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Chromatin structure, transcriptional activity and DNA repair efficiency affect the outcome of chemotherapy in multiple myeloma.

BackgroundMelphalan is one of the most active chemotherapeutic agents in the treatment of multiple myeloma (MM). However, the mechanism underlying differential patient responses to melphalan therapy is unknown.MethodsChromatin structure, transcriptional activity and DNA damage response signals were examined following ex vivo treatment with melphalan of both malignant bone marrow plasma cells (BMPCs) and peripheral blood mononuclear cells (PBMCs) of MM patients, responders (n=57) or non-responders (n=28) to melphalan therapy. PBMCs from healthy controls (n=25) were also included in the study.Re

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… Association between transcriptional activity, local chromatin structure and the efficiencies of both subpathways of nucleotide excision repair of melphalan adducts. Cancer Res. 2009;69:4424–4433. doi: 10.1158/0008-5472.CAN-08-3489. … Mammalian transcription-coupled excision repair. Cold Spring Harb Perspect Biol. 2013;5:a012625. doi: 10.1101/cshperspect.a012625. Walters DK, Wu X, Tschumper RC, Arendt BK, Huddleston PM, Henderson KJ, Dispenzieri A, Jelinek DF. …

Intrinsic retinoic acid synthesis is required for oligodendrocyte progenitor expansion during CNS remyelination.

Myelin regeneration (remyelination) in the CNS depends on the recruitment, proliferation and differentiation of oligodendrocyte precursor cells (OPCs) at demyelinated lesions. However, despite the presence of OPCs, very few oligodendrocytes and myelin are regenerated in chronic multiple sclerosis (MS) lesions for reasons that remain poorly understood. Here, using a spontaneous remyelination model in mice, we found that retinaldehyde dehydrogenase 2 (Raldh2), a rate-limiting enzyme for retinoic acid (RA) synthesis, is upregulated in OPCs and in a subpopulation of microglia/macrophages during re

Chemotherapeutic agents for the treatment of hepatocellular carcinoma: efficacy and mode of action.

Hepatocellular carcinoma (HCC) is a dreaded malignancy that every year causes half a million deaths worldwide. Being an aggressive cancer, its incidence exceeds 700,000 new cases per year worldwide with a median survival of 6-8 months. Despite advances in prognosis and early detection, effective HCC chemoprevention or treatment strategies are still lacking, therefore its dismal survival rate remains largely unchanged. This review will characterize currently available chemotherapeutic drugs used in the treatment of HCC. The respective mode(s) of action, side effects and recommendations will be

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… Sorenson CM Eastman A Influence of cis-diamminedichloroplatinum[II] on DNA synthesis and cell cycle progression in excision repair proficient and deficient Chinese hamster ovary cells . Cancer Res 1988 ; 48 : 6703 - 7 . 3180081 87. …

Current landscape of gene-editing technology in biomedicine: Applications, advantages, challenges, and perspectives.

The expanding genome editing toolbox has revolutionized life science research ranging from the bench to the bedside. These "molecular scissors" have offered us unprecedented abilities to manipulate nucleic acid sequences precisely in living cells from diverse species. Continued advances in genome editing exponentially broaden our knowledge of human genetics, epigenetics, molecular biology, and pathology. Currently, gene editing-mediated therapies have led to impressive responses in patients with hematological diseases, including sickle cell disease and thalassemia. With the discovery of more e

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… SSBs are repaired by nucleotide excision repair (NER) or base excision repair (BER). In the NHEJ pathway, DNA damage can be recognized by the Ku70/Ku80 complex and repaired by subsequent nucleases and ligases. The HDR pathway can achieve effective lesion repair using template‐directed DNA. … The structural basis of specific base‐excision repair by uracil‐DNA glycosylase. Nature. 1995;373(6514):487‐493. 64. Komor AC, Zhao KT, Packer MS, et al. …

A Holistic Review of Oncological Drug Targets and Trajectories of Resistance in Cancer Therapy.

