Rapid Proliferation Of Cancer Cells Research Articles

A novel bioprinted microtumour model for studying acute-leukemia-cell- contaminated in ovarian tissue

Microtumor models, combining cancer and stromal cells within 3D hydrogels, are vital for testing anticancer therapies. Bioprinting hydrogel scaffolds allows tailored in vitro models. We created a 3D microtumor model using a bioprinter, with varying ratios of ovarian stromal cells and leukemia cells (HL-60). PEGylated fibrinogen and alginate hydrogel were used. Cell dynamics and proliferation were assessed via immunofluorescence staining. Microtumors with different HL-60 ratios (1:1, 1:10, 1:100) were cultured for 5 days. Results showed tumor development modulation by cell ratios and culture time. A significant cell density increase occurred in 1:1 ratio microtumors, indicating rapid cancer cell proliferation. No HL-60 cells were found in 1:100 ratio microtumors by day 5. The 1:10 ratio closely mimicked leukemia invasion in ovarian tissue, showing detectable cancer cells by days 3 and 5 without altering total cell density dynamics significantly. This bioprinted leukemia microtumor model offers better physiological relevance than 2D assays, promising applications in cellular analysis and drug screening.

Deubiquitinase USP9x regulates the proline biosynthesis pathway in non-small cell lung cancer

Metabolic rewiring has been recognized as a hallmark of malignant transformation, supplying the biosynthetic and energetic demands for rapid cancer cell proliferation and tumor progression. A comprehensive understanding of the regulatory mechanisms governing these metabolic processes is still limited. Here, we identify the deubiquitinase ubiquitin-specific peptidase 9 X-linked (USP9x) as a positive regulator of the proline biosynthesis pathway in non-small cell lung cancer (NSCLC). Our findings demonstrate USP9x directly stabilizes pyrroline-5-carboxylate reductase 3 (PYCR3), a key enzyme in the proline cycle. Disruption of proline biosynthesis by either USP9x or PYCR3 knockdown influences the proline cycle leading to a decreased activity of the connected pentose phosphate pathway and mitochondrial respiration. We show that USP9x is elevated in human cancer tissues and its suppression impairs NSCLC growth in vitro and in vivo. Overall, our study uncovers a novel function of USP9x as a regulator of the proline biosynthesis pathway, which impacts lung cancer growth and progression, and implicates a new potential therapeutic avenue.

A critical appraisal of the role of metabolomics in breast cancer research and diagnostics

Breast cancer (BC) remains the most prevalent cancer among women worldwide, despite significant advancements in its prevention and treatment. The escalating incidence of BC globally necessitates continued research into novel diagnostic and therapeutic strategies. Metabolomics, a burgeoning field, offers a comprehensive analysis of all metabolites within a cell, tissue, system, or organism, providing crucial insights into the dynamic changes occurring during cancer development and progression. This review focuses on the metabolic alterations associated with BC, highlighting the potential of metabolomics in identifying biomarkers for early detection, diagnosis, treatment and prognosis. Metabolomics studies have revealed distinct metabolic signatures in BC, including alterations in lipid metabolism, amino acid metabolism, and energy metabolism. These metabolic changes not only support the rapid proliferation of cancer cells but also influence the tumour microenvironment and therapeutic response.Furthermore, metabolomics holds great promise in personalized medicine, facilitating the development of tailored treatment strategies based on an individual’s metabolic profile. By providing a holistic view of the metabolic changes in BC, metabolomics has the potential to revolutionize our understanding of the disease and improve patient outcomes.

Research progress in the metabolic reprogramming of hepatocellular carcinoma (Review).

