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

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.

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

Cancers ◽

10.3390/cancers13071521 ◽

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.

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Hydrogen Therapy in Cardiovascular and Metabolic Diseases: from Bench to Bedside

Cellular Physiology and Biochemistry ◽

10.1159/000489737 ◽

2018 ◽

Vol 47 (1) ◽

pp. 1-10 ◽

Cited By ~ 16

Author(s):

Yaxing Zhang ◽

Sihua Tan ◽

Jingting Xu ◽

Tinghuai Wang

Keyword(s):

Molecular Mechanisms ◽

Ventricular Remodeling ◽

Metabolic Diseases ◽

Therapeutic Potential ◽

Chemical Properties ◽

Obesity And Diabetes ◽

Gas Molecules ◽

Heart Injury ◽

Physical And Chemical ◽

And Chemical Properties

Hydrogen (H2) is colorless, odorless, and the lightest of gas molecules. Studies in the past ten years have indicated that H2 is extremely important in regulating the homeostasis of the cardiovascular system and metabolic activity. Delivery of H2 by various strategies improves cardiometabolic diseases, including atherosclerosis, vascular injury, ischemic or hypertrophic ventricular remodeling, intermittent hypoxia- or heart transplantation-induced heart injury, obesity and diabetes in animal models or in clinical trials. The purpose of this review is to summarize the physical and chemical properties of H2, and then, the functions of H2 with an emphasis on the therapeutic potential and molecular mechanisms involved in the diseases above. We hope this review will provide the future outlook of H2-based therapies for cardiometabolic disease.

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SpiceRx: an integrated resource for the health impacts of culinary spices and herbs

10.1101/273599 ◽

2018 ◽

Cited By ~ 1

Author(s):

Rakhi Nk ◽

Rudraksh Tuwani ◽

Neelansh Garg ◽

Jagriti Mukherjee ◽

Ganesh Bagler

Keyword(s):

Molecular Mechanisms ◽

Therapeutic Potential ◽

Large Body ◽

Health Impact ◽

Health Impacts ◽

Supplementary Information ◽

Development Framework ◽

Medicinal Value ◽

Disease Associations ◽

Molecular Editor

AbstractSpices and herbs are key dietary ingredients used in cuisines across the world. They have been reported to be of medicinal value for a wide variety of diseases through a large body of biomedical investigations. Bioactive phytochemicals in these plant products form the basis of their therapeutic potential as well as adverse effects. A systematic compilation of empirical data involving these aspects of culinary spices and herbs could help unravel molecular mechanisms underlying their effects on health.SpiceRx provides a platform for exploring the health impact of spices and herbs used in food preparations through a structured database of tripartite relationships with their phytochemicals and disease associations. Starting with an extensive dictionary of culinary spices and herbs, their disease associations were text mined from MEDLINE, the largest database of biomedical abstracts, assisted with manual curation. This information was further combined with spice-phytochemical and phytochemical-disease associations. SpiceRx is an integrated repertoire of evidence-based knowledge pertaining to the health impacts of culinary spices and herbs, and facilitates their disease-specific culinary recommendations as well as exploration of molecular mechanisms underlying their health effects.Availability and ImplementationSpiceRx is available at http://cosylab.iiitd.edu.in/spicerx and supports all modern browsers. SpiceRx is implemented with Python web development framework Django and relational database PostgreSQL; the front-end was built using HTML, CSS, JavaScript, AJAX, jQuery, JSME Molecular Editor, Bootstrap, Jmol, DataTables and Google Charts.Supplementary informationSupplementary data are available at Bioinformatics online.

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

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.664816 ◽

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.

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Role of PPARγ in renoprotection in Type 2 diabetes: molecular mechanisms and therapeutic potential

Clinical Science ◽

10.1042/cs20070462 ◽

2008 ◽

Vol 116 (1) ◽

pp. 17-26 ◽

Cited By ~ 41

Author(s):

Jichun Yang ◽

Dongjuan Zhang ◽

Jing Li ◽

Xiaoyan Zhang ◽

Fenling Fan ◽

...

Keyword(s):

Type 2 Diabetes ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Large Body ◽

Underlying Mechanism ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Underlying Mechanisms ◽

Stage Renal Disease

DN (diabetic nephropathy) is a chronic disease characterized by proteinuria, glomerular hypertrophy, decreased glomerular filtration and renal fibrosis with loss of renal function. DN is the leading cause of ESRD (end-stage renal disease), accounting for millions of deaths worldwide. TZDs (thiazolidinediones) are synthetic ligands of PPARγ (peroxisome-proliferator-activated receptor γ), which is involved in many important physiological processes, including adipose differentiation, lipid and glucose metabolism, energy homoeostasis, cell proliferation, inflammation, reproduction and renoprotection. A large body of research over the past decade has revealed that, in addition to their insulin-sensitizing effects, TZDs play an important role in delaying and preventing the progression of chronic kidney disease in Type 2 diabetes. Although PPARγ activation by TZDs is in general considered beneficial for the amelioration of diabetic renal complications in Type 2 diabetes, the underlying mechanism(s) remains only partially characterized. In this review, we summarize and discuss recent findings regarding the renoprotective effects of PPARγ in Type 2 diabetes and the potential underlying mechanisms.