The prolonged and intricate history of oncological treatments has transitioned significantly since the introduction of chemotherapy. Substantial therapeutic benefits in cancer therapy have been achieved by the integration of conventional treatments with molecular biosciences and omics technologies. Human epidermal growth factor receptor, hormone receptors, and angiogenesis factors are among the established therapies in tumor reduction and managing side effects. Novel targeted therapies like KRAS G12C, Claudin-18 isoform 2 (CLDN18.2), Trophoblast cell-surface antigen 2 (TROP2), and epigenetic r

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… The underlying mechanisms for DNA repair constitute the non-homologous end joining pathway, the base excision pathway, and nucleotide excision repair. … (ii) Nucleotide Excision Repair and Oxaliplatin Resistance One more resistance mechanism involves the upregulation of ERCC1, a key component of nucleotide excision repair (NER). In oxaliplatin-resistant tumors, ERCC1 expression is 1.5 times higher than in sensitive ones. …

The versatile emodin: A natural easily acquired anthraquinone possesses promising anticancer properties against a variety of cancers.

Cancers are generally recognized as the leading cause of death and a predominant barrier to prolonging life expectancy in both developed and developing countries. Emodin is a typical anthraquinone derivative from various plants that exhibits a wide spectrum of biological activities, such as anticancer, antibacterial, hepatoprotective and anti-inflammatory activities. Much previous preclinical evidence has demonstrated that emodin exhibits reliable effects on several cancer types, including lung cancer, liver cancer, colon cancer, breast cancer, pancreatic cancer, leukemia, cervical cancer, and

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… repair pathway FEBS J 2006 273 1600 1608 16623697 10.1111/j.1742-4658.2006.05189.x 87 Altaha R Liang X Yu JJ Reed E Excision repair cross complementing-group 1: gene expression and platinum resistance Int J Mol Med 2004 14 959 970 15547660 88 Qiu H Yashiro M Zhang X Miwa A Hirakawa K A FGFR2 inhibitor … repair in cisplatin-resistant ovarian cancer cells: role of ERCC1-XPF Biochem Pharmacol 2000 60 1305 1313 11008124 10.1016/s0006-2952(00)00441-x 122 Selvakumaran M Pisarcik DA Bao R Yeung AT Hamilton TC Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in ovarian …

Application and mechanistic research of novel therapeutic strategies in cisplatin-resistant small cell lung cancer.

IntroductionSmall cell lung cancer (SCLC) initially responds well to cisplatin-based chemotherapy, but rapid development of drug resistance limits long-term efficacy and subsequent treatment options. Understanding the multifactorial mechanisms of cisplatin resistance is essential for improving patient outcomes. This review synthesizes recent preclinical and clinical advances, focusing on seven key resistance mechanisms and emerging therapeutic strategies, including immunotherapy, targeted therapy, and novel chemotherapeutic agents.DiscussionCisplatin resistance in SCLC arises through multiple

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… The nucleotide excision repair (NER) pathway plays a crucial role in the repair of substantial DNA damage induced by chemical agents. In SCLC, the efficient operation of the NER pathway can remove cisplatin-DNA adducts, reducing their cytotoxicity [ 42 ]. … Platinum-DNA adduct, nucleotide excision repair and platinum based anti-cancer chemotherapy . Cancer Treat Rev . 1998 ; 24 ( 5 ): 331 – 344 . doi: 10.1016/s0305-7372(98)90056-1 . 9861196 45 Friboulet L , Olaussen KA , Pignon JP , et al. …

Role of Dietary Antioxidants in p53-Mediated Cancer Chemoprevention and Tumor Suppression.

