Emergence of community behaviors in the gut microbiota upon drug treatment.

Pharmaceuticals can directly inhibit the growth of gut bacteria, but the degree to which such interactions manifest in complex community settings is an open question. Here, we compared the effects of 30 drugs on a 32-species synthetic community with their effects on each community member in isolation. While most individual drug-species interactions remained the same in the community context, communal behaviors emerged in 26% of all tested cases. Cross-protection during which drug-sensitive species were protected in community was 6 times more frequent than cross-sensitization, the converse phenomenon. Cross-protection decreased and cross-sensitization increased at higher drug concentrations, suggesting that the resilience of microbial communities can collapse when perturbations get stronger. By metabolically profiling drug-treated communities, we showed that both drug biotransformation and bioaccumulation contribute mechanistically to communal protection. As a proof of principle, we molecularly dissected a prominent case: species expressing specific nitroreductases degraded niclosamide, thereby protecting both themselves and sensitive community members.

Role of oxidative stress-induced ferroptosis in cancer therapy.

Ferroptosis is a distinct mode of cell death, distinguishing itself from typical apoptosis by its reliance on the accumulation of iron ions and lipid peroxides. Cells manifest an imbalance between oxidative stress and antioxidant equilibrium during certain pathological contexts, such as tumours, resulting in oxidative stress. Notably, recent investigations propose that heightened intracellular reactive oxygen species (ROS) due to oxidative stress can heighten cellular susceptibility to ferroptosis inducers or expedite the onset of ferroptosis. Consequently, comprehending role of ROS in the initiation of ferroptosis has significance in elucidating disorders related to oxidative stress. Moreover, an exhaustive exploration into the mechanism and control of ferroptosis might offer novel targets for addressing specific tumour types. Within this context, our review delves into recent fundamental pathways and the molecular foundation of ferroptosis. Four classical ferroptotic molecular pathways are well characterized, namely, glutathione peroxidase 4-centred molecular pathway, nuclear factor erythroid 2-related factor 2 molecular pathway, mitochondrial molecular pathway, and mTOR-dependent autophagy pathway. Furthermore, we seek to elucidate the regulatory contributions enacted by ROS. Additionally, we provide an overview of targeted medications targeting four molecular pathways implicated in ferroptosis and their potential clinical applications. Here, we review the role of ROS and oxidative stress in ferroptosis, and we discuss opportunities to use ferroptosis as a new strategy for cancer therapy and point out the current challenges persisting within the domain of ROS-regulated anticancer drug research and development.

A review of the clinical efficacy of FDA-approved antibody‒drug conjugates in human cancers.

While strategies such as chemotherapy and immunotherapy have become the first-line standard therapies for patients with advanced or metastatic cancer, acquired resistance is still inevitable in most cases. The introduction of antibody‒drug conjugates (ADCs) provides a novel alternative. ADCs are a new class of anticancer drugs comprising the coupling of antitumor mAbs with cytotoxic drugs. Compared with chemotherapeutic drugs, ADCs have the advantages of good tolerance, accurate target recognition, and small effects on noncancerous cells. ADCs occupy an increasingly important position in the therapeutic field. Currently, there are 13 Food and Drug Administration (FDA)‒approved ADCs and more than 100 ADC drugs at different stages of clinical trials. This review briefly describes the efficacy and safety of FDA-approved ADCs, and discusses the related problems and challenges to provide a reference for clinical work.

Developing neural network diagnostic models and potential drugs based on novel identified immune-related biomarkers for celiac disease.