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

Blood ◽

10.1182/blood.v104.11.3409.3409 ◽

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.

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

Cancers ◽

10.3390/cancers13225796 ◽

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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Flavonolignans: One Step Further in the Broad-Spectrum Approach of Cancer

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200124112649 ◽

2020 ◽

Vol 20 (15) ◽

pp. 1817-1830

Author(s):

Diana S. Antal ◽

Florina Ardelean ◽

Stefana Avram ◽

Ioana Z. Pavel ◽

Corina Danciu ◽

...

Keyword(s):

Drug Resistance ◽

Anticancer Agents ◽

Molecular Mechanisms ◽

Biological Activities ◽

Large Body ◽

Experimental Models ◽

Supporting Evidence ◽

Phase I Clinical Trials ◽

Cancer Management ◽

Hybrid Molecules

Background: The small chemical class of flavonolignans encompasses unique hybrid molecules with versatile biological activities. Their anticancer effects have received considerable attention, and a large body of supporting evidence has accumulated. Moreover, their ability to interact with proteins involved in drug resistance, and to enhance the effects of conventional chemotherapeutics in decreasing cell viability make them influential partners in addressing cancer. Objective: The review provides an outline of the various ways in which flavonolignans advance the combat against cancer. While the main focus falls on flavonolignans from milk thistle, attention is drawn to the yet, underexplored potential of less known flavonolignan subgroups derived from isoflavonoids and aurones. Methods: Proceeding from the presentation of natural flavonolignan subtypes and their occurrence, the present work reviews these compounds with regard to their molecular targets in cancer, anti-angiogenetic effects, synergistic efficacy in conjunction with anticancer agents, reversal of drug resistance, and importance in overcoming the side effects of anticancer therapy. Recent advances in the endeavor to improve flavonolignan bioavailability in cancer are also presented. Conclusions: Significant progress has been achieved in detailing the molecular mechanisms of silybin and its congeners in experimental models of cancer. The availability of novel formulations with improved bioavailability, and data from phase I clinical trials in cancer patients provide an encouraging basis for more extensive trials aimed at evaluating the benefits of Silybum flavonolignans in cancer management. On the other hand, further research on the antitumor efficacy of iso-flavonolignans and other subtypes of flavonolignans should be pursued.

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

10.5772/intechopen.101514 ◽

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.

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Tumor Decelerating and Chemo-Potentiating Action of Methyl Jasmonate on a T Cell Lymphoma In Vivo: Role of Altered Regulation of Metabolism, Cell Survival, Drug Resistance, and Intratumoral Blood Flow

Frontiers in Oncology ◽

10.3389/fonc.2021.619351 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yugal Goel ◽

Saveg Yadav ◽

Shrish Kumar Pandey ◽

Mithlesh Kumar Temre ◽

Babu Nandan Maurya ◽

...

Keyword(s):

Drug Resistance ◽

Lipid Metabolism ◽

Tumor Growth ◽

Cell Survival ◽

Methyl Jasmonate ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Ph Homeostasis

Methyl jasmonate (MJ), a natural oxylipin, possesses a broad spectrum of antineoplastic potential in vitro. However, its tumor growth impeding and chemo-potentiating action has not been adequately investigated in vivo. Using a murine thymus-derived tumor named Dalton’s Lymphoma (DL), in the present study, we examined if intra-tumoral administration of MJ can cause tumor growth impedance. We also explored the associated molecular mechanisms governing cell survival, carbohydrate & lipid metabolism, chemo-potentiation, and angiogenesis. MJ administration to tumor-transplanted mice caused deceleration of tumor growth accompanying prolonged survival of the tumor-bearing mice. MJ-dependent tumor growth retardation was associated with the declined blood supply in tumor milieu, cell cycle arrest, augmented induction of apoptosis and necrosis, deregulated glucose and lipid metabolism, enhanced membrane fragility of tumor cells, and altered cytokine repertoire in the tumor microenvironment. MJ administration modulated molecular network implicating Hsp70, Bcl-2, TERT, p53, Cyt c, BAX, GLUT-1, HK 2, LDH A, PDK-1, HIF-1α, ROS, MCT-1, FASN, ACSS2, SREBP1c, VEGF, cytokine repertoire, and MDR1, involved in the regulation of cell survival, carbohydrate and fatty acid metabolism, pH homeostasis, and drug resistance. Thus, the present study unveils novel molecular mechanisms of the tumor growth decelerating action of MJ. Besides, this preclinical study also establishes the adjunct therapeutic potential of MJ. Hence, the present investigation will help to design novel anti-cancer therapeutic regimens for the treatment of hematological malignancies.

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