scholarly journals microRNAs: Are they Important in the Development of Resistance in Leishmaniasis?

2021 ◽  
Author(s):  
Sandra Alves de Araújo ◽  
Tatiane Aranha da Penha-Silva ◽  
Jaqueline Diniz Pinho ◽  
Marcelo de Souza Andrade ◽  
Ana Lucia Abreu-Silva
Keyword(s):  
Public Health ◽  
Immune Response ◽  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Mechanisms Of Action ◽  
Parasitic Disease ◽  
Development Of Resistance ◽  
Leishmania Spp ◽  
Antileishmanial Drug ◽  
Molecular Bases

Leishmaniasis is an infectious and parasitic disease of great importance in public health. Numerous studies indicate that biochemical and molecular mechanisms are factors that contribute to the emergence of antileishmanial drug resistance. Currently, miRNAs have been identified as targets for the invasion of pathogens to control the immune response and imply resistance to treatments. Considering the alarming growth in drug resistance, new possibilities for controlling leishmaniasis have been emerging. Natural compounds originating from medicinal plants are being increasingly explored as promising antileishmanial alternatives. The chapter aims to provide a brief review on mechanisms of action associated with traditional agents used to treat leishmaniasis, focusing mainly on molecular bases associated with the resistance of Leishmania spp. to current drugs and identifying the possible miRNAs involved in this process. In addition, we seek to describe some of the promising plant molecules that can be used as potential antileishmanial agents and their possible mechanisms of action.

scholarly journals Carboplatin: molecular mechanisms of action associated with chemoresistance

2014 ◽  
Vol 50 (4) ◽  
pp. 693-701 ◽  
Author(s):  
Graziele Fonseca de Sousa ◽  
Samarina Rodrigues Wlodarczyk ◽  
Gisele Monteiro
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Strategies ◽  
Mechanisms Of Action ◽  
Rational Drug Design ◽  
Full Potential ◽  
Mechanisms Of Resistance ◽  
Development Of Resistance ◽  
Rational Drug ◽  
Biochemical Mechanisms ◽  
Tumor Types

Carboplatin is a derivative of cisplatin; it has a similar mechanism of action, but differs in terms of structure and toxicity. It was approved by the FDA in the 1980s and since then it has been widely used in the treatment of several tumor types. This agent is characterized by its ability to generate lesions in DNA through the formation of adducts with platinum, thereby inhibiting replication and transcription and leading to cell death. However, its use can lead to serious inconvenience arising from the development of resistance that some patients acquire during treatment, limiting the scope of its full potential. Currently, the biochemical mechanisms related to resistance are not precisely known. Therefore, knowledge of pathways associated with resistance caused by carboplatin exposure may provide valuable clues for more efficient rational drug design in platinum-based therapy and the development of new therapeutic strategies. In this narrative review, we discuss some of the known mechanisms of resistance to platinum-based drugs, especially carboplatin.

scholarly journals Mechanisms of Action of the PGLYRP1/Tag7 Protein in Innate and Acquired Immunity

Acta Naturae ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 91-101
Author(s):  
Denis V. Yashin ◽  
Lidia P. Saschenko ◽  
George P. Georgiev
Keyword(s):  
Immune Response ◽  
Tumor Cells ◽  
Defense Mechanisms ◽  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Limited Proteolysis ◽  
Mechanisms Of Action ◽  
Acquired Immunity ◽  
Cytotoxic Lymphocytes ◽  
S100a4 Protein

One of the promising fields of modern molecular biology is the search for new proteins that regulate the various stages of the immune response and the investigation of the molecular mechanisms of action of these proteins. Such proteins include the multifunctional protein PGLYRP1/Tag7, belonging to the PGRP-S protein family, whose gene was discovered in mice at the Institute of Gene Biology, Russian Academy of Sciences, in 1996. PGLYRP1/Tag7 is classified as a protein of innate immunity; however, it can also participate in the regulation of acquired immunity mechanisms. In this paper, we consider the involvement of PGLYRP1/Tag7 in the triggering of antimicrobial defense mechanisms and formation of subsets of cytotoxic lymphocytes that kill tumor cells. The paper emphasizes that the multifaceted functional activity of Tag7 in the immune response has to do with its ability to interact with various proteins to form stable protein complexes. Hsp70-associated Tag7 can induce the death of tumor cells carrying the TNFR1 receptor. Tag7, associated with the Mts1 (S100A4) protein, can stimulate the migration of innate and adaptive immune cytotoxic lymphocytes to a lesion site. Involvement of Tag7 in the regulation of immunological processes suggests that it may be considered as a promising agent in cancer therapy. These properties of Tag7 were used to develop autologous vaccines that have passed the first and second phases of clinical trials in patients with end-stage melanoma and renal cancer. The C-terminal peptide of Tag7, isolated by limited proteolysis, was shown to protect the cartilage and bone tissue of the ankle joint in mice with induced autoimmune arthritis and may be a promising drug for suppressing the development of inflammatory processes.

