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International Journal of Molecular... Mar 2019Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent side effects caused by antineoplastic agents, with a prevalence from 19% to over 85%.... (Review)
Review
Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent side effects caused by antineoplastic agents, with a prevalence from 19% to over 85%. Clinically, CIPN is a mostly sensory neuropathy that may be accompanied by motor and autonomic changes of varying intensity and duration. Due to its high prevalence among cancer patients, CIPN constitutes a major problem for both cancer patients and survivors as well as for their health care providers, especially because, at the moment, there is no single effective method of preventing CIPN; moreover, the possibilities of treating this syndrome are very limited. There are six main substance groups that cause damage to peripheral sensory, motor and autonomic neurons, which result in the development of CIPN: platinum-based antineoplastic agents, vinca alkaloids, epothilones (ixabepilone), taxanes, proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide). Among them, the most neurotoxic are platinum-based agents, taxanes, ixabepilone and thalidomide; other less neurotoxic but also commonlyused drugs are bortezomib and vinca alkaloids. This paper reviews the clinical picture of CIPN and the neurotoxicity mechanisms of the most common antineoplastic agents. A better understanding of the risk factors and underlying mechanisms of CIPN is needed to develop effective preventive and therapeutic strategies.
Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; DNA Damage; Humans; Neoplasms; Oxidative Stress; Peripheral Nervous System Diseases; Platinum; Protein Kinase Inhibitors; Reactive Oxygen Species; Signal Transduction
PubMed: 30909387
DOI: 10.3390/ijms20061451 -
Journal of Translational Medicine Oct 2022Pancreatic adenocarcinoma (PAAD) is one of the most common malignant tumors of the digestive tract. Pyroptosis is a newly discovered programmed cell death that...
BACKGROUND
Pancreatic adenocarcinoma (PAAD) is one of the most common malignant tumors of the digestive tract. Pyroptosis is a newly discovered programmed cell death that highly correlated with the prognosis of tumors. However, the prognostic value of pyroptosis in PAAD remains unclear.
METHODS
A total of 178 pancreatic cancer PAAD samples and 167 normal samples were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. The "DESeq2" R package was used to identify differntially expressed pyroptosis-related genes between normal pancreatic samples and PAAD samples. The prognostic model was established in TCGA cohort based on univariate Cox and the least absolute shrinkage and selection operator (LASSO) Cox regression analyses, which was validated in test set from Gene Expression Omnibus (GEO) cohort. Univariate independent prognostic analysis and multivariate independent prognostic analysis were used to determine whether the risk score can be used as an independent prognostic factor to predict the clinicopathological features of PAAD patients. A nomogram was used to predict the survival probability of PAAD patients, which could help in clinical decision-making. The R package "pRRophetic" was applied to calculate the drug sensitivity of each samples from high- and low-risk group. Tumor immune infiltration was investigated using an ESTIMATE algorithm. Finally, the pro-tumor phenotype of GSDMC was explored in PANC-1 and CFPAC-1 cells.
RESULT
On the basis of univariate Cox and LASSO regression analyses, we constructed a risk model with identified five pyroptosis-related genes (IL18, CASP4, NLRP1, GSDMC, and NLRP2), which was validated in the test set. The PAAD samples were divided into high-risk and low-risk groups on the basis of the risk score's median. According to Kaplan Meier curve analysis, samples from high-risk groups had worse outcomes than those from low-risk groups. The time-dependent receiver operating characteristics (ROC) analysis revealed that the risk model could predict the prognosis of PAAD accurately. A nomogram accompanied by calibration curves was presented for predicting 1-, 2-, and 3-year survival in PAAD patients. More importantly, 4 small molecular compounds (A.443654, PD.173074, Epothilone. B, Lapatinib) were identified, which might be potential drugs for the treatment of PAAD patients. Finally, the depletion of GSDMC inhibits the proliferation, invasion, and migration of pancreatic adenocarcinoma cells.
CONCLUSION
In this study, we developed a pyroptosis-related prognostic model based on IL18, CASP4, NLRP1, NLRP2, and GSDMC , which may be helpful for clinicians to make clinical decisions for PAAD patients and provide valuable insights for individualized treatment. Our result suggest that GSDMC may promote the proliferation and migration of PAAD cell lines. These findings may provide new insights into the roles of pyroptosis-related genes in PAAD, and offer new therapeutic targets for the treatment of PAAD.