BACKGROUND: As one of the most common intestinal inflammatory diseases, celiac disease (CD) is typically characterized by an autoimmune disorder resulting from ingesting gluten proteins. Although the incidence and prevalence of CD have increased over time, the diagnostic methods and treatment options are still limited. Therefore, it is urgent to investigate the potential biomarkers and targeted drugs for CD. METHODS: Gene expression data was downloaded from GEO datasets. Differential gene expression analysis was performed to identify the dysregulated immune-related genes. Multiple machine algorithms, including randomForest, SVM-RFE, and LASSO, were used to select the hub immune-related genes (HIGs). The immune-related genes score (IG score) and artificial neural network (ANN) were constructed based on HIGs. Potential drugs targeting HIGs were identified by using the Enrichr platform and molecular docking method. RESULTS: We identified the dysregulated immune-related genes at a genome-wide level and demonstrated their roles in CD-related immune pathways. The hub genes (MR1, CCL25, and TNFSF13B) were further screened by integrating several machine algorithms. Meanwhile, the CD patients were divided into distinct subtypes with either high- or low-immunoactivity using single-sample gene set enrichment analysis (ssGSEA) and consensus clustering. By constructing IG score based on HIGs, we found that patients with high IG score were mainly attributed to high-immunoactivity subgroups, which suggested a strong link between HIGs and immunoactivity of CD patients. In addition, the novel constructed ANN model showed the sound diagnostic ability of HIGs. Mechanistically, we validated that the HIGs play pivotal roles in regulating CD's immune and inflammatory state. Through targeting the HIGs, we also found potential drugs for anti-CD treatment by using the Enrichr platform and molecular docking method. CONCLUSIONS: This study unveils the HIGs and elucidates the networks regulated by these genes in the context of CD. It underscores the pivotal significance of HIGs in accurately predicting the presence or absence of CD in patients. Consequently, this research offers promising prospects for the development of diagnostic biomarkers and therapeutic targets for CD.

The Trend of the Treatment of Advanced Hepatocellular Carcinoma: Combination of Immunotherapy and Targeted Therapy.

OPINION STATEMENT: Hepatocellular carcinoma (HCC) is a common type of tumor worldwide. The development of systemic treatment of advanced HCC has remained stagnant for a considerable period. During the last years, a series of new treatment regimens based on the combination of immunotherapeutic drugs and targeted drugs have been gradually developed, increased the objective response rate (ORR), overall survival (OS), and progression free survival (PFS) of HCC patients. Among the different combination therapy groups, atezolizumab plus bevacizumab and sintilimab plus IBI-305 seem to have unique advantages, while head-to-head comparisons are still needed. A comprehensive understanding of the developments, the ongoing clinical trials and the mechanisms of combination of immunotherapy and targeted therapy might lead to the development of new combination strategies and solving current challenges such as the molecular biomarkers, the clinical administration order of drugs and the second-line treatments after combination therapy.

The potential of Lycium barbarum miR166a in kidney cancer treatment.

Predator species of animal can absorb plant microRNA that can regulate target gene expression and physiological function across species. The herb Lycium barbarum, a traditional Chinese medicine, has a wide range of antitumor effects. However, there are no reports on the effects of microRNA derived from it on the cross-border regulation of renal cell carcinoma (RCC). We performed in vitro and in vivo experiments to explore the role and mechanism of the L. barbarum-derived microRNA miR166a (Lb-miR166a) in cross-border regulation of RCC. Our mRNA sequencing analysis showed that Lb-miR166a regulates the expression of various genes in tumor cells, including 1232 upregulated genes and 581 downregulated genes, which were enriched to 1094 Gene Ontology entries and 43 Kyoto Encyclopedia of Genes and Genomes pathways. In vitro cell experiments confirmed that Lb-miR166a can inhibit the proliferation of RCC cells, promote the apoptosis of tumor cells, and inhibit the invasion and metastasis of tumor cells by regulating the expression of related genes. Furthermore, our in vivo tumor-bearing experiment showed that subcutaneous tumor formation volume decreased in Lb-miR166a mice, along with the number of liver metastases. This study elucidates the role and mechanism of Lb-miR166a in RCC treatment (Fig. 1). Our results further mechanistically confirm the antitumor properties of L. barbarum. Our study may contribute to the clinical development of a targeted drug for RCC treatment.

Pathogenomics model for personalized medicine in cervical cancer: Cross-talk of gene expressions and pathological images related to oxidative stress.