scholarly journals Isoniazid, The Frontline of Resistance in Mycobacterium tuberculosis

2002 ◽  
Vol 6 (2) ◽  
Author(s):  
James B. Whitney ◽  
Mark A. Wainberg
Keyword(s):  
Public Health ◽  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Genome Sequence ◽  
Molecular Mechanisms ◽  
Close Association ◽  
Drug Resistant ◽  
Efficient Control ◽  
Control And Management ◽  
Developed Nations

Tuberculosis is an ancient disease that has held close association with humans for millennia. Through persistence, this remarkably successful organism has managed to infect an estimated third of the world's population. Declining rates of tuberculosis in developed nations have masked an emerging epidemic of drug resistant cases that have been reported in almost every country under scrutiny. The recent completion of the genome sequence of Mycobacterium tuberculosis has mandated more efficient control and management of this disease. The momentum for this public health imperative will come from information gleaned from advances in genomics and related technologies towards deciphering molecular mechanisms of mycobacterial drug resistance.

scholarly journals Cisplatin and beyond: molecular mechanisms of action and drug resistance development in cancer chemotherapy

2019 ◽  
Vol 53 (2) ◽  
pp. 148-158 ◽  
Author(s):  
Tomaz Makovec
Keyword(s):  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Large Body ◽  
Chemical Properties ◽  
Platinum Complexes ◽  
Platinum Drugs ◽  
Metal Compounds ◽  
Development Of Resistance ◽  
Covalent Adducts

AbstractBackgroundPlatinum-based anticancer drugs are widely used in the chemotherapy of human neoplasms. The major obstacle for the clinical use of this class of drugs is the development of resistance and toxicity. It is therefore very important to understand the chemical properties, transport and metabolic pathways and mechanism of actions of these compounds. There is a large body of evidence that therapeutic and toxic effects of platinum drugs on cells are not only a consequence of covalent adducts formation between platinum complexes and DNA but also with RNA and many proteins. These processes determine molecular mechanisms that underlie resistance to platinum drugs as well as their toxicity. Increased expression levels of various transporters and increased repair of platinum-DNA adducts are both considered as the most significant processes in the development of drug resistance. Functional genomics has an increasing role in predicting patients’ responses to platinum drugs. Genetic polymorphisms affecting these processes may play an important role and constitute the basis for individualized approach to cancer therapy. Similar processes may also influence therapeutic potential of nonplatinum metal compounds with anticancer activity.ConclusionsCisplatin is the most frequently used platinum based chemotherapeutic agent that is clinically proven to combat different types of cancers and sarcomas.

scholarly journals The Role of the Receptor Tyrosine Kinase Axl in Carcinogenesis and Development of Therapeutic Resistance: An Overview of Molecular Mechanisms and Future Applications

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1521
Author(s):  
Martha Wium ◽  
Aderonke F. Ajayi-Smith ◽  
Juliano D. Paccez ◽  
Luiz F. Zerbini
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
Cancer Progression ◽  
Receptor Tyrosine Kinase ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Chemotherapeutic Agents ◽  
Mesenchymal Transition ◽  
Development Of Resistance

Resistance to chemotherapeutic agents by cancer cells has remained a major obstacle in the successful treatment of various cancers. Numerous factors such as DNA damage repair, cell death inhibition, epithelial–mesenchymal transition, and evasion of apoptosis have all been implicated in the promotion of chemoresistance. The receptor tyrosine kinase Axl, a member of the TAM family (which includes TYRO3 and MER), plays an important role in the regulation of cellular processes such as proliferation, motility, survival, and immunologic response. The overexpression of Axl is reported in several solid and hematological malignancies, including non-small cell lung, prostate, breast, liver and gastric cancers, and acute myeloid leukaemia. The overexpression of Axl is associated with poor prognosis and the development of resistance to therapy. Reports show that Axl overexpression confers drug resistance in lung cancer and advances the emergence of tolerant cells. Axl is, therefore, an important candidate as a prognostic biomarker and target for anticancer therapies. In this review, we discuss the consequence of Axl upregulation in cancers, provide evidence for its role in cancer progression and the development of drug resistance. We will also discuss the therapeutic potential of Axl in the treatment of cancer.