Topics: Adenocarcinoma; Biomarkers, Tumor; DNA-Binding Proteins; Epothilones; Gene Expression Regulation, Neoplastic; Humans; Interleukin-18; Lapatinib; Pancreatic Neoplasms; Pore Forming Cytotoxic Proteins; Prognosis; Pyroptosis
PubMed: 36199146
DOI: 10.1186/s12967-022-03632-z -
Journal of Translational Medicine Oct 2022Liver carcinoma generally presents as an immunosuppressive microenvironment that promotes tumor evasion. The intercellular crosstalk of immune cells significantly...
BACKGROUND
Liver carcinoma generally presents as an immunosuppressive microenvironment that promotes tumor evasion. The intercellular crosstalk of immune cells significantly influences the construction of an immunosuppressive microenvironment. This study aimed to investigate the important interactions between immune cells and their targeting drugs in liver carcinoma, by using single-cell and bulk transcriptomic data.
METHODS
Single-cell and bulk transcriptomic data were retrieved from Gene Expression Omnibus (GSE159977, GSE136103, and GSE125449) and The Cancer Genome Atlas (TGCA-LIHC), respectively. Quality control, dimension reduction, clustering, and annotation were performed according to the Scanpy workflow based on Python. Cell-cell interactions were explored using the CellPhone database and CellChat. Trajectory analysis was executed using a partition-based graph abstraction method. The transcriptomic factors (TFs) were predicted using single-cell regulatory network inference and clustering (SCENIC). The target genes from TFs were used to establish a related score based on the TCGA cohort; this score was subsequently validated by survival, gene set enrichment, and immune cell infiltration analyses. Drug prediction was performed based on the Cancer Therapeutics Response Portal and PRISM Repurposing datasets.
RESULTS
Thirty-one patients at four different states, including health, hepatitis, cirrhosis, and cancer, were enrolled in this study. After dimension reduction and clustering, twenty-two clusters were identified. Cell-cell interaction analyses indicated that macrophage-naive CD4 + T cell interaction significantly affect cancerous state. In brief, macrophages interact with naive CD4 + T cells via different pathways in different states. The results of SCENIC indicated that macrophages present in cancer cells were similar to those present during cirrhosis. A macrophage-naive CD4 + T cell (MNT) score was generated by the SCENIC-derived target genes. Based on the MNT score, five relevant drugs (inhibitor of polo-like kinase 1, inhibitor of kinesin family member 11, dabrafenib, ispinesib, and epothilone-b) were predicted.
CONCLUSIONS
This study reveals the crucial role of macrophage-naive CD4 + T cell interaction in the immunosuppressive microenvironment of liver carcinoma. Tumor-associated macrophages may be derived from cirrhosis and can initiate liver carcinoma. Predictive drugs that target the macrophage-naive CD4 + T cell interaction may help to improve the immunosuppressive microenvironment and prevent immune evasion. The relevant mechanisms need to be further validated in experiments and cohort studies.
Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Communication; Epothilones; Humans; Kinesins; Liver Cirrhosis; Liver Neoplasms; Macrophages; T-Lymphocytes; Transcriptome; Tumor Microenvironment
PubMed: 36221095
DOI: 10.1186/s12967-022-03675-2 -
Gynecologic Oncology Aug 2018Paclitaxel and carboplatin (PC) is a standard initial therapy for advanced endometrial cancer. We evaluated the efficacy and tolerability of incorporating three novel... (Randomized Controlled Trial)
Randomized Controlled Trial
A phase II study of frontline paclitaxel/carboplatin/bevacizumab, paclitaxel/carboplatin/temsirolimus, or ixabepilone/carboplatin/bevacizumab in advanced/recurrent endometrial cancer.
OBJECTIVE
Paclitaxel and carboplatin (PC) is a standard initial therapy for advanced endometrial cancer. We evaluated the efficacy and tolerability of incorporating three novel agents into initial therapy.
METHODS
In this randomized phase II trial, patients with chemotherapy-naïve stage III/IVA (with measurable disease) and stage IVB or recurrent (with or without measurable disease) endometrial cancer were randomly assigned to treatment with PC plus bevacizumab (Arm 1), PC plus temsirolimus (Arm 2) or ixabepilone and carboplatin (IC) plus bevacizumab (Arm 3). The primary endpoint was progression-free survival (PFS). Comparable patients on the PC Arm of trial GOG209 were used as historical controls. Secondary endpoints were response rate, overall survival (OS), and safety.
