Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures

ABSTRACTDespite high initial efficacy, therapies that target oncogenic kinases eventually fail in advanced, metastatic cancers. This failure in initially responsive tumors is the direct result of the evolution of drug resistance under therapy-imposed selective pressures. In contrast to the massive body of experimental research on the molecular mechanisms of resistance, understanding of its evolutionary origins and dynamics remains fragmented. Using a combination of experimental studies and mathematical modeling, we sought to dissect the evolution of resistance to different clinical ALK inhibitors in an experimental model of ALK positive NSCLC. We found that resistance can originate from heterogeneous, weakly resistant, sub-populations with variable sensitivity to different ALK inhibitors. Instead of the commonly assumed stochastic single hit (epi) mutational transition, or drug-induced reprogramming, we found evidence of a hybrid scenario, of gradual, multifactorial development through acquisition of multiple cooperating genetic and epigenetic adaptive changes, amplified by selection. Additionally, we found that intermediate resistance phenotypes might present unique, temporally restricted collateral sensitivities, absent in therapy naïve or fully resistant cells, suggesting new opportunities for therapeutic interference.

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Emerging cellular and molecular mechanisms underlying anticancer indications of chrysin

Cancer Cell International ◽

10.1186/s12935-021-01906-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Marjan Talebi ◽

Mohsen Talebi ◽

Tahereh Farkhondeh ◽

Jesus Simal-Gandara ◽

Dalia M. Kopustinskiene ◽

...

Keyword(s):

Blood Cells ◽

Molecular Mechanisms ◽

Web Of Science ◽

Experimental Studies ◽

Protective Effects ◽

Pharmacological Activities ◽

Current Review ◽

Mesh Terms ◽

Online Databases ◽

Anti Cancer

AbstractChrysin has been shown to exert several beneficial pharmacological activities. Chrysin has anti-cancer, anti-viral, anti-diabetic, neuroprotective, cardioprotective, hepatoprotective, and renoprotective as well as gastrointestinal, respiratory, reproductive, ocular, and skin protective effects through modulating signaling pathway involved in apoptosis, oxidative stress, and inflammation. In the current review, we discussed the emerging cellular and molecular mechanisms underlying therapeutic indications of chrysin in various cancers. Online databases comprising Scopus, PubMed, Embase, ProQuest, Science Direct, Web of Science, and the search engine Google Scholar were searched for available and eligible research articles. The search was conducted by using MeSH terms and keywords in title, abstract, and keywords. In conclusion, experimental studies indicated that chrysin could ameliorate cancers of the breast, gastrointestinal tract, liver and hepatocytes, bladder, male and female reproductive systems, choroid, respiratory tract, thyroid, skin, eye, brain, blood cells, leukemia, osteoblast, and lymph. However, more studies are needed to enhance the bioavailability of chrysin and evaluate this agent in clinical trial studies. Graphic abstract

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Therapies for the Treatment of Cardiovascular Disease Associated with Type 2 Diabetes and Dyslipidemia

International Journal of Molecular Sciences ◽

10.3390/ijms22020660 ◽

2021 ◽

Vol 22 (2) ◽

pp. 660

Author(s):

María Aguilar-Ballester ◽

Gema Hurtado-Genovés ◽

Alida Taberner-Cortés ◽

Andrea Herrero-Cervera ◽

Sergio Martínez-Hervás ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Molecular Mechanisms ◽

Foam Cell ◽

Leukocyte Adhesion ◽

Experimental Studies ◽

Lipid Lowering ◽

Foam Cell Formation ◽

Relevant Parameter

Cardiovascular disease (CVD) is the leading cause of death worldwide and is the clinical manifestation of the atherosclerosis. Elevated LDL-cholesterol levels are the first line of therapy but the increasing prevalence in type 2 diabetes mellitus (T2DM) has positioned the cardiometabolic risk as the most relevant parameter for treatment. Therefore, the control of this risk, characterized by dyslipidemia, hypertension, obesity, and insulin resistance, has become a major goal in many experimental and clinical studies in the context of CVD. In the present review, we summarized experimental studies and clinical trials of recent anti-diabetic and lipid-lowering therapies targeted to reduce CVD. Specifically, incretin-based therapies, sodium-glucose co-transporter 2 inhibitors, and proprotein convertase subtilisin kexin 9 inactivating therapies are described. Moreover, the novel molecular mechanisms explaining the CVD protection of the drugs reviewed here indicate major effects on vascular cells, inflammatory cells, and cardiomyocytes, beyond their expected anti-diabetic and lipid-lowering control. The revealed key mechanism is a prevention of acute cardiovascular events by restraining atherosclerosis at early stages, with decreased leukocyte adhesion, recruitment, and foam cell formation, and increased plaque stability and diminished necrotic core in advanced plaques. These emergent cardiometabolic therapies have a promising future to reduce CVD burden.