scholarly journals Advances in Drug Resistance of Esophageal Cancer: From the Perspective of Tumor Microenvironment

2021 ◽  
Vol 9 ◽  
Author(s):  
Siyuan Luan ◽  
Xiaoxi Zeng ◽  
Chao Zhang ◽  
Jiajun Qiu ◽  
Yushang Yang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Esophageal Cancer ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Therapeutic Benefit ◽  
Therapeutic Agents ◽  
Development Of Resistance ◽  
Cellular Components

Drug resistance represents the major obstacle to get the maximum therapeutic benefit for patients with esophageal cancer since numerous patients are inherently or adaptively resistant to therapeutic agents. Notably, increasing evidence has demonstrated that drug resistance is closely related to the crosstalk between tumor cells and the tumor microenvironment (TME). TME is a dynamic and ever-changing complex biological network whose diverse cellular and non-cellular components influence hallmarks and fates of tumor cells from the outside, and this is responsible for the development of resistance to conventional therapeutic agents to some extent. Indeed, the formation of drug resistance in esophageal cancer should be considered as a multifactorial process involving not only cancer cells themselves but cancer stem cells, tumor-associated stromal cells, hypoxia, soluble factors, extracellular vesicles, etc. Accordingly, combination therapy targeting tumor cells and tumor-favorable microenvironment represents a promising strategy to address drug resistance and get better therapeutic responses for patients with esophageal cancer. In this review, we mainly focus our discussion on molecular mechanisms that underlie the role of TME in drug resistance in esophageal cancer. We also discuss the opportunities and challenges for therapeutically targeting tumor-favorable microenvironment, such as membrane proteins, pivotal signaling pathways, and cytokines, to attenuate drug resistance in esophageal cancer.

Molecular Mechanisms Underlying the Development of Drug Resistance in Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3409-3409
Author(s):  
Masood A. Shammas ◽  
Hemant Koley ◽  
Cheng Li ◽  
Kenneth C. Anderson ◽  
Robert J. S. Reis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Nickel Chloride ◽  
Genomic Diversity ◽  
Live Cells ◽  
Genetic Changes ◽  
Potent Inducer ◽  
Development Of Resistance ◽  
Molecular Events

Abstract A prominent feature of most cancers including multiple myeloma (MM) is a striking genetic instability, leading to ongoing accrual of mutational changes some of which underlie tumor progression, including development of drug resistance and metastasis. The molecular basis for the generation of genetic diversity in cancer cells has thus emerged as an important focus of investigation and a target for successful eradication. We have previously observed that homologous recombination (HR) is upregulated in MM. Utilizing a genomewide LOH assay based on SNP genotyping (Affymetrix) as a tool to estimate the rate of mutation and genomic instability, we have observed that over time elevated HR leads to progressive accumulation of genetic variation in MM cell lines and patient cells; and inhibition of HR activity in MM cells by altering components of the HR pathway concordantly affects the acquisition of new genetic changes. As HR activity is dependent on concerted action of number of genes, instead of over expressing single HR related gene, we utilized nickel chloride, a known recombinogen to evaluate effects of increased HR activity on the development of genomic diversity. We cultured ARP cells in the presence or absence of nickel chloride, over a period of 90 days. Genome-wide LOH was evaluated by comparing genotypes before and after the 90-day interval. In three independent experiments treatment of cells with nickel chloride increased the number of new LOH sites by more than 12-fold. We next evaluated the effect of induction of HR and the consequent increase in genetic aberrations, on development of drug resistance in MM. Myeloma cells were cultured with nickel chloride as a potent inducer of HR and dexamethasone (10−8M); control cells were exposed to dexamethasone alone. The cell viability was measured weekly. No live cells were detected in cultures exposed to dexamethasone alone; while >95% cells exposed to both nickel chloride and dexamethasone were alive following 2 weeks culture. These findings were confirmed by 3 independent experiments. The development of drug resistance was further confirmed by demonstrating no significant effects of dexamethasone on these cells at 10−6M concentrations for >1 week. Dexamethasone at this concentration kills all control cells by day 3. Evaluation of development of resistance to other agents is underway. We propose that continued accumulation of new genetic changes mediated by HR, as demonstrated here, provides the molecular events required to develop drug resistance; and its inhibition may allow us to successfully treat MM cells without the currently observed development of resistance. HR may be a potential therapeutic target to maintain chemo sensitivity of the tumors.

