Browse
Submit Data
Databases
API
Help

Dataset Information

10 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Advances in Our Understanding of the Molecular Mechanisms of Action of Cisplatin in Cancer Therapy.

ABSTRACT: Cisplatin and other platinum-based chemotherapeutic drugs have been used extensively for the treatment of human cancers such as bladder, blood, breast, cervical, esophageal, head and neck, lung, ovarian, testicular cancers, and sarcoma. Cisplatin is commonly administered intravenously as a first-line chemotherapy for patients suffering from various malignancies. Upon absorption into the cancer cell, cisplatin interacts with cellular macromolecules and exerts its cytotoxic effects through a series of biochemical mechanisms by binding to Deoxyribonucleic acid (DNA) and forming intra-strand DNA adducts leading to the inhibition of DNA synthesis and cell growth. Its primary molecular mechanism of action has been associated with the induction of both intrinsic and extrinsic pathways of apoptosis resulting from the production of reactive oxygen species through lipid peroxidation, activation of various signal transduction pathways, induction of p53 signaling and cell cycle arrest, upregulation of pro-apoptotic genes/proteins, and down-regulation of proto-oncogenes and anti-apoptotic genes/proteins. Despite great clinical outcomes, many studies have reported substantial side effects associated with cisplatin monotherapy, while others have shown substantial drug resistance in some cancer patients. Hence, new formulations and several combinational therapies with other drugs have been tested for the purpose of improving the clinical utility of cisplatin. Therefore, this review provides a comprehensive understanding of its molecular mechanisms of action in cancer therapy and discusses the therapeutic approaches to overcome cisplatin resistance and side effects.

SUBMITTER: Tchounwou PB

PROVIDER: S-EPMC7987268 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Autophagy in Cancer Therapy-Molecular Mechanisms and Current Clinical Advances.

Project description:Autophagy is a crucial general survival tactic of mammalian cells. It describes the capability of cells to disassemble and partially recycle cellular components (e.g., mitochondria) in case they are damaged and pose a risk to cell survival or simply if their resources are urgently needed elsewhere at the time. Autophagy-associated pathomechanisms have been increasingly recognized as important disease mechanisms in non-malignant (neurodegeneration, diffuse parenchymal lung disease) and malignant conditions alike. However, the overall consequences of autophagy for the organism depend particularly on the greater context in which autophagy occurs, such as the cell type or whether the cell is proliferating. In cancer, autophagy sustains cancer cell survival under challenging, i.e., resource-depleted, conditions. However, this leads to situations in which cancer cells are completely dependent on autophagy. Accordingly, autophagy represents a promising yet complex target in cancer treatment with therapeutically induced increase and decrease of autophagic flux as important therapeutic principles.

| S-EPMC8583685 | biostudies-literature

Molecular Mechanisms of Chemoresistance Induced by Cisplatin in NSCLC Cancer Therapy.

Project description:Cancer cells utilise several mechanisms to increase their survival and progression as well as their resistance to anticancer therapy: deregulation of growth regulatory pathways by acquiring grow factor independence, immune system suppression, reducing the expression of antigens activating T lymphocyte cells (mimicry), induction of anti-apoptotic signals to counter the action of drugs, activation of several DNA repair mechanisms and driving the active efflux of drugs from the cell cytoplasm, and epigenetic regulation by microRNAs (miRNAs). Because it is commonly diagnosed late, lung cancer remains a major malignancy with a low five-year survival rate; when diagnosed, the cancer is often highly advanced, and the cancer cells may have acquired drug resistance. This review summarises the main mechanisms involved in cisplatin resistance and interactions between cisplatin-resistant cancer cells and the tumour microenvironment. It also analyses changes in the gene expression profile of cisplatin sensitive vs. cisplatin-resistant non-small cell lung cancer (NSCLC) cellular model using the GSE108214 Gene Expression Omnibus database. It describes a protein-protein interaction network that indicates highly dysregulated TP53, MDM2, and CDKN1A genes as they encode the top networking proteins that may be involved in cisplatin tolerance, these all being upregulated in cisplatin-resistant cells. Furthermore, it illustrates the multifactorial nature of cisplatin resistance by examining the diversity of dysregulated pathways present in cisplatin-resistant NSCLC cells based on KEGG pathway analysis.