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Herb-target virtual screening and network pharmacology for prediction of molecular mechanism of Danggui Beimu Kushen Wan for prostate cancer

Scientific Reports ◽

10.1038/s41598-021-86141-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hong Li ◽

Andrew Hung ◽

Angela Wei Hong Yang

Keyword(s):

Prostate Cancer ◽

Binding Affinity ◽

Molecular Mechanisms ◽

Biological Activities ◽

Tight Binding ◽

Experimental Studies ◽

Network Pharmacology ◽

High Morbidity ◽

High Binding ◽

High Binding Affinity

AbstractProstate cancer (PCa) is a cancer that occurs in the prostate with high morbidity and mortality. Danggui Beimu Kushen Wan (DBKW) is a classic formula for patients with difficult urination including PCa. This study aimed to investigate the molecular mechanisms of DBKW for PCa. We obtained DBKW compounds from our previous reviews. We identified potential targets for PCa from literature search, currently approved drugs and Open Targets database and filtered them by protein–protein interaction network analysis. We selected 26 targets to predict three cancer-related pathways. A total of 621 compounds were screened via molecular docking using PyRx and AutoDock Vina against 21 targets for PCa, producing 13041 docking results. The binding patterns and positions showed that a relatively small number of tight-binding compounds from DBKW were predicted to interact strongly and selectively with three targets. The top five high-binding-affinity compounds were selected to generate a network, indicating that compounds from all three herbs had high binding affinity against the 21 targets and may have potential biological activities with the targets. DBKW contains multi-targeting agents that could act on more than one pathway of PCa simultaneously. Further studies could focus on validating the computational results via experimental studies.

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Mitochondrial Dynamics in Drug-Induced Liver Injury

Livers ◽

10.3390/livers1030010 ◽

2021 ◽

Vol 1 (3) ◽

pp. 102-115

Author(s):

Anup Ramachandran ◽

David S. Umbaugh ◽

Hartmut Jaeschke

Keyword(s):

Liver Injury ◽

Molecular Mechanisms ◽

Membrane Lipids ◽

Mitochondrial Dynamics ◽

Adaptive Responses ◽

Drug Induced ◽

Biologically Relevant ◽

Drug Induced Liver Injury ◽

Relevant Role ◽

Atp Generation

Mitochondria have been studied for decades from the standpoint of metabolism and ATP generation. However, in recent years mitochondrial dynamics and its influence on bioenergetics and cellular homeostasis is also being appreciated. Mitochondria undergo regular cycles of fusion and fission regulated by various cues including cellular energy requirements and pathophysiological stimuli, and the network of critical proteins and membrane lipids involved in mitochondrial dynamics is being revealed. Hepatocytes are highly metabolic cells which have abundant mitochondria suggesting a biologically relevant role for mitochondrial dynamics in hepatocyte injury and recovery. Here we review information on molecular mediators of mitochondrial dynamics and their alteration in drug-induced liver injury. Based on current information, it is evident that changes in mitochondrial fusion and fission are hallmarks of liver pathophysiology ranging from acetaminophen-induced or cholestatic liver injury to chronic liver diseases. These alterations in mitochondrial dynamics influence multiple related mitochondrial responses such as mitophagy and mitochondrial biogenesis, which are important adaptive responses facilitating liver recovery in several contexts, including drug-induced liver injury. The current focus on characterization of molecular mechanisms of mitochondrial dynamics is of immense relevance to liver pathophysiology and have the potential to provide significant insight into mechanisms of liver recovery and regeneration after injury.

