Cancer is one of the most significant public health challenges in the new millennium, and complex mechanisms are at work to contribute to its pathogenesis and progression. The Wnt signaling pathways, which are crucial conserved cascades involved in embryological development and tissue homeostasis, and mitochondria, the intracellular powerhouses responsible for energy production, calcium and iron homeostasis, as well as mitochondrial apoptosis in eukaryotic cells, have their own mechanisms regulating these pathological processes. In the past decade, accumulating evidence has indicated that Wnt signaling pathways directly regulate mitochondrial biogenesis and function under physiological and pathological conditions. In this review, we systemically summarize the current understanding of how Wnt signaling pathways, particularly the canonical Wnt cascade, regulate mitochondrial fission, respiration, metabolism, and mitochondrial-dependent apoptosis in cancer. In addition, we discuss recent advancements in the research of anticancer agents and related pharmacological mechanisms targeting the signaling transduction of canonical Wnt pathway and/or mitochondrial function. We believe that the combined use of pharmaceuticals targeting Wnt signaling and/or mitochondria with conventional therapies, immunotherapy and targeted therapy based on accurate molecular pathological diagnosis will undoubtedly be the future mainstream direction of personalized cancer treatment, which could benefit more cancer patients.

KRAS Q61H is an aggressive oncogenic driver mutation rendering cancer cells drug resistant to SHP2 inhibitors (SHP2i). Some metastatic and chemoresistant non-small cell lung cancer (NSCLC) cells, exhibit a hybrid metabolic state in which both glycolysis and oxidative phosphorylation (OXPHOS) coexist. Hence, we evaluated the in vitro and in vivo efficacy of a combination of hexokinase 2 (HK2) and pyruvate dehydrogenase (PDH) inhibitors, benserazide (Benz) and CPI-613, respectively, against NSCLC NCI-H460 cells harboring the driver KRAS Q61H mutation. This combination synergistically disrupted the hybrid metabolic state, inhibited NCI-H460 cell proliferation in vitro, and markedly suppressed tumor growth in NCI-H460 cell xenograft model in mice. The molecular basis underlying this antitumor activity was apparently due to suppression of SHP2/SOS1/RAS/MAPK signaling pathways, leading to enhanced apoptosis. Moreover, this drug combination restored the sensitivity to SHP2i. Consistently, SHP2 overexpression in NCI-H460 cells abrogated the antitumor activity of this drug combination. These findings reveal that the combination of Benz and CPI-613 targets the metabolic vulnerability of KRAS Q61H mutant-bearing NSCLC tumors. These results offer a combination therapeutic strategy for the possible treatment of cancer cells displaying a hybrid metabolic state, thereby surmounting chemoresistance.

OxPhos inhibitors have struggled to show a clinical benefit because of their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to acute myeloid leukemia (AML) mitochondria. Unlike healthy cells that couple respiration to ATP synthesis, AML mitochondria support inner-membrane polarization by consuming ATP. Matrix ATP consumption allows cells to survive bioenergetic stress. Thus, we hypothesized AML cells may resist chemotherapy-induced cell death by reversing the ATP synthase reaction. In support, BCL-2 inhibition with venetoclax abolished OxPhos flux without affecting mitochondrial polarization. In surviving AML cells, sustained mitochondrial polarization depended on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to down-regulations in the endogenous F1-ATPase inhibitor ATP5IF1. Knockdown of ATP5IF1 conferred venetoclax resistance, while ATP5IF1 overexpression impaired F1-ATPase activity and heightened sensitivity to venetoclax. These data identify matrix ATP consumption as a cancer cell-intrinsic bioenergetic vulnerability actionable in the context of BCL-2 targeted chemotherapy.