Cancer arises through a complex interplay between genetic, behavioral, metabolic, and environmental factors that combined trigger cellular changes that over time promote malignancy. In terms of cancer prevention, behavioral interventions such as diet can promote genetic programs that may facilitate tumor suppression; and one of the key tumor suppressors responsible for initiating such programs is p53. The p53 protein is activated by various cellular events such as DNA damage, hypoxia, heat shock, and overexpression of oncogenes. Due to its role in cell fate decisions after DNA damage, regulato

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… (NER) to reduce DNA damage and UV photoproducts [ 50 ]. p53 also exerts its regulation of DNA function by base excision repair (BER). … The role of p53 in base excision repair following genotoxic stress. Carcinogenesis. 2004;25(1):11–19. doi: 10.1093/carcin/bgg186. 51. Zhou J., Ahn J., Wilson S. H., Prives C. A role for p53 in base excision repair. The EMBO Journal. 2001;20(4):914–923. doi: 10.1093/emboj/20.4.914. 52. Vitre B. …

Identifying novel genes and biological processes relevant to the development of cancer therapy-induced mucositis: An informative gene network analysis.

Mucositis is a complex, dose-limiting toxicity of chemotherapy or radiotherapy that leads to painful mouth ulcers, difficulty eating or swallowing, gastrointestinal distress, and reduced quality of life for patients with cancer. Mucositis is most common for those undergoing high-dose chemotherapy and hematopoietic stem cell transplantation and for those being treated for malignancies of the head and neck. Treatment and management of mucositis remain challenging. It is expected that multiple genes are involved in the formation, severity, and persistence of mucositis. We used Ingenuity Pathway A

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… ERCC1 is a key component of the nucleotide excision repair complex [ 68 ]. XRCC1 repairs single-strand breaks and is part of the base excision repair pathway [ 69 ]. Polymorphisms of DNA repair genes may affect the fate of cells after DNA damage [ 70 ]. … BRCA1 has important roles in nucleotide excision repair, non-homologous end-joining, and homologous recombinational repair by interacting with components of these DNA repair mechanisms, and by regulating the expression of genes involved in these repair pathways [ 73 ]. …

APOBEC3B reporter myeloma cell lines identify DNA damage response pathways leading to APOBEC3B expression.

Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) DNA cytosine deaminase 3B (A3B) is a DNA editing enzyme which induces genomic DNA mutations in multiple myeloma and in various other cancers. APOBEC family proteins are highly homologous so it is especially difficult to investigate the biology of specifically A3B in cancer cells. To easily and comprehensively investigate A3B function in myeloma cells, we used CRISPR/Cas9 to generate A3B reporter cells that contain 3×FLAG tag and IRES-EGFP sequences integrated at the end of the A3B gene. These reporter cells stably express

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… DNA interstrand cross-linkers form a number of adducts with DNA, and thereafter activate a wide variety of DNA repair pathways [ 53 ] such as nucleotide excision repair (NER) [ 54 , 55 ], homology-directed repair (HDR) [ 56 ] and mismatch repair (MMR) [ 57 ]. … Nat Struct Mol Biol . 2012 ; 19 ( 4 ): 387 – 94 . 10.1038/nsmb.2245 22407014 PMC3319806 60 Li H , Chang TW , Tsai YC , Chu SF , Wu YY , Tzang BS , et al Colcemid inhibits the rejoining of the nucleotide excision repair of UVC-induced DNA damages in Chinese hamster ovary cells . …

Double jeopardy: how BRCA2, TP53, and DNMT3A redefine the link between infertility and cancer risk.

BackgroundGermline mutations in genes governing DNA repair, cell cycle regulation, and epigenetic modification are now recognized as common etiological factors for both cancer predisposition and reproductive dysfunction. This reveals a profound intersection between reproductive biology and oncogenesis.MethodA systematic narrative review was conducted. The literature search spanned PubMed/MEDLINE, Scopus, and Web of Science using keywords and MeSH terms related to infertility phenotypes, cancer predisposition syndromes, and shared molecular mechanisms (e.g., DNA repair, epigenetics).OutcomesThe

Epigenetic Mechanisms in DNA Double Strand Break Repair: A Clinical Review.

