DNA Repair Pathways in Cancer Therapy and Resistance

Frontiers in Pharmacology, Год журнала: 2021, Номер 11

Опубликована: Фев. 8, 2021

DNA repair pathways are triggered to maintain genetic stability and integrity when mammalian cells exposed endogenous or exogenous DNA-damaging agents. The deregulation of is associated with the initiation progression cancer. As primary anti-cancer therapies, ionizing radiation chemotherapeutic agents induce cell death by directly indirectly causing damage, dysregulation damage response may contribute hypersensitivity resistance cancer genotoxic targeting pathway can increase tumor sensitivity therapies. Therefore, be a potential therapeutic approach for treatment. A better understanding biology regulatory mechanisms has facilitate development inhibitors nuclear mitochondria enhancing anticancer effect damage-based therapy.

Язык: Английский

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A Decade of FDA-Approved Drugs (2010–2019): Trends and Future Directions

Journal of Medicinal Chemistry, Год журнала: 2021, Номер 64(5), С. 2312 - 2338

Опубликована: Фев. 22, 2021

A total of 378 novel drugs and 27 biosimilars approved by the U.S. Food Drug Administration (FDA) between 2010 2019 were evaluated according to approval numbers year, therapeutic areas, modalities, route administration, first-in-class designation, times, expedited review categories. From this review, oncology remains top therapy area (25%), followed infection (15%) central nervous system disorders (11%). Regulatory incentives have been effective as evidenced an increase in orphan well antibacterial under GAIN act. Clinical development times may be increasing, perhaps a result drug indications. Small molecules continue mostly adhere "Rule 5" (Ro5) parameters, but innovation new modalities is rapidly progressing with approvals for antisense oligonucleotides (ASO), small-interfering RNA (siRNAs), antibody-directed conjugates (ADCs). Finally, targets scientific breakthroughs that address areas unmet clinical need are discussed detail.

Язык: Английский

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Molecular mechanisms of tumor resistance to radiotherapy

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

Опубликована: Июнь 15, 2023

Abstract Background Cancer is the most prevalent cause of death globally, and radiotherapy considered standard care for solid tumors, including lung, breast, esophageal, colorectal cancers glioblastoma. Resistance to radiation can lead local treatment failure even cancer recurrence. Main body In this review, we have extensively discussed several crucial aspects that resistance therapy, radiation-induced DNA damage repair, cell cycle arrest, apoptosis escape, abundance stem cells, modification cells their microenvironment, presence exosomal non-coding RNA, metabolic reprogramming, ferroptosis. We aim focus on molecular mechanisms in relation these discuss possible targets improve outcomes. Conclusions Studying responsible its interactions with tumor environment will help responses radiotherapy. Our review provides a foundation identify overcome obstacles effective

Язык: Английский

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DNA repair defects in cancer and therapeutic opportunities

Genes & Development, Год журнала: 2022, Номер 36(5-6), С. 278 - 293

Опубликована: Март 1, 2022

DNA repair and damage signaling pathways are critical for the maintenance of genomic stability. Defects contribute to tumorigenesis, but also render cancer cells vulnerable reliant on remaining activities. Here, we review major classes defects in cancer, instability that they give rise to, therapeutic strategies exploit resulting vulnerabilities. Furthermore, discuss impacts both targeted therapy immunotherapy, highlight emerging principles targeting therapy.

Язык: Английский

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Mechanisms of radiotherapy resistance and radiosensitization strategies for esophageal squamous cell carcinoma

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

Опубликована: Авг. 19, 2023

Abstract Esophageal squamous cell carcinoma (ESCC) is the sixth most common cause of cancer-related mortality worldwide, with more than half them occurred in China. Radiotherapy (RT) has been widely used for treating ESCC. However, radiation-induced DNA damage response (DDR) can promote release cytokines and chemokines, triggers inflammatory reactions changes tumor microenvironment (TME), thereby inhibiting immune function causing invasion metastasis Radioresistance major disease progression cancer, it associated heterogeneity. Therefore, a better understanding radioresistance mechanisms may generate reversal strategies to improve cure rates survival periods ESCC patients. We mainly summarized possible order reveal new targets therapy. Then we compared current reverse radioresistance.

