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European Journal of Medicinal Chemistry Jun 2024Lactate dehydrogenase-A (LDHA) is the major isoform of lactate dehydrogenases (LDH) that is overexpressed and linked to poor survival in pancreatic ductal adenocarcinoma...
Lactate dehydrogenase-A (LDHA) is the major isoform of lactate dehydrogenases (LDH) that is overexpressed and linked to poor survival in pancreatic ductal adenocarcinoma (PDAC). Despite some progress, current LDH inhibitors have poor structural and physicochemical properties or exhibit unfavorable pharmacokinetics that have hampered their development. The present study reports the synthesis and biological evaluation of a novel class of LDHA inhibitors comprising a succinic acid monoamide motif. Compounds 6 and 21 are structurally related analogs that demonstrated potent inhibition of LDHA with ICs of 46 nM and 72 nM, respectively. We solved cocrystal structures of compound 21-bound to LDHA that showed that the compound binds to a distinct allosteric site between the two subunits of the LDHA tetramer. Inhibition of LDHA correlated with reduced lactate production and reduction of glycolysis in MIA PaCa-2 pancreatic cancer cells. The lead compounds inhibit the proliferation of human pancreatic cancer cell lines and patient-derived 3D organoids and exhibit a synergistic cytotoxic effect with the OXPHOS inhibitor phenformin. Unlike current LDHA inhibitors, 6 and 21 have appropriate pharmacokinetics and ligand efficiency metrics, exhibit up to 73% oral bioavailability, and a cumulative half-life greater than 4 h in mice.
PubMed: 38925013
DOI: 10.1016/j.ejmech.2024.116598 -
International Journal of Oral Science May 2024The efficient clinical treatment of oral squamous cell carcinoma (OSCC) is still a challenge that demands the development of effective new drugs. Phenformin has been...
The efficient clinical treatment of oral squamous cell carcinoma (OSCC) is still a challenge that demands the development of effective new drugs. Phenformin has been shown to produce more potent anti-tumor activities than metformin on different tumors, however, not much is known about the influence of phenformin on OSCC cells. We found that phenformin suppresses OSCC cell proliferation, and promotes OSCC cell autophagy and apoptosis to significantly inhibit OSCC cell growth both in vivo and in vitro. RNA-seq analysis revealed that autophagy pathways were the main targets of phenformin and identified two new targets DDIT4 (DNA damage inducible transcript 4) and NIBAN1 (niban apoptosis regulator 1). We found that phenformin significantly induces the expression of both DDIT4 and NIBAN1 to promote OSCC autophagy. Further, the enhanced expression of DDIT4 and NIBAN1 elicited by phenformin was not blocked by the knockdown of AMPK but was suppressed by the knockdown of transcription factor ATF4 (activation transcription factor 4), which was induced by phenformin treatment in OSCC cells. Mechanistically, these results revealed that phenformin triggers endoplasmic reticulum (ER) stress to activate PERK (protein kinase R-like ER kinase), which phosphorylates the transitional initial factor eIF2, and the increased phosphorylation of eIF2 leads to the increased translation of ATF4. In summary, we discovered that phenformin induces its new targets DDIT4 and especially NIBAN1 to promote autophagic and apoptotic cell death to suppress OSCC cell growth. Our study supports the potential clinical utility of phenformin for OSCC treatment in the future.
Topics: Phenformin; Endoplasmic Reticulum Stress; Humans; Mouth Neoplasms; Autophagy; Carcinoma, Squamous Cell; Cell Proliferation; Cell Line, Tumor; Transcription Factors; Mice; Apoptosis Regulatory Proteins; Apoptosis; AMP-Activated Protein Kinases; Animals; Blotting, Western
PubMed: 38719825
DOI: 10.1038/s41368-024-00297-w -
Arab Journal of Gastroenterology : the... May 2024The prognosis of colorectal cancer (CRC) is related to natural killer (NK) cells, but the molecular subtype features of CRC based on NK cells are still unknown. This...
BACKGROUND AND STUDY AIMS
The prognosis of colorectal cancer (CRC) is related to natural killer (NK) cells, but the molecular subtype features of CRC based on NK cells are still unknown. This study aimed to identify NK cell-related molecular subtypes of CRC and analyze the survival status and immune landscape of patients with different subtypes.
PATIENTS/MATERIAL AND METHODS
mRNA expression data, single nucleotide variant (SNV) data, and clinical information of CRC patients were obtained from The Cancer Genome Atlas. Differentially expressed genes (DEGs) were obtained through differential analysis, and the intersection was taken with NK cell-associated genes to obtain 103 NK cell-associated CRC DEGs (NCDEGs). Based on NCDEGs, CRC samples were divided into three clusters through unsupervised clustering analysis. Survival analysis, immune analysis, Gene Set Enrichment Analysis (GSEA), and tumor mutation burden (TMB) analysis were performed. Finally, NCDEG-related small-molecule drugs were screened using the CMap database.