Upon the induction of DNA damage, the chromatin structure unwinds to allow access to enzymes to catalyse the repair. The regulation of the winding and unwinding of chromatin occurs via epigenetic modifications, which can alter gene expression without changing the DNA sequence. Epigenetic mechanisms such as histone acetylation and DNA methylation are known to be reversible and have been indicated to play different roles in the repair of DNA. More importantly, the inhibition of such mechanisms has been reported to play a role in the repair of double strand breaks, the most detrimental type of DN

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… Some of these repair mechanisms involve base excision repair (BER), mismatch repair (MMR), post-replication repair and error-prone repair systems ( Iyama and Wilson, 2013 ; Vaz et al., 2017 ; Rajapakse et al., 2019 ). … Mechanisms of DNA Excision Repair. Science 266 (5193), 1954–1956. 10.1126/science.7801120 Sant D. W., Mustafi S., Gustafson C. B., Chen J., Slingerland J. M., Wang G. (2018). Vitamin C Promotes Apoptosis in Breast Cancer Cells by Increasing TRAIL Expression. Sci. …

Mechanisms and Clinical Applications of Genome Instability in Multiple Myeloma.

Ongoing genomic instability represents a hallmark of multiple myeloma (MM) cells, which manifests largely as whole chromosome- or translocation-based aneuploidy. Importantly, although it supports tumorigenesis, progression and, response to treatment in MM patients, it remains one of the least understood components of malignant transformation in terms of molecular basis. Therefore these aspects make the comprehension of genomic instability a pioneering strategy for novel therapeutic and clinical speculations to use in the management of MM patients. Here we will review mechanisms mediating genom

Circadian clock and cancer.

Circadian rhythms play a critical role in regulating physiological and behavioral processes, such as the sleep-wake cycle, hormone secretion, and metabolism. These rhythms are controlled by endogenous biological clocks, which are synchronized with environmental cues, primarily the light-dark cycle. Notably, disruption or reprogramming of circadian rhythms is closely associated with cancer initiation, progression, and treatment response. At the molecular level, the dysregulation of core clock genes can disturb normal cellular rhythms, leading to aberrant cell proliferation, impaired DNA repair,

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… Here, we explain how core clock components (such as CLOCK, BMAL1, PERs, and CRYs) control DDR pathways such as nucleotide excision repair (NER), homologous recombination (HR), and base excision repair (BER) through transcriptional control, protein interactions, and metabolic changes [56] . … Base excision repair; BMAL1. Brain and muscle ARNT-Like 1; BRCA1. Breast cancer type 1 susceptibility protein; BRCA2. Breast cancer type 2 susceptibility protein; CDKN1A. Cyclin-dependent kinase inhibitor 1A; CHK. Checkpoint kinase; CK2. Casein kinase 2; CLOCK. …

A Review of Approaches to Potentiate the Activity of Temozolomide against Glioblastoma to Overcome Resistance.

A glioblastoma (GBM) is one of the most aggressive, infiltrative, and treatment-resistant malignancies of the central nervous system (CNS). The current standard of care for GBMs include maximally safe tumor resection, followed by concurrent adjuvant radiation treatment and chemotherapy with the DNA alkylating agent temozolomide (TMZ), which was approved by the FDA in 2005 based on a marginal increase (~2 months) in overall survival (OS) levels. This treatment approach, while initially successful in containing and treating GBM, almost invariably fails to prevent tumor recurrence. In addition to

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… While N 7 -meG and N 3 -meA account for 70% and 9% of the adducts formed, respectively, these are efficiently repaired by the base excision repair (BER) pathway, and they normally contribute little to cytotoxicity. … Overcoming temozolomide resistance in glioblastoma via dual inhibition of NAD+ biosynthesis and base excision repair. Cancer Res. 2011;71:2308–2317. doi: 10.1158/0008-5472.CAN-10-3213. 37. …

The cGAS-STING pathway in senescence and aging-related diseases: mechanisms and therapeutic opportunities.

