номер unknown

Опубликована: Апрель 16, 2025

Язык: Английский

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Discovery of Tetrahydropyrazolopyrazine Derivatives as Potent and Selective MYT1 Inhibitors for the Treatment of Cancer

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 67(1), С. 420 - 432

Опубликована: Дек. 26, 2023

Breast and gynecological cancers are among the leading causes of death in women worldwide, illustrating urgent need for innovative treatment options. We identified MYT1 as a promising new therapeutic target breast cancer using PandaOmics, an AI-driven discovery platform. The synthetic lethal relationship tumor cell lines with CCNE1 amplification enhanced this rationale. Through structure-based drug design, we developed series novel, potent, highly selective inhibitors specifically targeting MYT1. Importantly, our lead compound, featuring tetrahydropyrazolopyrazine ring, exhibits remarkable selectivity over WEE1, related kinase associated bone marrow suppression upon inhibition. Optimization potency physical properties resulted compound 21, novel inhibitor, exhibiting optimal pharmacokinetic vivo antitumor efficacy.

Язык: Английский

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