RESULTS
Overall, 349 patients were randomized. PFS duration was not significantly increased in any experimental arm compared with historical controls (p > 0.039). Treatment HRs (92% CI) for Arms 1, 2, and 3 relative to controls were 0.81 (0.63-1.02), 1.22 (0.96-1.55) and 0.87 (0.68-1.11), respectively. Response rates were similar across arms (60%, 55% and 53%, respectively). Relative to controls, OS duration (with censoring at 36 months), was significantly increased in Arm 1 (p < 0.039) but not in Arms 2 and 3; the HRs (92% CIs) were 0.71 (0.55-0.91), 0.99 (0.78-1.26), and 0.97 (0.77-1.23), respectively. No new safety signals were identified. Common mutations and rates of mismatch repair protein loss are described by histotype. Potential predictive biomarkers for temsirolimus and bevacizumab were identified.
CONCLUSION
PFS was not significantly increased in any experimental arm compared to historical controls. NRG Oncology/Gynecologic Oncology Group Study GOG-86P.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carboplatin; Endometrial Neoplasms; Epothilones; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Paclitaxel; Sirolimus
PubMed: 29804638
DOI: 10.1016/j.ygyno.2018.05.018 -
Frontiers in Molecular Biosciences 2022Brain cancer and leukemia are the most common cancers diagnosed in the pediatric population and are often treated with lifesaving chemotherapy. However, chemotherapy... (Review)
Review
Brain cancer and leukemia are the most common cancers diagnosed in the pediatric population and are often treated with lifesaving chemotherapy. However, chemotherapy causes severe adverse effects and chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting and debilitating side effect. CIPN can greatly impair quality of life and increases morbidity of pediatric patients with cancer, with the accompanying symptoms frequently remaining underdiagnosed. Little is known about the incidence of CIPN, its impact on the pediatric population, and the underlying pathophysiological mechanisms, as most existing information stems from studies in animal models or adult cancer patients. Herein, we aim to provide an understanding of CIPN in the pediatric population and focus on the 6 main substance groups that frequently cause CIPN, namely the vinca alkaloids (vincristine), platinum-based antineoplastics (cisplatin, carboplatin and oxaliplatin), taxanes (paclitaxel and docetaxel), epothilones (ixabepilone), proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide). We discuss the clinical manifestations, assessments and diagnostic tools, as well as risk factors, pathophysiological processes and current pharmacological and non-pharmacological approaches for the prevention and treatment of CIPN.
PubMed: 36310587
DOI: 10.3389/fmolb.2022.1015746 -
The Journal of Neuroscience : the... Nov 2022Axons differ in their growth potential: whereas during development, axons rapidly grow to their targets, in the adult mammalian, CNS axons have lost their ability to...
Axons differ in their growth potential: whereas during development, axons rapidly grow to their targets, in the adult mammalian, CNS axons have lost their ability to grow and therefore fail to regenerate. Recent progress has enabled a better understanding of how developmental mechanisms direct axon regeneration. Focusing on neuronal polarization, where one neurite is singled out to become the axon, has uncovered the mechanisms initiating axon growth and growth restraint. This has helped to define the processes that need to be reactivated to induce axon regeneration: microtubule stabilization and actin dynamics. The molecular machinery underlying axon growth and axon regeneration is remarkably similar and includes the Rho-GTPases Cdc42, Rac-1, and RhoA, as well as the actin regulators cofilin and Myosin II. Importantly, neuron-intrinsic growth inhibitors in the adult nervous system, including the voltage-gated calcium channel subunit α2δ2 and the presynaptic active zone protein Munc13, restrain dynamics while the components driving axon growth remain largely present. The identified molecules suggest that synaptic transmission and axon growth may be processes that exclude each other. As a result, axon regeneration may be hampered by synaptic transmission and, thus, by the maturation of the CNS. This research has led to several translational avenues to induce axon regeneration and functional recovery after spinal cord injury and stroke; these include the drugs epothilones, gabapentinoids, and baclofen. Thus, the investigation of axon growth and regeneration side by side has been instrumental to coax the regenerative potential of the CNS.
Topics: Animals; Humans; Axons; Nerve Regeneration; Actins; Neurons; Spinal Cord Injuries; Mammals
PubMed: 36351827
DOI: 10.1523/JNEUROSCI.1131-22.2022 -
Cancer Chemotherapy and Pharmacology Dec 2015Cancer is a complex disease since it is adaptive in such a way that it can promote proliferation and invasion by means of an overactive cell cycle and in turn cellular... (Review)
Review
Cancer is a complex disease since it is adaptive in such a way that it can promote proliferation and invasion by means of an overactive cell cycle and in turn cellular division which is targeted by antimitotic drugs that are highly validated chemotherapy agents. However, antimitotic drug cytotoxicity to non-tumorigenic cells and multiple cancer resistance developed in response to drugs such as taxanes and vinca alkaloids are obstacles faced in both the clinical and basic research field to date. In this review, the classes of antimitotic compounds, their mechanisms of action and cancer cell resistance to chemotherapy and other limitations of current antimitotic compounds are highlighted, as well as the potential of novel 17-β estradiol analogs as cancer treatment.