The cGAS-STING pathway acts as a critical molecular hub connecting genomic instability with cellular senescence. Functioning as a key regulator of the innate immune system, this pathway detects aberrant cytoplasmic DNA to activate downstream inflammatory responses, thereby playing a pivotal role in aging-related diseases. This review systematically explores the core mechanisms by which the cGAS-STING pathway regulates cellular senescence, emphasizing its role in triggering senescence through the recognition of DNA damage signals (e.g., oxidative stress, telomere dysfunction) and promoting para

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… Under physiological conditions, a robust network of DNA repair pathways—such as nucleotide excision repair (NER), base excision repair (BER), and non-homologous end joining (NHEJ)—efficiently resolves such damage to maintain genomic integrity [ 43 – 45 ]. … During this process, the functionality of DNA repair pathways—including nucleotide excision repair (NER), base excision repair (BER), and non-homologous end joining (NHEJ)—is downregulated, further exacerbating DNA damage. …

Перепрофилированный активатор Nrf2 диметилфумарат спасает мышцы воспаление и фиброз в отягченной мышиной модели мышечной дистрофии Дученна.

В унаследованных нейромускульных болезнях мышечная дистрофия Дюченна (ДМД) глюкокортикоиды значительно медленнее прогрессируют, но в то же время создают достаточно серьезные побочные эффекты, исключающие применение в значительной части пациентов. Распространяя наши выводы о том, что в результате острого лечения с УЛХ были одобрены многочисленные склерозные препараты, диметилфумарат (ДМФ), спасающая мышечную патологию у молодых мышей Mdx, мы намеревались провести доклиническое тестирование на перевод. Чтобы усилить фенотип болезни у взрослых мышц mdx, у которых обычно нет эквивалентной человече

Poly(ADP-Ribose) Polymerase Inhibitors in Pancreatic Cancer: A New Treatment Paradigms and Future Implications.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy. Most of the patients of PDAC present at later stages of disease and have a five-year survival rate of less than 10%. About 5-10% PDAC cases are hereditary in nature and have DNA damage repair (DDR) mutations such as BRCA 1 and 2. Besides having implications on screening and prevention strategies, these mutations can confer sensitivity to platinum-based therapies and determine eligibility for poly(ADP-ribose) polymerase inhibitors (PARPi). In the presence of DDR mutations and PARPi, the cells are unable to utilize the error-fr

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… DNA damage repair (DDR) occurs via four major pathways; nucleotide excision repair (NER), base-excision repair (BER), MMR, HR, and non-homologous end joining (NHEJ) [ 18 ]. … (ADP-ribose)n participates in DNA excision repair Nature 1980 283 593 596 10.1038/283593a0 6243744 22. Krishnakumar R. Kraus W.L. The PARP side of the nucleus: Molecular actions, physiological outcomes, and clinical targets Mol. …

Ixazomib in combination with carboplatin in pretreated women with advanced triple-negative breast cancer, a phase I/II trial of the AGMT (AGMT MBC-10 trial).

BACKGROUND: Triple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with poor prognosis. Up to now, no targeted treatment beyond anti-VEGF therapy has been approved for TNBC and cytotoxic agents remain the mainstay of treatment. Ixazomib is a selective and reversible inhibitor of the proteasome, which has been mainly investigated in the treatment of multiple myeloma. In a preclinical study TNBC cells were treated with the first-generation proteasome inhibitor bortezomib in combination with cisplatin and synergistic efficacy was demonstrat

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… The FA signaling cascade coordinates a complex mechanism consisting of three classical DNA repair systems (homologous recombination, nucleotide excision repair, mutagenic translesion synthesis) in response to DNA damage [ 7 ]: Five FA proteins (A, C, E, F, and G) regulate the activation of FANCD2 by … Compared to luminal breast cancers, TNBC also have a reduced DNA repair capability due to a reduced expression of DNA repair genes including nucleotide excision repair, Fanconi Anemia pathways and CHK1 [ 34 ]. …

Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies.

Tumor suppressor p53 can transcriptionally activate downstream genes in response to stress, and then regulate the cell cycle, DNA repair, metabolism, angiogenesis, apoptosis, and other biological responses. p53 has seven functional domains and 12 splice isoforms, and different domains and subtypes play different roles. The activation and inactivation of p53 are finely regulated and are associated with phosphorylation/acetylation modification and ubiquitination modification, respectively. Abnormal activation of p53 is closely related to the occurrence and development of cancer. While targeted t