| S-EPMC8396273 | biostudies-literature

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

Project description:Background Platinum-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. Conclusions Cisplatin is the most frequently used platinum based chemotherapeutic agent that is clinically proven to combat different types of cancers and sarcomas.

| S-EPMC6572495 | biostudies-literature

Understanding the molecular mechanisms of bisphenol A action in spermatozoa.

Project description:Bisphenol A (BPA) is an endocrine-disrupting chemical that is capable of interfering with the normal function of the endocrine system in the body. Exposure to this chemical from BPA-containing materials and the environment is associated with deleterious health effects, including male reproductive abnormalities. A search of the literature demonstrated that BPA, as a toxicant, directly affects the cellular oxidative stress response machinery. Because of its hormone-like properties, it can also bind with specific receptors in target cells. Therefore, the tissue-specific effects of BPA mostly depend on its endocrine-disrupting capabilities and the expression of those particular receptors in target cells. Although studies have shown the possible mechanisms of BPA action in various cell types, a clear consensus has yet to be established. In this review, we summarize the mechanisms of BPA action in spermatozoa by compiling existing information in the literature.

| S-EPMC6736506 | biostudies-literature

Molecular Mechanisms Involving the Sonic Hedgehog Pathway in Lung Cancer Therapy: Recent Advances.

Project description:According to the latest statistics from the International Agency for Research on Cancer (IARC), lung cancer is one of the most lethal malignancies in the world, accounting for approximately 18% of all cancer-associated deaths. Yet, even with aggressive interventions for advanced lung cancer, the five-year survival rate remains low, at around 15%. The hedgehog signaling pathway is highly conserved during embryonic development and is involved in tissue homeostasis as well as organ development. However, studies have documented an increasing prevalence of aberrant activation of HH signaling in lung cancer patients, promoting malignant lung cancer progression with poor prognostic outcomes. Inhibitors targeting the HH pathway have been widely used in tumor therapy, however, they still cannot avoid the occurrence of drug resistance. Interestingly, natural products, either alone or in combination with chemotherapy, have greatly improved overall survival outcomes for lung cancer patients by acting on the HH signaling pathway because of its unique and excellent pharmacological properties. In this review, we elucidate on the underlying molecular mechanisms through which the HH pathway promotes malignant biological behaviors in lung cancer, as well as the potential of inhibitors or natural compounds in targeting HH signaling for clinical applications in lung cancer therapy.

| S-EPMC9010822 | biostudies-literature

Understanding molecular mechanisms of Cetuximab insensitivity in Colorectal Cancer (CRC)

Project description:Mutational status of KRAS in CRC is used to aid patient stratification for Cetuximab treatment. However, only a subset (10-40%) of patients with wt KRAS respond. We analyzed 40 mCRC tumors for Cetuximab response using a functional ex vivo platform. In the subset of non-responsive tumors, mutational (KRAS/BRAF and PIK3CA) and expression (AREG/EREG) analysis of key genes, transcriptomic profiling and GSEA were carried out to elucidate the molecular mechanisms underlying the response. Our analysis revealed deregulation of multiple pathways, notably Notch and Erbb2 and combined blockade of these two nodes elicited significant antitumor response. These findings collectively indicate the dependence of Cetuximab insensitive mCRC tumors on Notch and Erbb2 for survival and progression. 8 Primary tumors tested in ex vivo platform for response to Cetuximab were subjected to expression analysis

2014-04-01 | E-GEOD-56386 | biostudies-arrayexpress

Tissue fibrosis induced by radiotherapy: current understanding of the molecular mechanisms, diagnosis and therapeutic advances.