An increasing number of studies have shown that oxidative stress plays an important role in the development and progression of cancer. Cervical cancer (CC) is a disease of unique complexity that tends to exhibit high heterogeneity in molecular phenotypes. We aim here to characterize molecular features of cervical cancer by developing a classification system based on oxidative stress-related gene expression profiles. In this study, we obtained gene expression profiling data for cervical cancer from the TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) (GSE44001) databases. Oxidative stress-related genes used for clustering were obtained from GeneCards. Patients with cervical cancer were divided into two subtypes (C1 and C2) by non-negative matrix factorization (NMF) classification. By performing Kaplan-Meier survival analysis, differential expression analysis, and gene set enrichment analysis (GSEA) between the two subtypes, we found that subtype C2 had a worse prognosis and was highly enriched for immune-related pathways as well as epithelial-mesenchymal transition (EMT) pathways. Subsequently, we performed metabolic pathway analysis, gene mutation landscape analysis, immune microenvironment analysis, immunotherapy response analysis, and drug sensitivity analysis of the two isoforms. The results showed that the isoforms were significantly different between metabolic pathway enrichment and the immune microenvironment, and the chromosomes of subtype C1 were more unstable. In addition, we found that subtype C2 tends to respond to treatment with anti-CTLA4 agents, a conclusion that coincides with high chromosomal variation in C1, as well as C2 enrichment of immune-related pathways. Then, we screened 10 agents that were significantly susceptible to C2 subtype. Finally, we constructed pathogenomics models based on pathological features and linked them to molecular subtypes. This study establishes a novel CC classification based on gene expression profiles of oxidative stress-related genes and elucidates differences between immune microenvironments between CC subtypes, contributing to subtype-specific immunotherapy and drug therapy.

Biology and Development of DNA-Targeted Drugs, Focusing on Synthetic Lethality, DNA Repair, and Epigenetic Modifications for Cancer: A Review.

DNA-targeted drugs constitute a specialized category of pharmaceuticals developed for cancer treatment, directly influencing various cellular processes involving DNA. These drugs aim to enhance treatment efficacy and minimize side effects by specifically targeting molecules or pathways crucial to cancer growth. Unlike conventional chemotherapeutic drugs, recent discoveries have yielded DNA-targeted agents with improved effectiveness, and a new generation is anticipated to be even more specific and potent. The sequencing of the human genome in 2001 marked a transformative milestone, contributing significantly to the advancement of targeted therapy and precision medicine. Anticipated progress in precision medicine is closely tied to the continuous development in the exploration of synthetic lethality, DNA repair, and expression regulatory mechanisms, including epigenetic modifications. The integration of technologies like circulating tumor DNA (ctDNA) analysis further enhances our ability to elucidate crucial regulatory factors, promising a more effective era of precision medicine. The combination of genomic knowledge and technological progress has led to a surge in clinical trials focusing on precision medicine. These trials utilize biomarkers for identifying genetic alterations, molecular profiling for potential therapeutic targets, and tailored cancer treatments addressing multiple genetic changes. The evolving landscape of genomics has prompted a paradigm shift from tumor-centric to individualized, genome-directed treatments based on biomarker analysis for each patient. The current treatment strategy involves identifying target genes or pathways, exploring drugs affecting these targets, and predicting adverse events. This review highlights strategies incorporating DNA-targeted drugs, such as PARP inhibitors, SLFN11, methylguanine methyltransferase (MGMT), and ATR kinase.

Lipid metabolism reprogramming in colorectal cancer.

The hallmark feature of metabolic reprogramming is now considered to be widespread in many malignancies, including colorectal cancer (CRC). Of the gastrointestinal tumors, CRC is one of the most common with a high metastasis rate and long insidious period. The incidence and mortality of CRC has increased in recent years. Metabolic reprogramming also has a significant role in the development and progression of CRC, especially lipid metabolic reprogramming. Many studies have reported that lipid metabolism reprogramming is similar to the Warburg effect with typical features affecting tumor biology including proliferation, migration, local invasion, apoptosis, and other biological behaviors of cancer cells. Therefore, studying the role of lipid metabolism in the occurrence and development of CRC will increase our understanding of its pathogenesis, invasion, metastasis, and other processes and provide new directions for the treatment of CRC. In this paper, we mainly describe the molecular mechanism of lipid metabolism reprogramming and its important role in the occurrence and development of CRC. In addition, to provide reference for subsequent research and clinical diagnosis and treatment we also review the treatments of CRC that target lipid metabolism.

Intracellular spatially-targeted chemical chaperones increase native state stability of mutant SOD1 barrel.

Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder with currently no cure. Central to the cellular dysfunction associated with this fatal proteinopathy is the accumulation of unfolded/misfolded superoxide dismutase 1 (SOD1) in various subcellular locations. The molecular mechanism driving the formation of SOD1 aggregates is not fully understood but numerous studies suggest that aberrant aggregation escalates with folding instability of mutant apoSOD1. Recent advances on combining organelle-targeting therapies with the anti-aggregation capacity of chemical chaperones have successfully reduce the subcellular load of misfolded/aggregated SOD1 as well as their downstream anomalous cellular processes at low concentrations (micromolar range). Nevertheless, if such local aggregate reduction directly correlates with increased folding stability remains to be explored. To fill this gap, we synthesized and tested here the effect of 9 ER-, mitochondria- and lysosome-targeted chemical chaperones on the folding stability of truncated monomeric SOD1 (SOD1bar) mutants directed to those organelles. We found that compound ER-15 specifically increased the native state stability of ER-SOD1bar-A4V, while scaffold compound FDA-approved 4-phenylbutyric acid (PBA) decreased it. Furthermore, our results suggested that ER15 mechanism of action is distinct from that of PBA, opening new therapeutic perspectives of this novel chemical chaperone on ALS treatment.

Combination effects of amino acid transporter LAT1 inhibitor nanvuranlat and cytotoxic anticancer drug gemcitabine on pancreatic and biliary tract cancer cells.

BACKGROUND: Cytotoxic anticancer drugs widely used in cancer chemotherapy have some limitations, such as the development of side effects and drug resistance. Furthermore, monotherapy is often less effective against heterogeneous cancer tissues. Combination therapies of cytotoxic anticancer drugs with molecularly targeted drugs have been pursued to solve such fundamental problems. Nanvuranlat (JPH203 or KYT-0353), an inhibitor for L-type amino acid transporter 1 (LAT1; SLC7A5), has novel mechanisms of action to suppress the cancer cell proliferation and tumor growth by inhibiting the transport of large neutral amino acids into cancer cells. This study investigated the potential of the combined use of nanvuranlat and cytotoxic anticancer drugs. METHODS: The combination effects of cytotoxic anticancer drugs and nanvuranlat on cell growth were examined by a water-soluble tetrazolium salt assay in two-dimensional cultures of pancreatic and biliary tract cancer cell lines. To elucidate the pharmacological mechanisms underlying the combination of gemcitabine and nanvuranlat, we investigated apoptotic cell death and cell cycle by flow cytometry. The phosphorylation levels of amino acid-related signaling pathways were analyzed by Western blot. Furthermore, growth inhibition was examined in cancer cell spheroids. RESULTS: All the tested seven types of cytotoxic anticancer drugs combined with nanvuranlat significantly inhibited the cell growth of pancreatic cancer MIA PaCa-2 cells compared to their single treatment. Among them, the combined effects of gemcitabine and nanvuranlat were relatively high and confirmed in multiple pancreatic and biliary tract cell lines in two-dimensional cultures. The growth inhibitory effects were suggested to be additive but not synergistic under the tested conditions. Gemcitabine generally induced cell cycle arrest at the S phase and apoptotic cell death, while nanvuranlat induced cell cycle arrest at the G0/G1 phase and affected amino acid-related mTORC1 and GAAC signaling pathways. In combination, each anticancer drug basically exerted its own pharmacological activities, although gemcitabine more strongly influenced the cell cycle than nanvuranlat. The combination effects of growth inhibition were also verified in cancer cell spheroids. CONCLUSIONS: Our study demonstrates the potential of first-in-class LAT1 inhibitor nanvuranlat as a concomitant drug with cytotoxic anticancer drugs, especially gemcitabine, on pancreatic and biliary tract cancers.

Identification and comprehensive analysis of ferroptosis-related genes as potential biomarkers for the diagnosis and treatment of proliferative diabetic retinopathy by bioinformatics methods.