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and its morbidity is increasing worldwide due to increasing prevalence. Metabolic reprogramming has been recognized as a hallmark of cancer and serves a role in cancer progression. Glucose, lipids and amino acids are three major components whose altered metabolism can directly affect the energy production of cells, including liver cancer cells. Nutrients and energy are indispensable for the growth and proliferation of cancer cells, thus altering the metabolism of hepatoma cells can inhibit the progression of HCC. The present review summarizes recent studies on tumour regulatory molecules, including numerous noncoding RNAs, oncogenes and tumour suppressors, which regulate the metabolic activities of glucose, lipids and amino acids by targeting key enzymes, signalling pathways or interactions between the two. These regulatory molecules can regulate the rapid proliferation of cancer cells, tumour progression and treatment resistance. It is thought that these tumour regulatory factors may serve as therapeutic targets or valuable biomarkers for HCC, with the potential to mitigate HCC drug resistance. Furthermore, the advantages and disadvantages of metabolic inhibitors as a treatment approach for HCC, as well as possible solutions are discussed, providing insights for developing more effective treatment strategies for HCC.

Identification of tumor-suppressive miRNAs that target amino acid transporter LAT1 and exhibit anti-proliferative effects on cholangiocarcinoma cells

Amino acid transporter LAT1 is highly upregulated in various cancer types, including cholangiocarcinoma (CHOL), and contributes to the rapid proliferation of cancer cells and disease progression. However, the molecular mechanisms underlying the pathological upregulation of LAT1 remain largely unknown. This study pursued the possibility of miRNA-mediated regulation of the LAT1 expression in CHOL cells. Using online target prediction methods, we extracted five candidate miRNAs commonly predicted to regulate the LAT1 expression. Three of them, miR-194-5p, miR-122-5p, and miR-126-3p, were significantly downregulated in CHOL cancer compared to normal tissues. Correlation analysis revealed weak-to-moderate negative correlations between the expression of these miRNAs and LAT1 mRNA in CHOL cancer tissues. We selected miR-194-5p and miR-122-5p for further analyses and found that both miRNAs functionally target 3′UTR of LAT1 mRNA by a luciferase-based reporter assay. Transfection of the miRNA mimics significantly suppressed the LAT1 expression at mRNA and protein levels and inhibited the proliferation of CHOL cells, with a trend of affecting intracellular amino acids and amino acid-related signaling pathways. This study indicates that the decreased expression of these LAT1-targeting tumor-suppressive miRNAs contributes to the upregulation of LAT1 and the proliferation of CHOL cells, highlighting their potential for developing novel cancer therapeutics and diagnostics.

Characterization of hypoxia-responsive states in ovarian cancer to identify hot tumors and aid adjuvant therapy

BackgroundsThe hypoxia-responsive state of cancer is a complex pathophysiological process involving numerous genes playing different roles. Due to the rapid proliferation of cancer cells and chaotic angiogenesis, the clinical features of hypoxia-responsive states are not yet clear in patients with ovarian cancer.MethodsBased on the RNA expression levels of 14 hypoxic markers, our study screened out hypoxia-related genes and construct a hypoxic score pattern to quantify the hypoxia-responsive states of a single tumor. Combining clinical prognosis, tumor mutation burden, microsatellite instability, the expression level of the immune checkpoint, IC50, and other indicators to evaluate the impact of different hypoxia-responsive states on clinical prognosis and therapeutic sensitivity.ResultsOur study identified a subgroup with an active hypoxia-responsive state and they have a worse clinical prognosis but exhibit higher immunogenicity and higher sensitivity to immunotherapy.ConclusionsThis work revealed that hypoxia-responsive states played an important role in formation of tumor immunogenicity. Evaluating the hypoxia-responsive state will contribute to guiding more effective immunotherapy strategies.

Modification patterns and metabolic characteristics of m6A regulators in digestive tract tumors

M6A is essential for tumor occurrence and progression. The expression patterns of m6A regulators differ in various kinds of tumors. Transcriptomic expression statistics together with clinical data from a database were analyzed to distinguish patients with digestive tract tumors. Based on the expression patterns of diverse m6A regulators, patients were divided into several clusters. Survival analysis suggested significant differences in patient prognosis among the m6A clusters. The results showed overlapping of m6A expression patterns with energy metabolism and nucleotide metabolism. Functional analyses imply that m6A modifications in tumor cells probably drive metabolic reprogramming to sustain rapid proliferation of cancer cells. Our analysis highlights the m6A risk characterizes various kinds of metabolic features and predicts chemotherapy sensitivity in digestive tract tumors, providing evidence for m6A regulators as markers to predict patient outcomes.