Project description:Cancer remains the leading cause of death around the world. In cancer treatment, over 50% of cancer patients receive radiotherapy alone or in multimodal combinations with other therapies. One of the adverse consequences after radiation exposure is the occurrence of radiation-induced tissue fibrosis (RIF), which is characterized by the abnormal activation of myofibroblasts and the excessive accumulation of extracellular matrix. This phenotype can manifest in multiple organs, such as lung, skin, liver and kidney. In-depth studies on the mechanisms of radiation-induced fibrosis have shown that a variety of extracellular signals such as immune cells and abnormal release of cytokines, and intracellular signals such as cGAS/STING, oxidative stress response, metabolic reprogramming and proteasome pathway activation are involved in the activation of myofibroblasts. Tissue fibrosis is extremely harmful to patients' health and requires early diagnosis. In addition to traditional serum markers, histologic and imaging tests, the diagnostic potential of nuclear medicine techniques is emerging. Anti-inflammatory and antioxidant therapies are the traditional treatments for radiation-induced fibrosis. Recently, some promising therapeutic strategies have emerged, such as stem cell therapy and targeted therapies. However, incomplete knowledge of the mechanisms hinders the treatment of this disease. Here, we also highlight the potential mechanistic, diagnostic and therapeutic directions of radiation-induced fibrosis.

| S-EPMC10563272 | biostudies-literature

Estetrol: From Preclinical to Clinical Pharmacology and Advances in the Understanding of the Molecular Mechanism of Action.

Project description:Estetrol (E4) is the most recently described natural estrogen. It is produced by the human fetal liver during pregnancy and its physiological function remains unclear. E4 is the estrogenic component of a recently approved combined oral contraceptive. It is also in development for use as menopausal hormone therapy. In the context of these developments, the pharmacological activity of E4, alone or in combination with a progestin, has been extensively characterized in preclinical models as well as in clinical studies in women of reproductive age and postmenopausal women. Despite the clinical benefits, the use of oral estrogens for contraception or menopause is also associated with unwanted effects, such as an increased risk of breast cancer and thromboembolic events, due to their impact on non-target tissues. Preclinical and clinical data for E4 point to a tissue-specific activity and a more selective pharmacological profile compared with other estrogens, including a low impact on the liver and hemostasis balance. This review summarizes the characterization of the pharmacological properties of E4 as well as recent advances made in the understanding of the molecular mechanisms of action driving its activity. How the unique mode of action and the different metabolism of E4 might support its favorable benefit-risk ratio is also discussed.

| S-EPMC10293541 | biostudies-literature

A Systems Biology Approach to Understanding the Mechanisms of Action of an Alternative Anticancer Compound in Comparison to Cisplatin.

Project description:Many clinically available anticancer compounds are designed to target DNA. This commonality of action often yields overlapping cellular response mechanisms and can thus detract from drug efficacy. New compounds are required to overcome resistance mechanisms that effectively neutralise compounds like cisplatin and those with similar chemical structures. Studies have shown that 56MESS is a novel compound which, unlike cisplatin, does not covalently bind to DNA, but is more toxic to many cell lines and active against cisplatin-resistant cells. Furthermore, a transcriptional study of 56MESS in yeast has implicated iron and copper metabolism as well as the general yeast stress response following challenge with 56MESS. Beyond this, the cytotoxicity of 56MESS remains largely uncharacterised. Here, yeast was used as a model system to facilitate a systems-level comparison between 56MESS and cisplatin. Preliminary experiments indicated that higher concentrations than seen in similar studies be used. Although a DNA interaction with 56MESS had been theorized, this work indicated that an effect on protein synthesis/ degradation was also implicated in the mechanism(s) of action of this novel anticancer compound. In contrast to cisplatin, the different mechanisms of action that are indicated for 56MESS suggest that this compound could overcome cisplatin resistance either as a stand-alone treatment or a synergistic component of therapeutics.

| S-EPMC5302693 | biostudies-literature

Understanding molecular mechanisms of Cetuximab insensitivity in Colorectal Cancer (CRC)

2014-04-01 | GSE56386 | GEO