Diabetic retinopathy (DR) is the most common retinal vascular disease. Proliferative DR (PDR) is the aggressive stage of DR with angiogenesis as a pathological hallmark, which is the main cause of blindness. There is growing evidence that ferroptosis plays a vital role in diabetics as well as its complications including DR. However, the potential functions and mechanisms of ferroptosis have not been completely elucidated in PDR. The ferroptosis-related differentially expressed genes (FRDEGs) were identified in GSE60436 and GSE94019. Then we constructed a protein-protein interaction (PPI) network and screened ferroptosis-related hub genes (FRHGs). The GO functional annotation and the KEGG pathway enrichment analyses of FRHGs were performed. The miRNet and miRTarbase databases were applied to construct the ferroptosis-related mRNA-miRNA-lncRNA network, and the Drug-Gene Interaction Database (DGIdb) was used for predicting potential therapeutic drugs. Finally, we identified 21 upregulated and 9 downregulated FRDEGs, among which 10 key target genes (P53, TXN, PTEN, SLC2A1, HMOX1, PRKAA1, ATG7, HIF1A, TGFBR1, and IL1B) were recognized with enriched functions, mainly relating to responses to oxidative stress and hypoxia in biological processes of PDR. HIF-1, FoxO and MAPK signalling may be the main pathways that influence ferroptosis in PDR. Moreover, a mRNA-miRNA-lncRNA network was constructed based on the 10 FRHGs and their co-expressed miRNAs. Finally, potential drugs targeting 10 FRHGs for PDR were predicted. Results of the receiver operator characteristic (ROC) curve indicated, with high predictive accuracy in two testing datasets (AUC>0.8), that ATG7, TGFB1, TP53, HMOX1 and ILB1 had the potential to be biomarkers of PDR.

Identify the influences of systemic lupus erythematosus on acquired ADAMTS13-deficient thrombotic thrombocytopenic purpura using comprehensive bioinformatics analysis.

BACKGROUND: The association between acquired ADAMTS13-deficient thrombotic thrombocytopenic purpura (aTTP) and systemic lupus erythematosus (SLE) has been studied; however, the underlying molecular causes remain poorly understood. This research aimed to employ bioinformatics approaches to elucidate potential molecular mechanisms contributing to the pathogenesis of SLE and aTTP. MATERIAL AND METHODS: The Gene Expression Omnibus (GEO) database yielded GSE121239 and GSE36418 to get mutual different expression genes (DEGs). Subsequently, DEGs were subjected to process Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Then, the DEGs were used for protein-protein interaction (PPI) analysis and screened for hub genes and drugs by the DGIDB drug database. RESULTS: A total of 87 DEGs between the SLE and TTP datasets were identified. In the GO and KEGG analyses, DEGs were mainly enriched in the "regulation of transcription by RNA polymerase II" and "signaling pathways regulating pluripotency of stem cells." After a PPI analysis, three hub genes (BMPR2, SMAD5, and ATF2) were identified. Finally, two drugs targeted to ATF2 were predicted by the DGIDB drug database. CONCLUSIONS: Three core genes were linked to the molecular pathogenesis of SLE and aTTP, and two drugs may be viable treatments for both diseases.

DROID: dose-ranging approach to optimizing dose in oncology drug development.

In the era of targeted therapy, there has been increasing concern about the development of oncology drugs based on the "more is better" paradigm, developed decades ago for chemotherapy. Recently, the US Food and Drug Administration (FDA) initiated Project Optimus to reform the dose optimization and dose selection paradigm in oncology drug development. To accommodate this paradigm shifting, we propose a dose-ranging approach to optimizing dose (DROID) for oncology trials with targeted drugs. DROID leverages the well-established dose-ranging study framework, which has been routinely used to develop non-oncology drugs for decades, and bridges it with established oncology dose-finding designs to optimize the dose of oncology drugs. DROID consists of two seamlessly connected stages. In the first stage, patients are sequentially enrolled and adaptively assigned to investigational doses to establish the therapeutic dose range (TDR), defined as the range of doses with acceptable toxicity and efficacy profiles, and the recommended phase 2 dose set (RP2S). In the second stage, patients are randomized to the doses in RP2S to assess the dose-response relationship and identify the optimal dose. The simulation study shows that DROID substantially outperforms the conventional approach, providing a new paradigm to efficiently optimize the dose of targeted oncology drugs. DROID aligns with the approach of a randomized, parallel dose-response trial design recommended by the FDA in the Guidance on Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases.

Updates on risk stratification and management of lower-risk myelodysplastic syndromes/neoplasms.