RESULTS
Survival analysis revealed that cluster2 had a lower survival rate than cluster1 and cluster3 (p < 0.05). Immune infiltration analysis found that the immune infiltration levels and immune checkpoint expression levels of cluster1_3 were substantially higher than those of cluster2, and the tumor purity was the opposite (p < 0.05). GSEA presented that cluster1_3 was significantly enriched in the chemokine signaling pathway, ECM receptor interaction, and antigen processing and presentation pathways (p < 0.05). The TMB of cluster1_3 was significantly higher than that of cluster2 (p < 0.05). Genes with the highest mutation rate in CRC were APC, TP53, TTN, and KRAS. Drug prediction results showed that small-molecule drugs that reverse the upregulation of NCDEGs, deoxycholic acid, dipivefrine, phenformin, and other drugs may improve the prognosis of CRC.
CONCLUSION
NK cell-associated CRC subtypes can be used to evaluate the tumor characteristics of CRC patients and provide an important reference for CRC patients.
Topics: Humans; Colorectal Neoplasms; Killer Cells, Natural; Prognosis; Mutation; Survival Rate; Survival Analysis; Gene Expression Regulation, Neoplastic; Female; Male; Gene Expression Profiling
PubMed: 38719664
DOI: 10.1016/j.ajg.2024.03.005 -
Pharmaceuticals (Basel, Switzerland) Apr 2024Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by pathophysiological deposits of extracellular amyloid beta (Aβ) peptides and...
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by pathophysiological deposits of extracellular amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles of tau. The central role of Aβ in AD pathology is well-established, with its increased deposition attributed mainly to its decreased cerebral clearance. Here, it is noteworthy that apolipoprotein E (ApoE), the most significant risk factor for AD, has been shown to play an isoform-specific role in clearing Aβ deposits (ApoE2 > ApoE3 > ApoE4), owing mainly to its lipidation status. In addition to the pathophysiological Aβ deposits, AD is also characterized by abnormal glucose metabolism, which is a distinct event preceding Aβ deposition. The present study established, for the first time, a possible link between these two major AD etiologies, with glucose metabolism directly influencing ApoE lipidation and its secretion by astrocytes expressing human ApoE4. Specifically, glucose dose-dependently activated liver X receptor (LXR), leading to elevated ABCA1 and ABCG1 protein levels and enhanced ApoE lipidation. Moreover, co-treatment with a glycolytic inhibitor significantly inhibited this LXR activation and subsequent ApoE lipidation, further supporting a central role of glucose metabolism in LXR activation leading to enhanced ApoE lipidation, which may help against AD through potential Aβ clearance. Therefore, we hypothesized that pharmacological agents that can target cellular energy metabolism, specifically aerobic glycolysis, may hold significant therapeutic potential against AD. In this context, the present study also led to the discovery of novel, small-molecule stimulants of astrocytic glucose metabolism, leading to significantly enhanced lipidation status of ApoE4 in astrocytic cells. Three such newly discovered compounds (lonidamine, phenformin, and berberine), owing to their promising cellular effect on the glycolysis-ApoE nexus, warrant further investigation in suitable in vivo models of AD.
PubMed: 38675451
DOI: 10.3390/ph17040491 -
Glucose Metabolism as a Potential Therapeutic Target in Cytarabine-Resistant Acute Myeloid Leukemia.Pharmaceutics Mar 2024Altered glycolytic metabolism has been associated with chemoresistance in acute myeloid leukemia (AML). However, there are still aspects that need clarification, as well...
Altered glycolytic metabolism has been associated with chemoresistance in acute myeloid leukemia (AML). However, there are still aspects that need clarification, as well as how to explore these metabolic alterations in therapy. In the present study, we aimed to elucidate the role of glucose metabolism in the acquired resistance of AML cells to cytarabine (Ara-C) and to explore it as a therapeutic target. Resistance was induced by stepwise exposure of AML cells to increasing concentrations of Ara-C. Ara-C-resistant cells were characterized for their growth capacity, genetic alterations, metabolic profile, and sensitivity to different metabolic inhibitors. Ara-C-resistant AML cell lines, KG-1 Ara-R, and MOLM13 Ara-R presented different metabolic profiles. KG-1 Ara-R cells exhibited a more pronounced glycolytic phenotype than parental cells, with a weaker acute response to 3-bromopyruvate (3-BP) but higher sensitivity after 48 h. KG-1 Ara-R cells also display increased respiration rates and are more sensitive to phenformin than parental cells. On the other hand, MOLM13 Ara-R cells display a glucose metabolism profile similar to parental cells, as well as sensitivity to glycolytic inhibitors. These results indicate that acquired resistance to Ara-C in AML may involve metabolic adaptations, which can be explored therapeutically in the AML patient setting who developed resistance to therapy.
