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Biomedicine & Pharmacotherapy =... Jul 2023Celastrol is a pentacyclic triterpenoid extracted from the traditional Chinese medicine Tripterygium wilfordii Hook F., which has multiple pharmacological activities. In... (Review)
Review
Celastrol is a pentacyclic triterpenoid extracted from the traditional Chinese medicine Tripterygium wilfordii Hook F., which has multiple pharmacological activities. In particular, modern pharmacological studies have demonstrated that celastrol exhibits significant broad-spectrum anticancer activities in the treatment of a variety of cancers, including lung cancer, liver cancer, colorectal cancer, hematological malignancies, gastric cancer, prostate cancer, renal carcinoma, breast cancer, bone tumor, brain tumor, cervical cancer, and ovarian cancer. Therefore, by searching the databases of PubMed, Web of Science, ScienceDirect and CNKI, this review comprehensively summarizes the molecular mechanisms of the anticancer effects of celastrol. According to the data, the anticancer effects of celastrol can be mediated by inhibiting tumor cell proliferation, migration and invasion, inducing cell apoptosis, suppressing autophagy, hindering angiogenesis and inhibiting tumor metastasis. More importantly, PI3K/Akt/mTOR, Bcl-2/Bax-caspase 9/3, EGFR, ROS/JNK, NF-κB, STAT3, JNK/Nrf2/HO-1, VEGF, AR/miR-101, HSF1-LKB1-AMPKα-YAP, Wnt/β-catenin and CIP2A/c-MYC signaling pathways are considered as important molecular targets for the anticancer effects of celastrol. Subsequently, studies of its toxicity and pharmacokinetic properties showed that celastrol has some adverse effects, low oral bioavailability and a narrow therapeutic window. In addition, the current challenges of celastrol and the corresponding therapeutic strategies are also discussed, thus providing a theoretical basis for the development and application of celastrol in the clinic.
Topics: Male; Humans; Signal Transduction; Proto-Oncogene Proteins c-myc; Phosphatidylinositol 3-Kinases; Pentacyclic Triterpenes; Antineoplastic Agents; Triterpenes; Prostatic Neoplasms; Apoptosis; Cell Line, Tumor
PubMed: 37196541
DOI: 10.1016/j.biopha.2023.114882 -
Frontiers in Oncology 2023Radioligand therapy (RLT) agents are demonstrating a crucial role in the clinical approach to aggressive malignancies such as metastatic castrate-resistant prostate... (Review)
Review
Radioligand therapy (RLT) agents are demonstrating a crucial role in the clinical approach to aggressive malignancies such as metastatic castrate-resistant prostate cancer (m-CRPC). With the recent FDA approval of prostate-specific membrane antigen (PSMA)-targeted RLT for m-CRPC, the field has broadened its gaze to explore other cancers that express PSMA in the tumor parenchyma or tumor neovasculature. In this review article, we discuss current progress in the clinical use of PSMA RLTs in non-prostate cancers such salivary gland cancers, renal cell carcinoma, high grade glioma, and soft tissue sarcoma. We highlight early reports in small case series and clinical trials indicating promise for PSMA-targeted RLT and highlighting the importance of identifying patient cohorts who may most benefit from these interventions. Further study is indicated in non-prostate cancers investigating PSMA RLT dosimetry, PSMA PET/CT imaging as a biomarker, and assessing PSMA RLT safety and efficacy in these cancers.
PubMed: 37645427
DOI: 10.3389/fonc.2023.1220586 -
International Journal of Molecular... Jan 2024This review summarizes the current understanding of the role of transient receptor potential melastatin-subfamily member 7 (TRPM7) channels in the pathophysiology of... (Review)
Review
This review summarizes the current understanding of the role of transient receptor potential melastatin-subfamily member 7 (TRPM7) channels in the pathophysiology of neoplastic diseases. The TRPM family represents the largest and most diverse group in the TRP superfamily. Its subtypes are expressed in virtually all human organs playing a central role in (patho)physiological events. The TRPM7 protein (along with TRPM2 and TRPM6) is unique in that it has kinase activity in addition to the channel function. Numerous studies demonstrate the role of TRPM7 chanzyme in tumorigenesis and in other tumor hallmarks such as proliferation, migration, invasion and metastasis. Here we provide an up-to-date overview about the possible role of TRMP7 in a broad range of malignancies such as tumors of the nervous system, head and neck cancers, malignant neoplasms of the upper gastrointestinal tract, colorectal carcinoma, lung cancer, neoplasms of the urinary system, breast cancer, malignant tumors of the female reproductive organs, prostate cancer and other neoplastic pathologies. Experimental data show that the increased expression and/or function of TRPM7 are observed in most malignant tumor types. Thus, TRPM7 chanzyme may be a promising target in tumor therapy.