Three-dimensional thermophotonic super-resolution imaging by spatiotemporal diffusion reversal method.

Spatial super-resolution in thermophotonic imaging was achieved using a combination of spatial second-derivative forming, spatial gradient adaptive filtering, and Richardson-Lucy deconvolution in conjunction with the construction of an experimental point spread function. When implemented through enhanced truncation-correlation photothermal coherence tomography (eTC-PCT), it was possible to restore blurred infrared thermophotonic images to their prediffusion optical resolution state. This modality was tested in various biological applications and proved to be capable of imaging fine axial cracks in human teeth, well-patterned anatomical subsurface structures of a mouse brain, and neovascularization in a mouse thigh due to the rapid proliferation of cancer cells. This modality was found to be immune to optical scattering and could reveal the true spatial extent of biological features at subsurface depths that conventional thermal imaging cannot reach because of limitations imposed by the physics of spreading diffusion.

Mitochondrial Dynamics in Ovarian Cancer: Pathophysiology and Therapeutic Implications

Background: Ovarian cancer is often characterized by aggressive growth and chemoresistance, leading to a poor prognosis. The energy and nutrient acquisition through metabolic reprogramming has been reported to facilitate cancer cell proliferation, invasion, and metastasis. Therefore, a therapeutic strategy to consider is to rewire energy metabolism. Mitochondrial dynamics have a profound impact on the metabolic profiles. In this review, we summarize the current understanding of the molecular mechanisms governing mitochondrial dynamics and their impact on cell proliferation and invasion and discuss future perspectives for therapeutic strategies and research directions. Methods: A search was conducted for literature published up to 30 June 2023 using the online databases PubMed and Google Scholar in this narrative literature review. Results: Mitochondria are essential for regulating metabolic reprogramming to meet the increasing energy demand for rapid cancer cell proliferation and invasion. A metabolic switch from OXPHOS to glycolysis may promote invasion, and OXPHOS-driven metabolism may be associated with proliferation, chemoresistance, and stemness. Many ovarian cancer cells are known to favor glycolysis over OXPHOS, but the opposite takes place in the subpopulation of cancer cells. The preference for glycolysis versus OXPHOS in ovarian cancer cells may be determined by histopathologic types, the unique genetic profile of energy metabolism, and intrinsic (e.g., oncogenic signaling) and extrinsic (e.g., nutritional status and hypoxia) factors. Conclusions: Preclinical studies suggest that mitochondrial dynamics regulators have therapeutic potential in ovarian cancer, but some factors limit their beneficial effects.

Circulating Plasma Cell-free DNA (cfDNA) as a Predictive Biomarker for Radiotherapy: Results from a Prospective Trial in Head and Neck Cancer.

The plasma levels of cell-free DNA (cfDNA) in cancer patients increase due to rapid cancer cell proliferation and death. Therefore, cfDNA can be used to study specific tumor-DNA features. In addition, the non-specific cfDNA concentration may be an important biomarker of cancer prognosis. We prospectively examined the predictive role of cfDNA levels and the kinetics in the outcome of chemo-radiotherapy (CRT) in a cohort of 47 patients with locally advanced squamous cell head-neck cancer (SCHNC) treated with definitive chemo-radiotherapy. Increased cfDNA levels after therapy completion (after/before treatment ratio; A/B-ratio >1) were found in 26/47 patients (55.3%). Locally advanced T4-stage was significantly associated with higher cfDNA levels after CRT (3.3 ng/μl in T4-stage vs. 1.3 ng/μl in T1-3 stages, p=0.007). Patients who responded to CRT (partial/complete response) had significantly lower cfDNA levels before therapy (mean values 1.2 ng/μl vs. 2.7 ng/μl, p=0.03). A significantly worse locoregional progression-free survival in patients with an A/B-ratio >1 was documented (p=0.01; hazard ratio 3.5, 95%CI=1.2-9.7). This was also confirmed in multivariate analysis, where the A/B-ratio was an independent predictive variable of locoregional relapse (p=0.03, hazard ratio 3.9, 95%CI=1.2-13). High post-CRT cfDNA levels could be an early biomarker for the immediate recruitment of patients with SCHNC in consolidation chemo-immunotherapy protocols.

