Understanding and targeting resistance mechanisms in cancer

MedComm, Год журнала: 2023, Номер 4(3)

Опубликована: Май 22, 2023

Resistance to cancer therapies has been a commonly observed phenomenon in clinical practice, which is one of the major causes treatment failure and poor patient survival. The reduced responsiveness cells multifaceted that can arise from genetic, epigenetic, microenvironmental factors. Various mechanisms have discovered extensively studied, including drug inactivation, intracellular accumulation by uptake or increased efflux, target alteration, activation compensatory pathways for cell survival, regulation DNA repair death, tumor plasticity, microenvironments (TMEs). To overcome resistance, variety strategies proposed, are designed enhance effectiveness reduce resistance. These include identifying biomarkers predict response new targets, developing targeted drugs, combination targeting multiple signaling pathways, modulating TME. present article focuses on different resistance corresponding tackling approaches with recent updates. Perspectives polytherapy mechanisms, novel nanoparticle delivery systems, advanced design tools overcoming also reviewed.

Язык: Английский

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Understanding Drug Sensitivity and Tackling Resistance in Cancer

Cancer Research, Год журнала: 2022, Номер 82(8), С. 1448 - 1460

Опубликована: Фев. 21, 2022

Abstract Decades of research into the molecular mechanisms cancer and development novel therapeutics have yielded a number remarkable successes. However, our ability to broadly assign effective, rationally targeted therapies in personalized manner remains elusive for many patients, drug resistance persists as major problem. This is part due well-documented heterogeneity cancer, including diversity tumor cell lineages states, spectrum somatic mutations, complexity microenvironments, immune-suppressive features immune repertoires, which collectively require numerous different therapeutic approaches. Here, we describe framework understand types biological causes resistance, providing translational opportunities tackle by rational strategies.

Язык: Английский

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Computational Methods for the Analysis and Prediction of EGFR-Mutated Lung Cancer Drug Resistance: Recent Advances in Drug Design, Challenges and Future Prospects

IEEE/ACM Transactions on Computational Biology and Bioinformatics, Год журнала: 2022, Номер 20(1), С. 238 - 255

Опубликована: Янв. 10, 2022

Lung cancer is a major cause of deaths worldwide, and has very low survival rate. Non-small cell lung (NSCLC) the largest subset cancers, which accounts for about 85% all cases. It been well established that mutation in epidermal growth factor receptor (EGFR) can lead to cancer. EGFR Tyrosine Kinase Inhibitors are developed target kinase domain EGFR. These TKIs produce promising results at initial stage therapy, but efficacy becomes limited due development drug resistance. In this paper, we provide comprehensive overview computational methods, understanding resistance mechanisms. Next, evaluate role important parameters mechanism, including structural dynamics, stability, dimerization, binding free energies, signaling pathways. Personalized prediction models, response curves, synergy, other data-driven methods also discussed. We explore limitations current methodologies discuss strategies overcome them. believe review will serve as reference researchers; apply techniques precision medicine, analyzing structures protein-drug complexes, discovery, mechanisms patients.

Язык: Английский

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Bioactivity of natural biflavonoids in metabolism-related disease and cancer therapies

Pharmacological Research, Год журнала: 2021, Номер 167, С. 105525 - 105525

Опубликована: Март 3, 2021

Язык: Английский

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Activation of Nrf2 signaling pathway by natural and synthetic chalcones: a therapeutic road map for oxidative stress

Expert Review of Clinical Pharmacology, Год журнала: 2021, Номер 14(4), С. 465 - 480

Опубликована: Март 11, 2021

Introduction:Nuclear factor erythroid 2-related 2 (Nrf2) signaling pathway plays a key role in diverse gene expressions responsible for protection against oxidative stress and xenobiotics. Chalcones with common chemical scaffold of 1,3-diaryl-2- propen-1-one, are abundantly present nature wide variety pharmacological properties. This review will discuss the interactions natural synthetic chalcones Nrf2 signaling.Areas covered:Chalcones reportedly found to activate pathway, expression Nrf2-regulated antioxidant genes, induce cytoprotective proteins upregulate multidrug resistance-associated proteins. being soft electrophiles less prone hostile off-target effects unlikely carcinogenicity mutagenicity. Furthermore, their low toxicity, structural diversity, feasibility reorganization presence α,β-unsaturated carbonyl group which makes them suitable drug candidates targeting Nrf2-dependent diseases.Expert opinion:Nrf2-Keap1 central redox signaling. However, available therapeutic agents activation have limited practical applications due associated risks, relatively efficacy bioavailability. The designing fabrication new entities chalcone scaffold-based Michael acceptor mechanism should be aimed as potential activators target inflammation-mediated diseases such atherosclerosis, Parkinson's disease many more.