The majority of lower-risk myelodysplastic syndromes/neoplasms patients present with anemia. Historically, these patients were treated with erythropoiesis-stimulating agents (ESA), with modest responses. A subset of these patients with del(5q) may do better with lenalidomide. Recently, in randomized trials, luspatercept has shown better responses compared with ESAs in treatment-naive patients and imetelstat in patients refractory to ESAs. Other evaluated novel compounds (fostamatinib, H3B-880, roxadustat, pyruvate kinase receptor activator) have not yet shown meaningful efficacy. More needs to be done to improve outcomes; in pursuance of this, participation in clinical trials evaluating novel therapies should be encouraged. While lower-risk myelodysplastic syndromes/neoplasms tend to have an indolent course, a subset of them has a dismal prognosis. Improving prognostication and serial monitoring will help in identifying high-risk patients for appropriate management.

The efficacy of the treat-repair-treat strategy for severe pulmonary arterial hypertension associated with congenital heart disease: a meta-analysis.

BACKGROUND: This meta-analysis was conducted to evaluate the efficacy of the treat-repair-treat (TRT) strategy in the treatment of severe pulmonary arterial hypertension with congenital heart disease (PAH-CHD). METHODS: PubMed, EMBASE, Cochrane and Web of Science online databases were searched by two independent investigators for studies that used the TRT strategy for PAH-CHD, and the retrieved studies were reviewed by a third investigator. The main outcomes were pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), 6-minute walk distance (6MWD), and transcutaneous oxygen saturation (SpO2). The changes were compared between follow-up and baseline. Stata version 14.0 was used for data analysis. A random-effects model was selected for meta-analysis. Subgroup analysis and meta-regression were used to find the source of heterogeneity. RESULTS: A total of 335 patients from 9 single-arm studies were included. Meta-analysis showed significant reductions in PAP and PVR and improvements in 6MWD and SpO2 (PAP: SMD -2.73 95% CI -2.97, - 2.50 p = < 0.001; PVR: SMD -1.27 95% CI -1.53, - 1.02 p = < 0.001; 6MWD: SMD 1.88 95% CI 1.49, 2.27 p = < 0.001; SpO2: SMD 3.72 95% CI 3.13, 4.32 p = < 0.001). Subgroup analysis showed that younger patients had better efficacy, and the change in SpO2 was an indication for patient selection. The combined mortality rate was 5% at follow-up. CONCLUSIONS: In this meta-analysis, we demonstrated that the TRT strategy may have positive effects on haemodynamics and cardiac function in patients with severe PAH-CHD at short-term follow-up. Our analysis suggests that changes in age and SpO2 may be related to patient prognosis. TRIAL REGISTRATION: The protocol was registered on the PROSPERO website with the registration number CRD42022366552. The relevant registration information can be obtained from the website https://www.crd.york.ac.uk/prospero/#searchadvanced .

Review of novel and supplemental approvals of the targeted cancer drugs by the Food and Drug Administration in 2021.

OBJECTIVE: This review aims to present the most recent results from clinical trials of targeted cancer drugs that led to the Food and Drug Administration approval in 2021 and reflect the changing treatment landscape of solid malignancies. DATA SOURCES: Novel approvals and supplemental approvals in 2021 were retrieved from the official web page of the Food and Drug Administration (Drugs@FDA). This review did not include approvals for generics, biosimilars, imaging, and diagnostics agents. DATA SUMMARY: This review included 10 novel drugs approved for 11 indications and 10 already-approved drugs approved for 21 indications by the Food and Drug Administration in 2021. Novel approvals mainly were related to treating an orphan disease. In addition, one-third of the supplemental approvals were given for neoadjuvant or adjuvant treatment, while the number of indications for each tumor site was as follows: gastrointestinal (7), genitourinary (5), skin (3), lung (2), breast (2), thyroid (1), and cervix (1). CONCLUSIONS: Targeted cancer treatments are gaining more importance than ever in treating malignant diseases. As the approval of targeted cancer drugs provides a possibility for patients and this trend is expected to continue in the future, it remains vital for healthcare providers to stay up-to-date with newer therapeutic options.

Synthesis of mitochondria-targeted menadione cation derivatives: Inhibiting mitochondrial thioredoxin reductase (TrxR2) and inducing apoptosis in MGC-803 cells.