Targeting ONECUT3 blocks glycolytic metabolism and potentiates anti-PD-1 therapy in pancreatic cancer.

Reprogramming glucose metabolism, also known as the Warburg effect (aerobic glycolysis), is a hallmark of cancers. Increased tumor glycolysis not only favors rapid cancer cell proliferation but reprograms the immune microenvironment to enable tumor progression. The transcriptional factor ONECUT3 plays key roles in the development of the liver and pancreas, however, limited is known about its oncogenic roles, particularly metabolic reprogramming. Immunohistochemistry and Western blotting are applied to determine the expression pattern of ONECUT3 and its clinical relevance in pancreatic ductal adenocarcinoma (PDAC). Knockdown and overexpression strategies are employed to determine the in vitro and in vivo functions of ONECUT3. Chromatin immunoprecipitation, luciferase reporter assay, and gene set enrichment analysis are used to decipher the molecular mechanisms. The glycolytic metabolism is inversely associated with T-cell infiltration in PDAC. ONECUT3 is identified as a key regulator for PDAC glycolysis and CD8+ T-cell infiltration. Genetic silencing of ONECUT3 inhibits cell proliferation, promotes cell apoptosis, and reduces glycolytic metabolism as evidenced by glucose uptake, lactate production, and extracellular acidification rate. Opposite effects of ONECUT3 are observed in overexpression studies. ONECUT3 enhances aerobic glycolysis via transcriptional regulation of PDK1. Targeting ONECUT3 effectively suppresses tumor growth, increases CD8+ T-cell infiltration, and potentiates anti-PD-1 therapy in PDAC. Pharmacological inhibition of PDK1 also shows a synergistic effect with anti-PD-1 therapy. In clinical setting, ONECUT3 is closely associated with PDK1 expression and T-cell infiltration in PDAC and acts as an independent prognostic factor. Our study reveals a previous unprecedented regulatory role of ONECUT3 in PDAC glycolysis and provides in vivo evidence that increased glycolysis is linked to an immunosuppressive microenvironment. Moreover, targeting ONECUT3-PDK1 axis may serve as a promising therapeutic approach for the treatment of PDAC.

Uridine as a novel fuel for cancer cells

Cancer cells are known to have an enormous appetite for calorie. This is something they are addicted to sustain their unrestricted growth and rapid proliferation. In order to accomplish this feat, cancer cells has evolved multiple mechanisms, rewiring their metabolic circuitry such that metabolic fuels are preferentially diverted to meet their energy demands. A classic example (Warburg effect) of this is aerobic glycolysis and preferential production of lactate to produce ATP (without relying on mitochondrial oxidative phosphorylation). Further, rapid proliferation of cancer cells, exhausts the nutrient and oxygen supply derived from the existing vasculature, making them hypoxic. In turn triggers the upregulation of pro angiogenic factors from the hypoxic tumor sites( HIF), which in turn re-vascularizes the tumor mass, bringing in metabolic cargo.
 When it comes to cancer metabolism, cancer cells are highly innovative to devise novel mechanisms to bypass metabolic regulations and In a recent article published in Nature Metabolism, Skinner et al. identified an unusual source of glucose in cancer cells. Ribose moiety of uridine can be repurposed to replenish the energy requirements in cancer cells thorough the uridine phosphorylase UPP1/UPP2 mediated cleavage of uridine into its constituents , uracil and ribose-1-phosphate (R1P). R1P is then utilized to convert into fructose-6-P and glyceraldehyde-3-P by the non-oxidative branch of the HMP shunt back to glycolysis and ATP production.
 These findings are novel and intuitive. It means that the cancer cells has the ability to salvage glucose from uridine, when needed. This also indicates that cutting off Uridine supply to cancer cells maybe a mechanism to target cancer cells .

Lactate Decreases Bortezomib Sensitivity and Predicts Poor Clinical Outcomes of Multiple Myeloma.