Язык: Английский

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The role of UDP-glycosyltransferases in xenobioticresistance

Drug Metabolism Reviews, Год журнала: 2022, Номер 54(3), С. 282 - 298

Опубликована: Май 28, 2022

Uridine diphosphate sugar-utilizing glycosyltransferases (UGTs) are an enzyme superfamily that catalyzes glycosyl residues transfer from activated nucleotide sugars to acceptor molecules. In addition various endogenous compounds, numerous xenobiotics substrates of UGTs. As the glycosides formed generally less active/toxic and more hydrophilic than aglycones, UGTs effectively protect organisms potentially harmful xenobiotics. Therefore, increased UGT expression and/or activity improve protection organism may contribute development individuals become resistant certain While function in resistance human cancer cells chemotherapy is now well known, other have attracted much attention. This review was designed fill this knowledge gap by presenting complex information about role xenobiotic-resistance organisms. summarization evaluation available reveals play important defense against not only humans, but countless such as parasites, insects, plants. Moreover, many recent studies clearly show participation nematodes anthelmintics, insects insecticides, weeds herbicides humans drugs (not those used therapy also treatment epilepsy, psychiatric disorders, hypertension, hypercholesterolemia, HIV infection). Nevertheless, although contribution xenobiotic diverse has obvious, pieces remain missing, for example with regard mechanisms regulation.

Язык: Английский

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The Uridine diphosphate (UDP)-glycosyltransferases (UGTs) superfamily: the role in tumor cell metabolism

Frontiers in Oncology, Год журнала: 2023, Номер 12

Опубликована: Янв. 19, 2023

UDP-glycosyltransferases (UGTs), important enzymes in biotransformation, control the levels and distribution of numerous endogenous signaling molecules metabolism a wide range exogenous chemicals. The UGT superfamily mammals consists UGT1, UGT2, UGT3, UGT8 families. UGTs are rate-limiting glucuronate pathway, tumors, they either overexpressed or underexpressed. Alterations their can affect gluconeogenesis lipid pathways, leading to alterations tumor cell metabolism, which cancer development prognosis. Glucuronidation is most common mammalian conjugation pathway. Most its reactions mainly catalyzed by UGT1A, UGT2A UGT2B. body excretes UGT-bound small lipophilic through bile, urine, feces. conjugate variety tiny sugars, such as galactose, xylose, acetylglucosamine, glucuronic acid, glucose, thereby inactivating making water-soluble substrates, carcinogens, medicines, steroids, lipids, fatty acids, bile acids. This review summarizes roles members four enzyme families function, multiple regulatory mechanisms, Inhibitors inducers. function drug hormone cells among topics covered.

Язык: Английский

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Multidisciplinary approaches for enzyme biocatalysis in pharmaceuticals: protein engineering, computational biology, and nanoarchitectonics

EES Catalysis, Год журнала: 2023, Номер 2(1), С. 14 - 48

Опубликована: Окт. 28, 2023

This article reviews the integration of multidisciplinary approaches, including protein engineering, computational biology, and nanoarchitectonics, to advance pharmaceutical enzyme biocatalysis.

Язык: Английский

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Personalized Statin Therapy: Targeting Metabolic Processes to Modulate the Therapeutic and Adverse Effects of Statins

Heliyon, Год журнала: 2025, Номер 11(1), С. e41629 - e41629

Опубликована: Янв. 1, 2025

Язык: Английский

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Ibrutinib in the Treatment of Solid Tumors: Current State of Knowledge and Future Directions

Cells, Год журнала: 2022, Номер 11(8), С. 1338 - 1338

Опубликована: Апрель 14, 2022

Bruton's Tyrosine Kinase (BTK) is considered crucial in the activation and survival of both physiological malignant B-cells. In recent years, ibrutinib, an oral BTK inhibitor, became a breakthrough therapy for hematological malignancies, such as chronic lymphocytic. However, ibrutinib's feasibility might not end there. Several other kinases with established involvement solid malignancies (i.e., EGFR, HER2) have been found to be inhibited by this agent. Recent discoveries indicate that potential anti-solid tumor target. Consequently, BTK-inhibitor, has studied therapeutic option malignancies. While most preclinical studies ibrutinib effective some specific indications, NSCLC breast cancer, clinical trials contradict these observations. Nevertheless, while failed monotherapy, it become interesting part multidrug regime: only synergism between compounds, trametinib or dactolisib, observed vitro, but inhibitor also radio- chemosensitizer. This review aims describe milestones translating inhibitors tumors order understand future agent better.

Язык: Английский

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