PubMed: 38675105
DOI: 10.3390/pharmaceutics16040442 -
Photochemical & Photobiological... Mar 2024Squamous cell carcinoma represents the second most common type of keratinocyte carcinoma with ultraviolet radiation (UVR) making up the primary risk factor. Oral...
Squamous cell carcinoma represents the second most common type of keratinocyte carcinoma with ultraviolet radiation (UVR) making up the primary risk factor. Oral photoprotection aims to reduce incidence rates through oral intake of photoprotective compounds. Recently, drug repurposing has gained traction as an interesting source of chemoprevention. Because of their reported photoprotective properties, we investigated the potential of bucillamine, carvedilol, metformin, and phenformin as photoprotective compounds following oral intake in UVR-exposed hairless mice. Tumour development was observed in all groups in response to UVR, with only the positive control (Nicotinamide) demonstrating a reduction in tumour incidence (23.8%). No change in tumour development was observed in the four repurposed drug groups compared to the UV control group, whereas nicotinamide significantly reduced carcinogenesis (P = 0.00012). Metformin treatment significantly reduced UVR-induced erythema (P = 0.012), bucillamine and phenformin increased dorsal pigmentation (P = 0.0013, and P = 0.0005), but no other photoprotective effect was observed across the repurposed groups. This study demonstrates that oral supplementation with bucillamine, carvedilol, metformin, or phenformin does not affect UVR-induced carcinogenesis in hairless mice.
Topics: Mice; Animals; Ultraviolet Rays; Carvedilol; Mice, Hairless; Phenformin; Carcinoma, Squamous Cell; Carcinogenesis; Niacinamide; Skin Neoplasms; Skin; Cysteine
PubMed: 38337129
DOI: 10.1007/s43630-024-00535-4 -
IScience Feb 2024Metformin is the first-line treatment for type 2 diabetes, yet its mechanism of action is not fully understood. Recent studies suggest metformin's interactions with gut...
Metformin is the first-line treatment for type 2 diabetes, yet its mechanism of action is not fully understood. Recent studies suggest metformin's interactions with gut microbiota are responsible for exerting therapeutic effects. In this study, we report that metformin targets the gut microbial enzyme agmatinase, as a competitive inhibitor, which may impair gut agmatine catabolism. The metformin inhibition constant (K) of agmatinase is 1 mM and relevant in the gut where the drug concentration is 1-10 mM. Metformin analogs phenformin, buformin, and galegine are even more potent inhibitors of agmatinase (K = 0.6, 0.1, and 0.007 mM, respectively) suggesting a shared mechanism. Agmatine is a known effector of human host metabolism and has been reported to augment metformin's therapeutic effects for type 2 diabetes. This gut-derived inhibition mechanism gives new insights on metformin's action in the gut and may lead to significant discoveries in improving metformin therapy.
PubMed: 38318350
DOI: 10.1016/j.isci.2024.108900 -
ACS Applied Bio Materials Feb 2024Adipose tissue macrophages (ATMs) are crucial in maintaining a low-grade inflammatory microenvironment in adipose tissues (ATs). Modulating ATM polarization to attenuate...
Adipose tissue macrophages (ATMs) are crucial in maintaining a low-grade inflammatory microenvironment in adipose tissues (ATs). Modulating ATM polarization to attenuate inflammation represents a potential strategy for treating obesity with insulin resistance. This study develops a combination therapy of celastrol (CLT) and phenformin (PHE) using chondroitin sulfate-derived micelles. Specifically, CLT-loaded 4-aminophenylboronic acid pinacol ester-modified chondroitin sulfate micelle (CS-PBE/CLT) and chondroitin sulfate-phenformin conjugate micelles (CS-PHE) were synthesized, which were shown to actively target ATs through CD44-mediated pathways. Furthermore, the dual micellar systems significantly reduced inflammation and lipid accumulation via protein quantification and Oil Red O staining. In preliminary studies, we performed H&E staining, immunohistochemical staining, insulin tolerance test, and glucose tolerance test, and the results showed that the combination therapy using CS-PBE/CLT and CS-PHE micelles significantly reduced the average body weight, white adipose tissue mass, and liver mass of high-fat diet-fed mice while improving their systemic glucose homeostasis. Overall, this combination therapy presents a promising alternative to current treatment options for diet-induced obesity.