Metabolic disorders are regarded as hallmarks of multiple myeloma (MM) and are responsible for rapid cancer cell proliferation and tumor growth. However, the exact biological roles of metabolites in MM cells have not been fully explored. This study aimed to explore the feasibility and clinical significance of lactate for MM and investigate the molecular mechanism of lactic acid (Lac) in the proliferation of myeloma cells and cell sensitivity to bortezomib (BTZ). Metabolomic analysis of the serum was carried out to obtain metabolites expression and clinical characteristics in MM patients. The CCK8 assay and flow cytometry were used to detect cell proliferation, apoptosis, and cell cycle changes. Western blotting was used to detect the potential mechanism and apoptosis- and cycle-related protein changes. Lactate was highly expressed in both the peripheral blood and bone marrow of MM patients. It was significantly correlated with Durie-Salmon Staging (DS Staging) and the International Staging System (ISS Staging) and the serum and urinary involved/uninvolved free light chain ratios. Patients with relatively high lactate levels had a poor treatment response. Moreover, in vitro experiments showed that Lac could promote the proliferation of tumor cells and decrease the proportion of G0/G1-phase cells, which was accompanied by an increased proportion of S-phase cells. In addition, Lac could decrease tumor sensitivity to BTZ by disrupting the expression of nuclear factor kappa B subunit 2 (NFkB2) and RelB. Metabolic changes are important in MM cell proliferation and treatment response; lactate could be used as a biomarker in MM and as a therapeutic target to overcome cell resistance to BTZ.

Flux estimation analysis systematically characterizes the metabolic shifts of the central metabolism pathway in human cancer.

Glucose and glutamine are major carbon and energy sources that promote the rapid proliferation of cancer cells. Metabolic shifts observed on cell lines or mouse models may not reflect the general metabolic shifts in real human cancer tissue. In this study, we conducted a computational characterization of the flux distribution and variations of the central energy metabolism and key branches in a pan-cancer analysis, including the glycolytic pathway, production of lactate, tricarboxylic acid (TCA) cycle, nucleic acid synthesis, glutaminolysis, glutamate, glutamine, and glutathione metabolism, and amino acid synthesis, in 11 cancer subtypes and nine matched adjacent normal tissue types using TCGA transcriptomics data. Our analysis confirms the increased influx in glucose uptake and glycolysis and decreased upper part of the TCA cycle, i.e., the Warburg effect, in almost all the analyzed cancer. However, increased lactate production and the second half of the TCA cycle were only seen in certain cancer types. More interestingly, we failed to detect significantly altered glutaminolysis in cancer tissues compared to their adjacent normal tissues. A systems biology model of metabolic shifts through cancer and tissue types is further developed and analyzed. We observed that (1) normal tissues have distinct metabolic phenotypes; (2) cancer types have drastically different metabolic shifts compared to their adjacent normal controls; and (3) the different shifts in tissue-specific metabolic phenotypes result in a converged metabolic phenotype through cancer types and cancer progression. This study strongly suggests the possibility of having a unified framework for studies of cancer-inducing stressors, adaptive metabolic reprogramming, and cancerous behaviors.

Characteristics of long‐chain acyl‐CoA synthetases in metabolism and cancer

AbstractThe deregulation of the metabolic network of cancer cells is now considered one of the characteristics of cancer. Aberrant lipid synthesis and additional lipid intake promote the rapid proliferation of cancer cells. In mammals, there are five members of the long‐chain acyl‐CoA synthase family involved in de novo lipid synthesis, fatty acid (FA) degradation and subsequent membrane modification. Their main function is to activate long‐chain FAs through the CoA chain link, and these conjugates are mainly used for the synthesis of triglycerides. In a variety of cancers, the expression of long‐chain acyl‐CoA synthetases (ACSLs) is different, and it also changes in different cancer subtypes. This review summarized recent research on the biological functions of ACSL, as well as recent advances in related diseases, and explored the potential therapeutic role of ACSL genes.

Enhancement of immune surveillance in breast cancer by targeting hypoxic tumor endothelium: Can it be an immunological switch point?