Menadione (VK3) is used as a powerful inducer of cellular reactive oxygen species (ROS) for many years and displays the high anti-cancer activities in vivo. Recently, the development of mitochondria-targeted drugs has been more and more appreciated. Here, the thirteen derivatives of VK3 were synthesized, which could localize in mitochondria by the triphenylphosphonium (TPP) cation or the nitrogen-based cation. The results of cytotoxicity from six human cancer cell lines showed that the targeted compounds T1-T13 displayed higher activity than VK3 with the average IC50 value around 1 µM. The results of cytotoxicity indicated that the substitutes on C-2, the linear alkyl chains on C-3 and cation moiety all could affect the cytotoxicity. The mechanistic studies showed that five representative compounds (T2, T3, T5, T8 and T13) could localize in cellular mitochondria, elicit ROS burst and collapse mitochondrial membrane potential (ΔΨm), leading to cytochrome C release and apoptosis in MGC-803 cells. Particularly, they could obviously inhibit mitochondrial thioredoxin reductase TrxR2 expression, thus leading to aggravate cellular oxidative stress.

The Molecular Mechanisms of Cardiotoxicity Induced by HER2, VEGF, and Tyrosine Kinase Inhibitors: an Updated Review.

AIM: In recent decades, there has been a revolutionary decrease in cancer-related mortality and an increase in survival due to the introduction of novel targeted drugs. Nevertheless, drugs targeting human epidermal growth factor receptor 2 (HER-2), angiogenesis, and other tyrosine kinases also come with unexpected cardiac side effects, including heart failure, hypertension, arterial thrombosis, and arrhythmias, and have mechanisms that are unlike those of classic chemotherapeutic agents. In addition, it is challenging to address some problems, as the existing guidelines need to be more specific, and further large-scale clinical trials and experimental studies are required to confirm the benefit of administering cardioprotective agents to patients treated with targeted therapies. Therefore, an improved understanding of cardiotoxicity becomes increasingly important to minimize the pernicious effects and maximize the beneficial effects of targeted agents. METHODS: "Cardiotoxicity", "targeted drugs", "HER2", "trastuzumab", "angiogenesis inhibitor", "VEGF inhibitor" and "tyrosine kinase inhibitors" are used as keywords for article searches. RESULTS: In this article, we report several targeted therapies that induce cardiotoxicity and update knowledge of the clinical evidence, molecular mechanisms, and management measures.

Efficacy and safety of targeted drugs in advanced or metastatic gastric and gastroesophageal junction cancer: A network meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: An increasing number of targeted drugs have been used to treat advanced or metastatic gastric cancer (GC) and gastroesophageal junction cancer (GEJC). However, the optimal treatment efficacy of these drugs is still controversial. The aims of this study are to systematically summarize the efficacy and safety of current targeted drugs for advanced or metastatic GC and GEJC. METHODS: PubMed, EmBase, Cochrane Library, Web of Science and ClinicalTrials were searched for double-blind randomized controlled trials (RCTs) on GC and GEJC up to December 2019. Additionally, we updated the literature search from Jan, 1, 2020 to September 30, 2021. Narrative and quantitative analysis were performed to analyse the efficacy and safety. STATA 15.1 was used to identify publication bias, and the SUCRA (surface under the cumulative ranking) curve was conducted to rank the treatments for each outcome. RESULTS: A total of 27 RCTs with 9295 GC and GEJC patients treated by 19 drugs were included. SUCRA showed that regorafenib was the most likely to improve patients' progression-free survival (96.4%), followed by apatinib (90.7%), nivolumab (82.4%), everolimus (76.5%) and pertuzumab (68.5%). Meanwhile, apatinib (92.4%) was most likely to improve overall survival, followed by nivolumab (87.9%), regorafenib (72.5%), olaparib (67.7%) and lapatinib (63.2%). Additionally, neutropenia, diarrhoea and fatigue were the most common adverse events caused by these drugs, followed by pain, nausea, decreased appetite, anaemia and vomiting. WHAT IS NEW AND CONCLUSION: Regorafenib and nivolumab have higher efficacy and tolerability and are the most advantageous for advanced GC and GEJC. Moreover, apatinib has higher efficacy but lower tolerability. Everolimus and pertuzumab combined with chemotherapy have best secondary higher efficacy for progression-free survival and good tolerability. Lapatinib and olaparib combined with chemotherapy have moderate efficacy for overall survival and good tolerability.