Topics: Humans; Carcinogenesis; Cell Transformation, Neoplastic; Lung Neoplasms; Prostatic Neoplasms; Protein Serine-Threonine Kinases; TRPM Cation Channels
PubMed: 38255793
DOI: 10.3390/ijms25020719 -
Journal of Hematology & Oncology Nov 2023Significant scientific advances in immunotherapy and targeted therapy approaches have improved clinical outcomes and increased treatment options for patients with...
Significant scientific advances in immunotherapy and targeted therapy approaches have improved clinical outcomes and increased treatment options for patients with genitourinary (GU) malignancies. We highlight the clinical trial developments released at the ASCO 2023 annual meeting, including PARP inhibitors for prostate cancer, antibody drug conjugates and fibroblast growth factor receptor inhibitors for urothelial cancer, and HIF2a inhibitors for renal cell carcinoma. Novel agents such as bispecific antibodies, chimeric antigen receptor T-cells, and radiopharmaceuticals are currently in early phase development and also have high potential impact for the GU cancer landscape. With more treatment options, the field will need to define best treatment sequencing to optimize outcomes for each patient.
Topics: Male; Humans; Urogenital Neoplasms; Immunoconjugates; Immunotherapy; Carcinoma, Renal Cell; Kidney Neoplasms
PubMed: 37990343
DOI: 10.1186/s13045-023-01511-8 -
BMC Medicine Mar 2024While circulating metabolites have been increasingly linked to cancer risk, the causality underlying these associations remains largely uninterrogated.
BACKGROUND
While circulating metabolites have been increasingly linked to cancer risk, the causality underlying these associations remains largely uninterrogated.
METHODS
We conducted a comprehensive 2-sample Mendelian randomization (MR) study to evaluate the potential causal relationship between 913 plasma metabolites and the risk of seven cancers among European-ancestry individuals. Data on variant-metabolite associations were obtained from a genome-wide association study (GWAS) of plasma metabolites among 14,296 subjects. Data on variant-cancer associations were gathered from large-scale GWAS consortia for breast (N = 266,081), colorectal (N = 185,616), lung (N = 85,716), ovarian (N = 63,347), prostate (N = 140,306), renal cell (N = 31,190), and testicular germ cell (N = 28,135) cancers. MR analyses were performed with the inverse variance-weighted (IVW) method as the primary strategy to identify significant associations at Bonferroni-corrected P < 0.05 for each cancer type separately. Significant associations were subjected to additional scrutiny via weighted median MR, Egger regression, MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and reverse MR analyses. Replication analyses were performed using an independent dataset from a plasma metabolite GWAS including 8,129 participants of European ancestry.
RESULTS
We identified 94 significant associations, suggesting putative causal associations between 66 distinct plasma metabolites and the risk of seven cancers. Remarkably, 68.2% (45) of these metabolites were each associated with the risk of a specific cancer. Among the 66 metabolites, O-methylcatechol sulfate and 4-vinylphenol sulfate demonstrated the most pronounced positive and negative associations with cancer risk, respectively. Genetically proxied plasma levels of these two metabolites were significantly associated with the risk of lung cancer and renal cell cancer, with an odds ratio and 95% confidence interval of 2.81 (2.33-3.37) and 0.49 (0.40-0.61), respectively. None of these 94 associations was biased by weak instruments, horizontal pleiotropy, or reverse causation. Further, 64 of these 94 were eligible for replication analyses, and 54 (84.4%) showed P < 0.05 with association patterns consistent with those shown in primary analyses.
CONCLUSIONS
Our study unveils plausible causal relationships between 66 plasma metabolites and cancer risk, expanding our understanding of the role of circulating metabolites in cancer genetics and etiology. These findings hold promise for enhancing cancer risk assessment and prevention strategies, meriting further exploration.