Topics: Animals; Mice; Micelles; Chondroitin Sulfates; Phenformin; Adipose Tissue; Obesity; Inflammation; Diet, High-Fat; Pentacyclic Triterpenes
PubMed: 38315869
DOI: 10.1021/acsabm.3c01216 -
Scientific Reports Jan 2024Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer. Since the tricarboxylic acid cycle is widely involved in tumor metabolic reprogramming and...
Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer. Since the tricarboxylic acid cycle is widely involved in tumor metabolic reprogramming and cuproptosis, investigating related genes may help to identify prognostic signature of patients with HCC. Data on patients with HCC were sourced from public datasets, and were divided into train, test, and single-cell cohorts. A variety of machine learning algorithms were used to identify different molecular subtypes and determine the prognostic risk model. Our findings revealed that the risk score (TRscore), based on the genes OGDHL, CFHR4, and SPP1, showed excellent predictive performance in different datasets. Pathways related to cell cycle and immune inflammation were enriched in the high-risk group, whereas metabolism-related pathways were significantly enriched in the low-risk group. The high-risk group was associated with a greater number of mutations of detrimental biological behavior and higher levels of immune infiltration, immune checkpoint expression, and anti-cancer immunotherapy response. Low-risk patients demonstrated greater sensitivity to erlotinib and phenformin. SPP1 was mainly involved in the interaction among tumor-associated macrophages, T cells, and malignant cells via SPP1-CD44 and SPP1-(ITGA5 + ITGB1) ligand-receptor pairs. In summary, our study established a prognostic model, which may contribute to individualized treatment and clinical management of patients with HCC.
Topics: Humans; Carcinoma, Hepatocellular; Prognosis; Citric Acid Cycle; Liver Neoplasms; Algorithms; Tumor Microenvironment
PubMed: 38282028
DOI: 10.1038/s41598-024-52632-0 -
BMC Cancer Jan 2024Pancreatic adenocarcinoma (PDAC) ranks as the fourth leading cause for cancer-related deaths worldwide. N6-methyladenosine (m6A) and long non-coding RNAs (lncRNAs) are...
BACKGROUND
Pancreatic adenocarcinoma (PDAC) ranks as the fourth leading cause for cancer-related deaths worldwide. N6-methyladenosine (m6A) and long non-coding RNAs (lncRNAs) are closely related with poor prognosis and immunotherapeutic effect in PDAC. The aim of this study is to construct and validate a m6A-related lncRNAs signature and assess immunotherapeutic drug sensitivity in PDAC.
METHODS
RNA-seq data for 178 cases of PDAC patients and 167 cases of normal pancreatic tissue were obtained from TCGA and GTEx databases, respectively. A set of 21 m6A-related genes were downloaded based on the previous report. Co-expression network was conducted to identify m6A-related lncRNAs in PDAC. Cox analyses and least absolute shrinkage and selection operator (Lasso) regression model were used to construct a risk prognosis model. The relationship between signature genes and immune function was explored by single-sample GSEA (ssGSEA). The tumor immune dysfunction and exclusion (TIDE) score and tumor mutation burden (TMB) were utilized to evaluate the response to immunotherapy. Furthermore, the expression levels of 4 m6A-related lncRNAs on PDAC cell lines were measured by the quantitative real-time PCR (qPCR). The drug sensitivity between the high- and low-risk groups was validated using PDAC cell lines by Cell-Counting Kit 8 (CCK8).
RESULTS
The risk prognosis model was successfully constructed based on 4 m6A-related lncRNAs, and PDAC patients were divided into the high- and low-risk groups. The overall survival (OS) of the high-risk groups was more unfavorable compared with the low-risk groups. Receiver operating characteristic (ROC) curves demonstrated that the risk prognosis model reasonably predicted the 2-, 3- and 5-year OS of PDAC patients. qPCR analysis confirmed the decreased expression levels of 4 m6A-related lncRNAs in PDAC cells compared to the normal pancreatic cells. Furthermore, CCK8 assay revealed that Phenformin exhibited higher sensitivity in the high-risk groups, while Pyrimethamine exhibited higher sensitivity in the low-risk groups.
CONCLUSION
The prognosis of patients with PDAC were well predicted in the risk prognosis model based on m6A-related lncRNAs, and selected immunotherapy drugs have potential values for the treatment of pancreatic cancer.
Topics: Humans; Adenocarcinoma; RNA, Long Noncoding; Pancreatic Neoplasms; Pancreas; Adenine
PubMed: 38262966
DOI: 10.1186/s12885-024-11885-8