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Deafness-in-a-dish: modeling hereditary deafness with inner ear organoids

Human Genetics ◽

10.1007/s00439-021-02325-9 ◽

2021 ◽

Author(s):

Daniel R. Romano ◽

Eri Hashino ◽

Rick F. Nelson

Keyword(s):

Animal Models ◽

Inner Ear ◽

Auditory System ◽

Hearing Aids ◽

Molecular Mechanisms ◽

Functional Disability ◽

Experimental Studies ◽

Hereditary Deafness ◽

Human Auditory System ◽

Human Inner Ear

AbstractSensorineural hearing loss (SNHL) is a major cause of functional disability in both the developed and developing world. While hearing aids and cochlear implants provide significant benefit to many with SNHL, neither targets the cellular and molecular dysfunction that ultimately underlies SNHL. The successful development of more targeted approaches, such as growth factor, stem cell, and gene therapies, will require a yet deeper understanding of the underlying molecular mechanisms of human hearing and deafness. Unfortunately, the human inner ear cannot be biopsied without causing significant, irreversible damage to the hearing or balance organ. Thus, much of our current understanding of the cellular and molecular biology of human deafness, and of the human auditory system more broadly, has been inferred from observational and experimental studies in animal models, each of which has its own advantages and limitations. In 2013, researchers described a protocol for the generation of inner ear organoids from pluripotent stem cells (PSCs), which could serve as scalable, high-fidelity alternatives to animal models. Here, we discuss the advantages and limitations of conventional models of the human auditory system, describe the generation and characteristics of PSC-derived inner ear organoids, and discuss several strategies and recent attempts to model hereditary deafness in vitro. Finally, we suggest and discuss several focus areas for the further, intensive characterization of inner ear organoids and discuss the translational applications of these novel models of the human inner ear.

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HIV Protease: Historical Perspective and Current Research

Viruses ◽

10.3390/v13050839 ◽

2021 ◽

Vol 13 (5) ◽

pp. 839

Author(s):

Irene T. Weber ◽

Yuan-Fang Wang ◽

Robert W. Harrison

Keyword(s):

Molecular Mechanisms ◽

Subsequent Development ◽

Historical Background ◽

Hiv Protease ◽

Drug Resistant ◽

Immunodeficiency Virus ◽

Evolution Of Resistance ◽

Retroviral Proteases ◽

And Function ◽

Retroviral Protease

The retroviral protease of human immunodeficiency virus (HIV) is an excellent target for antiviral inhibitors for treating HIV/AIDS. Despite the efficacy of therapy, current efforts to control the disease are undermined by the growing threat posed by drug resistance. This review covers the historical background of studies on the structure and function of HIV protease, the subsequent development of antiviral inhibitors, and recent studies on drug-resistant protease variants. We highlight the important contributions of Dr. Stephen Oroszlan to fundamental knowledge about the function of the HIV protease and other retroviral proteases. These studies, along with those of his colleagues, laid the foundations for the design of clinical inhibitors of HIV protease. The drug-resistant protease variants also provide an excellent model for investigating the molecular mechanisms and evolution of resistance.

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Animal models of drug-induced pulmonary fibrosis: an overview of molecular mechanisms and characteristics

Cell Biology and Toxicology ◽

10.1007/s10565-021-09676-z ◽

2021 ◽

Author(s):

Shuchan Li ◽

Jianrong Shi ◽

Huifang Tang

Keyword(s):

Animal Models ◽

Pulmonary Fibrosis ◽

Molecular Mechanisms ◽

Drug Induced

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Circadian Rhythms, the Mesolimbic Dopaminergic Circuit, and Drug Addiction

The Scientific World JOURNAL ◽

10.1100/tsw.2007.213 ◽

2007 ◽

Vol 7 ◽

pp. 194-202 ◽

Cited By ~ 65

Author(s):

Colleen A. McClung

Keyword(s):

Circadian Rhythms ◽

Drug Addiction ◽

Molecular Mechanisms ◽

Dopaminergic System ◽

Treatment Options ◽

Drug Induced ◽

Circadian Genes ◽

Dopaminergic Transmission ◽

Central Pacemaker

Drug addiction is a devastating disease that affects millions of individuals worldwide. Through better understanding of the genetic variations that create a vulnerability for addiction and the molecular mechanisms that underlie the progression of addiction, better treatment options can be created for those that suffer from this condition. Recent studies point to a link between abnormal or disrupted circadian rhythms and the development of addiction. In addition, studies suggest a role for specific genes that make up the molecular clock in the regulation of drug sensitivity, sensitization, and reward. The influence of circadian genes and rhythms on drug-induced behaviors may be mediated through the mesolimbic dopaminergic system. This system has long been implicated in the development of addiction, and recent evidence supports a regulatory role for the brain's central pacemaker and circadian gene expression in the regulation of dopaminergic transmission. This review highlights the association between circadian genes and drug addiction, and the possible role of the mesolimbic dopaminergic system in this association.

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