Topics: Antimitotic Agents; Apoptosis; Biomarkers, Tumor; Cell Cycle; Cell Proliferation; Drug Resistance, Neoplasm; Humans; Neoplasms; Taxoids; Vinca Alkaloids
PubMed: 26563258
DOI: 10.1007/s00280-015-2903-8 -
Current Topics in Medicinal Chemistry 2014Epothilones are natural compounds isolated from a myxobacterium at the beginning of the 1990s, and showed a remarkable anti-neoplastic activity. They act through the... (Review)
Review
Epothilones are natural compounds isolated from a myxobacterium at the beginning of the 1990s, and showed a remarkable anti-neoplastic activity. They act through the same mechanism of action of paclitaxel, by stabilizing microtubules and inducing apoptosis. Although, their chemical structure, simpler than taxanes, makes them more suitable for derivatization. Their interesting pharmacokinetic and bioavailabilty profiles, and the activity against paclitaxel-resistant cell lines make them interesting therapeutic agents. Here a brief historical perspective of epothilones is presented, since their isolation, the identification of their mechanism of action and activity, to the recent clinical trials.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Clinical Trials as Topic; Drug Design; Epothilones; Humans; Microtubules; Mitosis; Molecular Docking Simulation; Neoplasms; Paclitaxel; Protein Binding; Structure-Activity Relationship; Tubulin Modulators
PubMed: 25434353
DOI: 10.2174/1568026614666141130095855 -
International Journal of Molecular... Mar 2023Epothilone is a natural 16-membered macrolide cytotoxic compound produced by the metabolism of the cellulose-degrading myxobacterium . This review summarizes results in... (Review)
Review
Epothilone is a natural 16-membered macrolide cytotoxic compound produced by the metabolism of the cellulose-degrading myxobacterium . This review summarizes results in the study of epothilones against cancer with preclinical results and clinical studies from 2010-2022. Epothilone have mechanisms of action similar to paclitaxel by inducing tubulin polymerization and apoptosis with low susceptibility to tumor resistance mechanisms. It is active against refractory tumors, being superior to paclitaxel in many respects. Since the discovery of epothilones, several derivatives have been synthesized, and most of them have failed in Phases II and III in clinical trials; however, ixabepilone and utidelone are currently used in clinical practice. There is robust evidence that triple-negative breast cancer (TNBC) treatment improves using ixabepilone plus capecitabine or utidelone in combination with capecitabine. In recent years innovative synthetic strategies resulted in the synthesis of new epothilone derivatives with improved activity against refractory tumors with better activities when compared to ixabepilone or taxol. These compounds together with specific delivery mechanisms could be developed in anti-cancer drugs.
Topics: Humans; Epothilones; Capecitabine; Antineoplastic Agents; Tubulin Modulators; Paclitaxel; Neoplasms
PubMed: 37047035
DOI: 10.3390/ijms24076063 -
Microbial Cell Factories Sep 2013Drug-resistance and therapy failure due to drug-drug interactions are the main challenges in current treatment against Human Immunodeficiency Virus (HIV) infection. As...
BACKGROUND
Drug-resistance and therapy failure due to drug-drug interactions are the main challenges in current treatment against Human Immunodeficiency Virus (HIV) infection. As such, there is a continuous need for the development of new and more potent anti-HIV drugs. Here we established a high-throughput screen based on the highly permissive TZM-bl cell line to identify novel HIV inhibitors. The assay allows discriminating compounds acting on early and/or late steps of the HIV replication cycle.
RESULTS
The platform was used to screen a unique library of secondary metabolites derived from myxobacteria. Several hits with good anti-HIV profiles were identified. Five of the initial hits were tested for their antiviral potency. Four myxobacterial compounds, sulfangolid C, soraphen F, epothilon D and spirangien B, showed EC50 values in the nM range with SI > 15. Interestingly, we found a high amount of overlapping hits compared with a previous screen for Hepatitis C Virus (HCV) using the same library.
CONCLUSION
The unique structures and mode-of-actions of these natural compounds make myxobacteria an attractive source of chemicals for the development of broad-spectrum antivirals. Further biological and structural studies of our initial hits might help recognize smaller drug-like derivatives that in turn could be synthesized and further optimized.
Topics: Anti-HIV Agents; Drug Resistance; High-Throughput Screening Assays; Humans; Myxococcales
PubMed: 24063434
DOI: 10.1186/1475-2859-12-85