An Overview of Available Antimalarials: Discovery, Mode of Action and Drug Resistance

2020 ◽  
Vol 20 (8) ◽  
pp. 583-592 ◽  
Author(s):  
Yu-Qing Tang ◽  
Qian Ye ◽  
He Huang ◽  
Wei-Yi Zheng
Keyword(s):  
Public Health ◽  
Drug Resistance ◽  
Artemisinin Resistance ◽  
Mechanisms Of Action ◽  
Antimalarial Drugs ◽  
Public Health Burden ◽  
The Public ◽  
Health Burden ◽  
Frequent Use ◽  
The World

: Malaria is one of the three most deadly infectious diseases in the world and seriously endangers human health and life. To reduce the public health burden of this disease, scientists have focused on the discovery and development of effective antimalarial drugs, from quinine and chloroquine to antifolates and artemisinin and its derivatives, which all play a profound role in the treatment of malaria. However, drugresistant strains of Plasmodium falciparum have emerged due to frequent use of antimalarials and have become increasingly resistant to existing antimalarial drugs, causing disastrous consequences in the world. In particular, artemisinin resistance is of greatest concern which was reported in 2008. Resistance to artenisinins has been a major obstacle for malaria control, and current efforts to curb artemisinin resistance have not been successful. Based on the current situation, it is urgent to develop more effective new antimalarials with distinct targets from conventional antimalarials in the world, which could facilitate to minimize the phenomenon of drug resistance. This review aims to summarize different kinds of antimalarial therapeutic efficacy, mechanisms of action and resistance, and proposes new solutions aiming towards further improvement of malaria elimination.

MOLECULAR MECHANISMS OF RESISTANCE IN ANTIMALARIAL CHEMOTHERAPY: The Unmet Challenge

2005 ◽  
Vol 45 (1) ◽  
pp. 565-585 ◽  
Author(s):  
Ravit Arav-Boger ◽  
Theresa A. Shapiro
Keyword(s):  
Public Health ◽  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Point Mutations ◽  
Public Health Problem ◽  
Genetic Studies ◽  
Genetic Mechanisms ◽  
Clinically Significant ◽  
Parasite Populations

▪ Abstract  The enormous public health problem posed by malaria has been substantially worsened in recent years by the emergence and worldwide spread of drug-resistant parasites. The utility of two major therapies, chloroquine and the synergistic combination of pyrimethamine/sulfadoxine, is now seriously compromised. Although several genetic mechanisms have been described, the major source of drug resistance appears to be point mutations in protein target genes. Clinically significant resistance to these agents requires the accumulation of multiple mutations, which genetic studies of parasite populations suggest arise focally and sweep through the population. Efforts to circumvent resistance range from the use of combination therapy with existing agents to laboratory studies directed toward discovering novel targets and therapies. The prevention and management of drug resistance are among the most important practical problems of tropical medicine and public health. Leonard J. Bruce-Chwatt, 1972

scholarly journals FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5796
Author(s):  
Jakub Szymczyk ◽  
Katarzyna Dominika Sluzalska ◽  
Izabela Materla ◽  
Lukasz Opalinski ◽  
Jacek Otlewski ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Treatment Strategies ◽  
Cancer Drug ◽  
Cancer Therapies ◽  
Development Of Resistance ◽  
Cancer Drug Resistance ◽  
Anti Cancer ◽  
Novel Therapeutic Strategies ◽  
Further Development

Increased expression of both FGF proteins and their receptors observed in many cancers is often associated with the development of chemoresistance, limiting the effectiveness of currently used anti-cancer therapies. Malfunctioning of the FGF/FGFR axis in cancer cells generates a number of molecular mechanisms that may affect the sensitivity of tumors to the applied drugs. Of key importance is the deregulation of cell signaling, which can lead to increased cell proliferation, survival, and motility, and ultimately to malignancy. Signaling pathways activated by FGFRs inhibit apoptosis, reducing the cytotoxic effect of some anti-cancer drugs. FGFRs-dependent signaling may also initiate angiogenesis and EMT, which facilitates metastasis and also correlates with drug resistance. Therefore, treatment strategies based on FGF/FGFR inhibition (using receptor inhibitors, ligand traps, monoclonal antibodies, or microRNAs) appear to be extremely promising. However, this approach may lead to further development of resistance through acquisition of specific mutations, metabolism switching, and molecular cross-talks. This review brings together information on the mechanisms underlying the involvement of the FGF/FGFR axis in the generation of drug resistance in cancer and highlights the need for further research to overcome this serious problem with novel therapeutic strategies.

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