Targeting the Ubiquitin–Proteasome System and Recent Advances in Cancer Therapy

Cells, Год журнала: 2023, Номер 13(1), С. 29 - 29

Опубликована: Дек. 22, 2023

Ubiquitination is a reversible post-translational modification based on the chemical addition of ubiquitin to proteins with regulatory effects various signaling pathways. can alter molecular functions tagged substrates respect protein turnover, biological activity, subcellular localization or protein–protein interaction. As result, wide variety cellular processes are under ubiquitination-mediated control, contributing maintenance homeostasis. It follows that dysregulation ubiquitination reactions plays relevant role in pathogenic states human diseases such as neurodegenerative diseases, immune-related pathologies and cancer. In recent decades, enzymes ubiquitin–proteasome system (UPS), including E3 ligases deubiquitinases (DUBs), have attracted attention novel druggable targets for development new anticancer therapeutic approaches. This perspective article summarizes peculiarities shared by involved reaction which, when deregulated, lead tumorigenesis. Accordingly, an overview main pharmacological interventions targeting UPS clinical use still trials provided, also highlighting limitations efficacy these Therefore, attempts circumvent drug resistance side well UPS-related emerging technologies therapeutics discussed.

Язык: Английский

---

Flash Radiotherapy: Innovative Cancer Treatment

Encyclopedia, Год журнала: 2023, Номер 3(3), С. 808 - 823

Опубликована: Июнь 26, 2023

Flash radiotherapy (Flash-RT) is an innovative technique used in for cancer treatment because it delivers extremely high dose of radiation (>40 Gy/s) to the tumour a very short period time, typically within fraction second. This ultra-fast delivery distinguishes Flash-RT from conventional radiotherapy, which involves over longer time period, often several minutes. Studies conducted cell and preclinical models suggested that may spare normal tissues radiation-related side effects, such as skin toxicity, gastrointestinal complications, damage organs-at-risk. believed be due unique tissue response ultra-high rate. Nevertheless, while shows promising results early clinical studies, one should note still stages development. entry provides comprehensive exploration immense potentials Flash-RT, covering its background, mechanisms, sources, recent experimental findings based on models, future prospects. It aims provide valuable insights into this technology anyone interested subject.

Язык: Английский

---

Splicing modulators impair DNA damage response and induce killing of cohesin-mutant MDS and AML

Science Translational Medicine, Год журнала: 2024, Номер 16(728)

Опубликована: Янв. 3, 2024

Splicing modulation is a promising treatment strategy pursued to date only in splicing factor-mutant cancers; however, its therapeutic potential poorly understood outside of this context. Like factors, genes encoding components the cohesin complex are frequently mutated cancer, including myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (AML), where they associated with poor outcomes. Here, we showed that mutations biomarkers sensitivity drugs targeting factor 3B subunit 1 (SF3B1) H3B-8800 E-7107. We identified drug-induced alterations splicing, corresponding reduced gene expression, number DNA repair genes, BRCA1 BRCA2 , as mechanism underlying cell line models, primary patient samples patient-derived xenograft (PDX) models AML. found damage particularly sensitive exon skipping induced by SF3B1 modulators due their long length large exons per transcript. Furthermore, demonstrated cohesin-mutant cells not resulted impaired response accumulation damage, but it sensitized subsequent killing poly(ADP-ribose) polymerase (PARP) inhibitors chemotherapy led improved overall survival PDX AML vivo. Our findings expand benefits include MDS

Язык: Английский

---

Understanding Cancer’s Defense against Topoisomerase-Active Drugs: A Comprehensive Review

Cancers, Год журнала: 2024, Номер 16(4), С. 680 - 680

Опубликована: Фев. 6, 2024

In recent years, the emergence of cancer drug resistance has been one crucial tumor hallmarks that are supported by level genetic heterogeneity and complexities at cellular levels. Oxidative stress, immune evasion, metabolic reprogramming, overexpression ABC transporters, stemness among several key contributing molecular response mechanisms. Topo-active drugs, e.g., doxorubicin topotecan, clinically active utilized extensively against a wide variety human tumors often result in development failure to therapy. Thus, there is an urgent need for incremental comprehensive understanding mechanisms specifically context topo-active drugs. This review delves into intricate mechanistic aspects these intracellular extracellular explores use potential combinatorial approaches utilizing various drugs inhibitors pathways involved resistance. We believe this will help guide basic scientists, pre-clinicians, clinicians, policymakers toward holistic interdisciplinary strategies transcend resistance, renewing optimism ongoing battle cancer.

Язык: Английский

---

BRCAness, DNA gaps, and gain and loss of PARP inhibitor–induced synthetic lethality

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(14)

Опубликована: Июль 14, 2024

Mutations in the tumor-suppressor genes BRCA1 and BRCA2 resulting BRCA1/2 deficiency are frequently identified breast, ovarian, prostate, pancreatic, other cancers. Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cancer cells by inducing synthetic lethality, providing an effective biomarker-guided strategy for targeted therapy. However, a substantial fraction of patients carrying mutations do not respond to PARPis, most develop resistance PARPis over time, highlighting major obstacle PARPi therapy clinic. Recent studies have revealed that changes specific functional defects cells, particularly their suppressing protecting single-stranded DNA gaps, contribute gain or loss PARPi-induced lethality. These findings only shed light on mechanism action but also lead revised models explain how BRCA-deficient cells. Furthermore, new mechanistic principles sensitivity emerged from these studies, generating potentially useful guidelines predicting response design therapies overcoming resistance. In this Review, we will discuss recent put them context with classic views aiming stimulate development therapeutic strategies overcome improve

Язык: Английский

---