Breast cancer ranks second among the causes of cancer-related deaths in women. In spite of the recent advances achieved in the diagnosis and treatment of breast cancer, further study is required to overcome the risk of cancer resistance to treatment and thereby improve the prognosis of individuals with advanced-stage breast cancer. The existence of a hypoxic microenvironment is a well-known event in the development of mutagenesis and rapid proliferation of cancer cells. Tumor cells, purposefully cause local hypoxia in order to induce angiogenesis and growth factors that promote tumor growth and metastatic characteristics, while healthy tissue surrounding the tumor suffers damage or mutate. It has been found that these settings with low oxygen levels cause immunosuppression and a lack of immune surveillance by reducing the activation and recruitment of tumor infiltrating leukocytes (TILs). The immune system is further suppressed by hypoxic tumor endothelium through a variety of ways, which creates an immunosuppressive milieu in the tumor microenvironment. Non responsiveness of tumor endothelium to inflammatory signals or endothelial anergy exclude effector T cells from the tumor milieu. Expression of endothelial specific antigens and immunoinhibitory molecules like Programmed death ligand 1,2 (PDL-1, 2) and T cell immunoglobulin and mucin-domain containing-3 (TIM-3) by tumor endothelium adds fuel to the fire by inhibiting T lymphocytes while promoting regulatory T cells. The hypoxic microenvironment in turn recruits Myeloid Derived Suppressor Cells (MDSCs), Tumor Associated Macrophages (TAMs) and T regulatory cells (Treg). The structure and function of newly generated blood vessels within tumors, on the other hand, are aberrant, lacking the specific organization of normal tissue vasculature. Vascular normalisation may work for a variety of tumour types and show to be an advantageous complement to immunotherapy for improving tumour access. By enhancing immune response in the hypoxic tumor microenvironment, via immune-herbal therapeutic and immune-nutraceuticals based approaches that leverage immunological evasion of tumor, will be briefly reviewed in this article. Whether these tactics may be the game changer for emerging immunological switch point to attenuate the breast cancer growth and prevent metastatic cell division, is the key concern of the current study.

QSPR Modeling with Topological Indices of Some Potential Drugs against Cancer

In Sri Lanka as well as the rest of the globe, cancer is the top cause of mortality. One of the key medicines in treating tumors is anticancer medications and delivery dendrimers. To prevent the formation of the rapid proliferation of cancer cells, several tests were carried out. Because of this, research on dendrimers and anti-cancer medications is crucial. Topological indices (TIs) are molecular descriptors numerical values corresponding to the physical characteristics of a molecule’s chemical structure. It costs money to determine a molecule’s physical characteristics in a lab since it takes a lot of materials, medications, and time. Therefore, the relevant information about molecules may be obtained by computing TIs. This study’s goals are to compute hitherto uncalculated eccentricity-based TIs for various anticancer structures and to use curvilinear regression models to forecast the physical characteristics of particular anticancer medications. These anticancer medications were given different TIs developed in this work, allowing the researchers to understand the physical, physicochemical, and chemical characteristics related to them. In addition comparative study of the novel indices with some well-known and mostly used indices in structure–property modeling and anticancer drugs in performed.

Candidate Oncogenes,ARHGAP4, NOS3, andOR51B5, for the Development of Scirrhous-type Gastric Cancer

Scirrhous-type gastric cancer (SGC), one of the most intractable cancer subtypes, is characterized by rapid cancer cell proliferation and infiltration accompanied by extensive stromal fibrosis. One of the reasons for its poor prognosis may be the lack of molecular target drugs for SGC, because of the unknown driver genes. Exploration of somatic mutations in the human samples of SGC using next-generation sequencing (NGS) has been hampered by abundant fibrous tissues in these samples. Therefore, this study aimed to determine a novel oncogene by RNA-sequencing using SGC cell lines, avoiding contamination with fibrosis. In silico analysis of RNA-sequencing public data of the gastric cancer cell line, and RNA- sequencing using five of our unique SGC cell lines, OCUM1, OCUM2MLN, OCUM8, OCUM12, and OCUM14 were performed. We found three differentially expressed genes, ARHGAP4, NOS3, and OR51B5 that are significantly over-expressed in SGC cells. Immunohistochemical analysis indicated that the protein expression levels of these three genes were significantly higher in SGC than in other types of gastric cancer. The prognosis of patients with positive expression of these three genes was significantly poorer than those with negative expression. In particular, ARHGAP4 expression was an independent predictor of poor prognosis and recurrence. ARHGAP4, NOS3, and OR51B5 may be candidate driver genes for SGC. ARHGAP4 may be a promising molecular target for SGC.