Topics: Male; Humans; Genome-Wide Association Study; Mendelian Randomization Analysis; Carcinoma, Renal Cell; Lung Neoplasms; Kidney Neoplasms
PubMed: 38433226
DOI: 10.1186/s12916-024-03272-8 -
Clinical & Translational Oncology :... Jan 2024Recent studies have revealed the impact of microRNAs (miRNAs) in the carcinogenic process. miR-424 is a miRNA whose role in this process is being to be identified.... (Review)
Review
Recent studies have revealed the impact of microRNAs (miRNAs) in the carcinogenic process. miR-424 is a miRNA whose role in this process is being to be identified. Experiments in the ovarian cancer, cervical cancer, hepatocellular carcinoma, neuroblastoma, breast cancer, osteosarcoma, intrahepatic cholangiocarcinoma, prostate cancer, endometrial cancer, non-small cell lung cancer, hemangioma and gastric cancer have reported down-regulation of miR-424. On the other hand, this miRNA has been found to be up-regulated in melanoma, laryngeal and esophageal squamous cell carcinomas, glioma, multiple myeloma and thyroid cancer. Expression of this miRNA is regulated by methylation status of its promoter. Besides, LINC00641, CCAT2, PVT1, LIN00657, LINC00511 and NNT-AS1 are among lncRNAs that act as molecular sponges for miR-424, thus regulating its expression. Moreover, several members of SNHG family of lncRNAs have been found to regulate expression of miR-424. This miRNA is also involved in the regulation of E2F transcription factors. The current review aims at summarization of the role of miR-424 in the process of cancer evolution and its impact on clinical outcome of patients in order to find appropriate markers for malignancies.
Topics: Male; Female; Humans; Carcinoma, Non-Small-Cell Lung; RNA, Long Noncoding; Lung Neoplasms; MicroRNAs; Carcinogenesis; Esophageal Neoplasms; Gene Expression Regulation, Neoplastic; Cell Proliferation; Cell Line, Tumor
PubMed: 37178445
DOI: 10.1007/s12094-023-03209-2 -
European Urology Nov 2023Prostate-specific Membrane Antigen Reporting and Data System (PSMA-RADS) was introduced for standardized reporting, and PSMA-RADS version 1.0 allows classification of...
Prostate-specific Membrane Antigen Reporting and Data System (PSMA-RADS) was introduced for standardized reporting, and PSMA-RADS version 1.0 allows classification of lesions based on their likelihood of representing a site of prostate cancer on PSMA-targeted positron emission tomography (PET). In recent years, this system has extensively been investigated. Increasing evidence has accumulated that the different categories reflect their actual meanings, such as true positivity in PSMA-RADS 4 and 5 lesions. Interobserver agreement studies demonstrated high concordance among a broad spectrum of Ga- or F-labeled, PSMA-directed radiotracers, even for less experienced readers. Moreover, this system has also been applied to challenging clinical scenarios and to assist in clinical decision-making, for example, to avoid overtreatment in oligometastatic disease. Nonetheless, with an increasing use of PSMA-RADS 1.0, this framework has shown not only benefits, but also limitations, for example, for follow-up assessment of locally treated lesions. Thus, we aimed to update the PSMA-RADS framework to include a refined set of categories in order to optimize lesion-level characterization and best assist in clinical decision-making (PSMA-RADS version 2.0).
Topics: Humans; Male; Antigens, Surface; Data Systems; Glutamate Carboxypeptidase II; Positron-Emission Tomography; Prostatic Neoplasms
PubMed: 37414701
DOI: 10.1016/j.eururo.2023.06.008 -
Clinical Cancer Research : An Official... Sep 2023Despite promising preclinical studies, toxicities have precluded combinations of chemotherapy and DNA damage response (DDR) inhibitors. We hypothesized that...
PURPOSE
Despite promising preclinical studies, toxicities have precluded combinations of chemotherapy and DNA damage response (DDR) inhibitors. We hypothesized that tumor-targeted chemotherapy delivery might enable clinical translation of such combinations.
PATIENTS AND METHODS
In a phase I trial, we combined sacituzumab govitecan, antibody-drug conjugate (ADC) that delivers topoisomerase-1 inhibitor SN-38 to tumors expressing Trop-2, with ataxia telangiectasia and Rad3-related (ATR) inhibitor berzosertib. Twelve patients were enrolled across three dose levels.
RESULTS
Treatment was well tolerated, with improved safety over conventional chemotherapy-based combinations, allowing escalation to the highest dose. No dose-limiting toxicities or clinically relevant ≥grade 4 adverse events occurred. Tumor regressions were observed in 2 patients with neuroendocrine prostate cancer, and a patient with small cell lung cancer transformed from EGFR-mutant non-small cell lung cancer.
CONCLUSIONS
ADC-based delivery of cytotoxic payloads represents a new paradigm to increase efficacy of DDR inhibitors. See related commentary by Berg and Choudhury, p. 3557.
Topics: Male; Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Camptothecin; Immunoconjugates
PubMed: 37227187
DOI: 10.1158/1078-0432.CCR-23-0536