Pyruvate dehydrogenase kinase-1 (PDK1) plays a crucial role in cancer cell metabolism by regulating the glycolytic pathway. Although, inhibitors targeting PDK1 have been effective in inhibiting glycolysis in multiple cancers, their lack of selectivity leading to off-target effects limit their therapeutic benefit. Herein, we investigated the inhibitory potential of six PDK1 inhibitors on cellular proliferation, migration, and invasion of androgen-sensitive LNCaP and androgen-negative PC-3 prostate cancer cells. Of the six PDK1 inhibitors, radicicol and dicumarol significantly inhibited cellular proliferation and exhibited lower metabolic activity in both LNCaP and PC-3 metastatic prostate cancer cells. Radicicol was highly effective at lower concentration. Moreover, radicicol significantly inhibited migration and invasion in PC-3 cells. We then developed a lactoferrin nanoparticle (LF-NP) encapsulated with Radicicol (Ra-LF-NP), using a rotary evaporation method. Spheroid assays confirmed the higher inhibitory potential of Ra-LF-NP with a reduction in spheroid area by 80%, and invasiveness compared to radicicol alone. Lactoferrin receptors are overexpressed on the surface of many cancer cells, including prostate cancer. Conjugating radicicol with lactoferrin nanoparticles, potentially enhanced the specific uptake of the drug by prostate cancer cells while minimizing the off-target effects on healthy cells. This targeted therapy approach could lead to improved treatment outcomes and reduced side effects. Our study demonstrated the potential of radicicol delivery by lactoferrin-conjugated nanoparticle as an efficient drug delivery strategy for prostate cancer treatment.

Lung cancer exhibits altered metabolism, influencing its response to radiation. To investigate the metabolic regulation of radiation response, we conducted a comprehensive, metabolic-wide CRISPR-Cas9 loss-of-function screen using radiation as selection pressure in human non-small cell lung cancer. Lipoylation emerged as a key metabolic target for radiosensitization, with lipoyltransferase 1 (LIPT1) identified as a top hit. LIPT1 covalently conjugates mitochondrial 2-ketoacid dehydrogenases with lipoic acid, facilitating enzymatic functions involved in the tricarboxylic acid cycle. Inhibiting lipoylation, either through genetic LIPT1 knockout or a lipoylation inhibitor (CPI-613), enhanced tumor control by radiation. Mechanistically, lipoylation inhibition increased 2-hydroxyglutarate, leading to H3K9 trimethylation, disrupting TIP60 recruitment and ataxia telangiectasia mutated (ATM)-mediated DNA damage repair signaling, impairing homologous recombination repair. In summary, our findings reveal a critical role of LIPT1 in regulating DNA damage and chromosome stability and may suggest a means to enhance therapeutic outcomes with DNA-damaging agents.

Multiple myeloma (MM) is an incurable malignant hematological neoplasm characterized by clonal proliferation of plasma cells accumulating in the bone marrow. Currently, the treatment of MM is usually based on a multi-drug combination strategy, and the remission rates of MM patients have been greatly improved. However, MM is still not immune to drug resistance and recurrence and is an incurable tumor. In this study, a comprehensive screen of the TCA cycle identified oxoglutarate dehydrogenase (OGDH) and pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) as the most clinically relevant genes in MM, highlighting their potential as therapeutic targets. CPI-613, a novel non-redox-active lipoic acid analog that causes mitochondrial metabolism dysfunction by targeting OGDH and PDHA1, is currently in clinical trials in a variety of malignancies. In our study, CPI-613 was found to inhibit the proliferation of MM cells, and its combination with bortezomib (BTZ) produced a significant inhibitory effect at lower doses. In addition, CPI-613 can disrupt various mitochondrial functions, such as disrupting mitochondrial morphology, reducing oxidative phosphorylation, decreasing 5'- adenylate triphosphate production, and increasing reactive oxygen species, which ultimately leads to cell death mediated by the intrinsic apoptotic pathway in vitro. Furthermore, we found CPI-613 significantly inhibited tumor growth and induced intrinsic apoptosis in the MM mouse xenograft model. This study reveals the mechanism and effect of CPI-613 in MM, which suggests that CPI-613 may be a new drug option for the clinical treatment of MM, but further clinical trials are needed for evaluation.