Identification of Monobenzone as a Novel Potential Anti-Acute Myeloid Leukaemia Agent That Inhibits RNR and Suppresses Tumour Growth in Mouse Xenograft Model.

Simple SummaryThe clinical treatment of acute myeloid leukaemia is still dominated by chemotherapy. Clinically used anti-leukaemia drugs have shortcomings such as myelosuppression, toxicity and drug resistance. Therefore, the need to develop other chemotherapeutic drugs to meet more clinical needs is urgent. Ribonucleotide reductase (RNR) consists of a catalytic large subunit M1 (RRM1) and a regulatory small subunit M2 (RRM2), which provides dNTPs for DNA synthesis. The rapid proliferation of cancer cells requires large amounts of dNTPs. Therefore, the use of RNR inhibitors is a promising strategy for the clinical treatment of various malignancies. Monobenzone is an FDA-approved depigmenting agent for vitiligo patients. In this study, we demonstrate that monobenzone is a potent inhibitor of RNR enzyme activity by targeting RRM2 protein, and thus has significant anti-leukaemia efficacy in vitro and in vivo. This finding suggests that monobenzone has the potential to be optimized as a novel anti-AML therapeutic drug in the future. Acute myeloid leukaemia (AML) is one of the most common types of haematopoietic malignancy. Ribonucleotide reductase (RNR) is a key enzyme required for DNA synthesis and cell proliferation, and its small subunit RRM2 plays a key role for the enzymatic activity. We predicted monobenzone (MB) as a potential RRM2 target compound based on the crystal structure of RRM2. In vitro, MB inhibited recombinant RNR activity (IC50 = 0.25 μM). Microscale thermophoresis indicated that MB inhibited RNR activity by binding to RRM2. MB inhibited cell proliferation (MTT IC50 = 6–18 μM) and caused dose-dependent DNA synthesis inhibition, cell cycle arrest, and apoptosis in AML cells. The cell cycle arrest was reversed by the addition of deoxyribonucleoside triphosphates precursors, suggesting that RNR was the intracellular target of the compound. Moreover, MB overcame drug resistance to the common AML drugs cytarabine and doxorubicin, and treatment with the combination of MB and the Bcl-2 inhibitor ABT-737 exerted a synergistic inhibitory effect. Finally, the nude mice xenografts study indicated that MB administration produced a significant inhibitory effect on AML growth with relatively weak toxicity. Thus, we propose that MB has the potential as a novel anti-AML therapeutic agent in the future.

Creatine riboside is a cancer cell-derived metabolite associated with arginine auxotrophy.

The metabolic dependencies of cancer cells have substantial potential to be exploited to improve the diagnosis and treatment of cancer. Creatine riboside (CR) is identified as a urinary metabolite associated with risk and prognosis in lung and liver cancer. However, the source of high CR levels in patients with cancer as well as their implications for the treatment of these aggressive cancers remain unclear. By integrating multiomics data on lung and liver cancer, we have shown that CR is a cancer cell–derived metabolite. Global metabolomics and gene expression analysis of human tumors and matched liquid biopsies, together with functional studies, revealed that dysregulation of the mitochondrial urea cycle and a nucleotide imbalance were associated with high CR levels and indicators of a poor prognosis. This metabolic phenotype was associated with reduced immune infiltration and supported rapid cancer cell proliferation that drove aggressive tumor growth. CRhi cancer cells were auxotrophic for arginine, revealing a metabolic vulnerability that may be exploited therapeutically. This highlights the potential of CR not only as a poor-prognosis biomarker but also as a companion biomarker to inform the administration of arginine-targeted therapies in precision medicine strategies to improve survival for patients with cancer.