Язык: Английский

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Ubiquitination and deubiquitination in cancer: from mechanisms to novel therapeutic approaches

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Июль 25, 2024

Abstract Ubiquitination, a pivotal posttranslational modification of proteins, plays fundamental role in regulating protein stability. The dysregulation ubiquitinating and deubiquitinating enzymes is common feature various cancers, underscoring the imperative to investigate ubiquitin ligases deubiquitinases (DUBs) for insights into oncogenic processes development therapeutic interventions. In this review, we discuss contributions ubiquitin–proteasome system (UPS) all hallmarks cancer progress drug discovery. We delve multiple functions UPS oncology, including its regulation cancer-associated pathways, metabolic reprogramming, engagement with tumor immune responses, function phenotypic plasticity polymorphic microbiomes, other essential cellular functions. Furthermore, provide comprehensive overview novel anticancer strategies that leverage UPS, application proteolysis targeting chimeras (PROTACs) molecular glues.

Язык: Английский

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Precise genome-editing in human diseases: mechanisms, strategies and applications

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Фев. 26, 2024

Precise genome-editing platforms are versatile tools for generating specific, site-directed DNA insertions, deletions, and substitutions. The continuous enhancement of these has led to a revolution in the life sciences, which promises deliver novel therapies genetic disease. can be traced back 1950s with discovery DNA's double-helix and, after 70 years development, evolved from crude vitro applications wide range sophisticated capabilities, including vivo applications. Nonetheless, precise faces constraints such as modest efficiency, delivery challenges, off-target effects. In this review, we explore genome-editing, focus on introduction landmark events its history, various platforms, systems, First, discuss history genome-editing. Second, describe current state strategies explain how techniques offer unprecedented precision versatility modifying human genome. Third, introduce systems used deploy components through DNA, RNA, RNPs. Finally, summarize labeling endogenous genes, screening variants, molecular recording, disease models, gene therapy, ex therapy potential future advances.

Язык: Английский

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Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(15), С. 8199 - 8199

Опубликована: Июль 30, 2021

Platinum-based chemotherapies, such as cisplatin, play a large role in cancer treatment. The development of resistance and treatment toxicity creates substantial barriers to disease control, yet. To enhance the therapeutic index cisplatin-based chemotherapy, it is imperative circumvent while optimizing tumor sensitization. One primary mechanisms by which cells develop cisplatin through upregulation DNA repair pathways. In this review, we discuss damage response context cisplatin-induced damage. We describe proteins involved pathways their roles development. Common biomarkers for utilization improve patient risk stratification personalization are addressed. Finally, some current treatments future strategies resistance.

Язык: Английский

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Contributions of DNA Damage to Alzheimer’s Disease

International Journal of Molecular Sciences, Год журнала: 2020, Номер 21(5), С. 1666 - 1666

Опубликована: Фев. 28, 2020

Alzheimer’s disease (AD) is the most common type of neurodegenerative disease. Its typical pathology consists extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Mutations in APP, PSEN1, PSEN2 genes increase Aβ production aggregation, thus cause early onset or familial AD. Even with this strong genetic evidence, recent studies support AD to result from complex etiological alterations. Among them, aging strongest risk factor for vast majority cases: Sporadic late (LOAD). Accumulation DNA damage a well-established factor. In regard, large amount evidence reveals as critical pathological Clinically, accumulated brains patients. Genetically, defects repair resulted mutations BRAC1 other occur brain facilitate pathogenesis. Abnormalities can be used diagnostic biomarkers review, we discuss association, causative potential, biomarker values

Язык: Английский

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Biochemical predictors of response to immune checkpoint inhibitors in unresectable hepatocellular carcinoma

Cancer Treatment and Research Communications, Год журнала: 2021, Номер 27, С. 100328 - 100328

Опубликована: Янв. 1, 2021

Hepatocellular carcinoma (HCC) represents the most commonly diagnosed liver cancer worldwide, and overall survival of patients with unresectable disease is poor. In last five years, immune checkpoint inhibitors (ICIs) have revolutionized treatment scenario several hematological solid tumors, these agents been actively explored in HCC. Firstly, promising findings phase I II clinical studies reporting durable responses a tolerable safety profile led to assessment ICIs as single III studies; however, latter provided controversial results, activity ICI monotherapy seems limited small subgroup patients. Conversely, IMbrave150 trial recently showed that, among previously untreated HCC, atezolizumab plus bevacizumab resulted significantly longer progression-free compared sorafenib monotherapy. addition, other under investigation, combination immunotherapy well combinations antiangiogenic agents. Nonetheless, there are currently no validated predictive biomarkers able guide choice this setting, where identification specific predictors response major challenge. review, we aim provide critical overview recent evidence on biochemical especially focusing PD-L1, TMB, MSI, emerging biomarkers.

Язык: Английский

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