Recently there has been an increasing number of studies have explored apoptosis mechanisms in lung cancer (LC). However, no researchers have conducted a bibliometric analysis of the most cited articles in this field.

To examine the top 100 most influential and cited publications on apoptosis in non-small cell lung cancer (NSCLC) from 2004 to 2023, summarizing research trends and key focus areas.

This study utilized the Web of Science Core Database (WOSCC) to research NSCLC apoptosis from 2004 to 2023, using keyword selection and manual screening for article searches. Bibliometrix package of R software 4.3.1 was used to generate distribution statistics for the top ten institutions, journals and authors. Citespace6.2. R6 was used to create the visualization maps for keyword co-occurrence and clustering. VOSviewer1.6.19 was used to conduct cluster analysis of publishing countries (regions), with data exported to SCImago Graphica for geographic visualization and cooperation analysis. VOSviewer1.6.19 was used to produced co-citation maps of institutions, journals, authors, and references.

From 2004 to 2023, 13316 articles were retrieved, and the top 100 most cited were chosen. These were authored by 934 individuals from 269 institutions across 18 countries and appeared in 45 journals. Citations ranged from 150 to 1,389, with a median of 209.5. The most influential articles appeared in 2005 and 2007 (n=13). The leading countries (regions), institutions, journals and authors were identified as the United States (n=60), Harvard University (n=64), CANCER RESEARCH (n=15), SUN M and YANG JS (n=6). The top five keywords were "expression", "activation", "apoptosis", "pathway" and "gefitinib". This study indicates that enhancing apoptosis through circular RNA regulation and targeting the Nrf2 signaling pathway could become a key research focus in recent years.

Apoptosis has been the subject of extensive research over many years, particularly in relation to its role in the pathogenesis, diagnosis, and treatment of NSCLC. This study aims to identify highly influential articles and forecast emerging research trends, thereby offering insights into novel therapeutic targets and strategies to overcome drug resistance. The findings are intended to serve as a valuable reference for scholars engaged in this field of study.

Mitochondria are pivotal contributors to cancer mechanisms due to their homeostatic and pathological roles in cellular bioenergetics, biosynthesis, metabolism, signaling, and survival. During transformation and tumor initiation, mitochondrial function is often disrupted by oncogenic mutations, leading to a metabolic profile distinct from precursor cells. In this review, we focus on hepatocellular carcinoma, a cancer arising from metabolically robust and nutrient rich hepatocytes, and discuss the mechanistic impact of altered metabolism in this setting. We provide distinctions between normal mitochondrial activity versus disease-related function which yielded therapeutic opportunities, along with highlighting recent preclinical and clinical efforts focused on targeting mitochondrial metabolism. Finally, several novel strategies for exploiting mitochondrial programs to eliminate hepatocellular carcinoma cells in metabolism-specific contexts are presented to integrate these concepts and gain foresight into the future of mitochondria-focused therapeutics.

During embryonic development, arteriovenous (AV) differentiation ensures proper blood vessel formation and maturation. Defects in arterial or venous identity cause inappropriate fusion of vessels, resulting in atypical shunts, so-called AV malformations (AVMs). Currently, the mechanism behind AVM formation remains unclear, and treatment options are fairly limited. Mammalian AV differentiation is initiated before the onset of blood flow in the embryo; however, this pre-flow mechanism is poorly understood. Here, we aimed to unravel the role of Smad1/5 signalling in pre-flow arterial identity and, in the process, uncovered an unexpected control mechanism of Smad1/5 signalling.

We establish that despite Notch1 being expressed in the pre-flow mouse embryo, it is not activated, nor is it necessary for the expression of the earliest arterial genes in the dorsal aortae (i.e. Hey1 and Gja4). Furthermore, interrupting blood flow by using the Ncx1 KO model completely prevents the activation of Notch1 signalling, suggesting a strong role of shear stress in maintaining arterial identity. We demonstrate that early expression of Hey1 and Gja4 requires SMAD1/5 signalling. Using embryo cultures, we show that Smad1/5 signalling is activated through the Alk1/Alk5/transforming growth factor (TGF)βR2 receptor complex, with TGFβ1 as a necessary ligand. Furthermore, our findings demonstrate that early arterial gene expression requires the acetylation of Smad1/5 proteins, rendering them more sensitive to TGFβ1 stimulation. Blocking acetyl-CoA production prevents pre-flow arterial expression of Hey1 and Gja4, while stabilizing acetylation rescues their expression.

Our findings highlight the importance of the acetyl-CoA production in the cell and provide a novel control mechanism of Smad1/5 signalling involving protein acetylation. As disturbed canonical Smad1/5 signalling is involved in several vascular conditions, our results offer new insights in treatment options for circumventing canonical Smad1/5 signalling.

There is evidence indicating that chemoresistance in tumor cells is mediated by the reconfiguration of the tricarboxylic acid cycle, leading to heightened mitochondrial activity and oxidative phosphorylation (OXPHOS). Previously, we have shown that ovarian cancer cells that are resistant to chemotherapy display increased OXPHOS, mitochondrial function, and metabolic flexibility. To exploit this weakness in chemoresistant ovarian cancer cells, we examined the effectiveness of the mitochondrial inhibitor CPI-613 in treating preclinical ovarian cancer.

Chemosensitive OVCAR3, and chemoresistant CAOV3 and F2 ovarian cancer cells lines and their xenografts in nude mice were used. Functional metabolic studies were performed using Seahorse instrument. Metabolite quantification was performed using LC/MS/MS.

Mice treated with CPI-613 exhibited a notable increase in overall survival and a reduction in tumor development and burden in OVCAR3, F2, and CAOV3 xenografts. CPI-613 suppressed the activity of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complex, which are two of its targets. This led to a reduction in OXPHOS and tricarboxylic acid cycle activity in all 3 xenografts. The addition of CPI-613 enhanced the responsiveness of chemotherapy in the chemoresistant F2 and CAOV3 tumors, resulting in a notable improvement in survival rates and a reduction in tumor size as compared to using chemotherapy alone. CPI-613 reduced the chemotherapy-induced OXPHOS in chemoresistant tumors. The study revealed that the mechanism by which CPI-613 inhibits tumor growth is through mitochondrial collapse. This is evidenced by an increase in superoxide production within the mitochondria, a decrease in ATP generation, and the release of cytochrome C, which triggers mitochondria-induced apoptosis.

Our study demonstrates the translational potential of CPI-613 against chemoresistant ovarian tumors.

The most important issues in acute myeloid leukemia are preventing relapse and treating relapse. Although the remission rate has improved to approximately 80%, the 5-year survival rate is only around 30%. The main reasons for this are the high relapse rate and the limited treatment options. In chronic myeloid leukemia patients, when a deep molecular response is achieved for a certain period of time through tyrosine kinase inhibitor treatment, about half of them will reach treatment-free remission, but relapse is still a problem. Therefore, potential therapeutic targets for myeloid leukemias are eagerly awaited. Autophagy suppresses the development of cancer by maintaining cellular homeostasis; however, it also promotes cancer progression by helping cancer cells survive under various metabolic stresses. In addition, autophagy is promoted or suppressed in cancer cells by various genetic mutations. Therefore, the development of therapies that target autophagy is also being actively researched in the field of leukemia. In this review, studies of the role of autophagy in hematopoiesis, leukemogenesis, and myeloid leukemias are presented, and the impact of autophagy regulation on leukemia treatment and the clinical trials of autophagy-related drugs to date is discussed.

Metastatic pancreatic adenocarcinoma (mPC) remains a difficult-to-treat disease. Fluorouarcil, oxaliplatin, irinotecan, and leucovorin (FFX) is a standard first-line therapy for mPC for patients with a favorable performance status and good organ function. In a phase I study, devimistat (CPI-613) in combination with modified FFX (mFFX) was deemed safe and exhibited promising efficacy in mPC.

The AVENGER 500 trial (ClinicalTrials.gov identifier: NCT03504423) is a global, randomized phase III trial conducted at 74 sites across six countries to investigate the efficacy and safety of devimistat in combination with mFFX (experimental arm) compared with standard-dose FFX (control arm) in treatment-naïve patients with mPC. Treatment, administered in once-every-2-weeks cycles until disease progression or intolerable toxicity, included intravenous devimistat at 500 mg/m2 total per day on days 1 and 3 in the experimental arm. The primary end point of the study was overall survival (OS).

Five hundred and twenty-eight patients were randomly assigned (266 in the experimental arm and 262 in the control arm). The median OS was 11.10 months for devimistat plus mFFX versus 11.73 months for FFX (hazard ratio [HR], 0.95 [95% CI, 0.77 to 1.18]; P = .655) and median progression-free survival was 7.8 months versus 8.0 months, respectively (HR, 0.99 [95% CI, 0.76 to 1.29]; P = .94). Grade ≥3 treatment-emergent adverse events with >10% frequency in the devimistat plus mFFX arm versus the FFX arm were neutropenia (29.0% v 34.5%), diarrhea (11.2% v 19.6%), hypokalemia (13.1% v 14.9%), anemia (13.9% v 13.6%), thrombocytopenia (11.6% v 13.6%), and fatigue (10.8% v 11.5%), respectively.

Devimistat in combination with mFFX did not improve long- and short-term mPC patient outcomes compared with standard FFX. There were no new toxicity signals with the addition of devimistat.

Lactate is the highest turnover circulating metabolite in mammals. While traditionally viewed as a waste product, lactate is an important energy source for many organs, but first must be oxidized to pyruvate for entry into the tricarboxylic acid cycle (TCA cycle). This reaction is thought to occur in the cytosol, with pyruvate subsequently transported into mitochondria via the mitochondrial pyruvate carrier (MPC). Using 13C stable isotope tracing, we demonstrated that lactate is oxidized in the myocardial tissue of mice even when the MPC is genetically deleted. This MPC-independent lactate import and mitochondrial oxidation is dependent upon the monocarboxylate transporter 1 (MCT1/Slc16a1). Mitochondria isolated from the myocardium without MCT1 exhibit a specific defect in mitochondrial lactate, but not pyruvate, metabolism. The import and subsequent mitochondrial oxidation of lactate by mitochondrial lactate dehydrogenase (LDH) acts as an electron shuttle, generating sufficient NADH to support respiration even when the TCA cycle is disrupted. In response to diverse cardiac insults, animals with hearts lacking MCT1 undergo rapid progression to heart failure with reduced ejection fraction. Thus, the mitochondrial import and oxidation of lactate enables carbohydrate entry into the TCA cycle to sustain cardiac energetics and maintain myocardial structure and function under stress conditions.

Cancer cells display an altered metabolic phenotype, characterised by increased glycolysis and lactate production, even in the presence of sufficient oxygen - a phenomenon known as the Warburg effect. This metabolic reprogramming is a crucial adaptation that enables cancer cells to meet their elevated energy and biosynthetic demands. Importantly, the tumor microenvironment plays a pivotal role in shaping and sustaining this metabolic shift in cancer cells. This review explores the intricate relationship between the tumor microenvironment and the Warburg effect, highlighting how communication within this niche regulates cancer cell metabolism and impacts tumor progression and therapeutic resistance. We discuss the potential of targeting the Warburg effect as a promising therapeutic strategy, with the aim of disrupting the metabolic advantage of cancer cells and enhancing our understanding of this complex interplay within the tumor microenvironment.

Besides producing cellular energy, mitochondria are crucial in controlling oxidative stress and modulating cellular metabolism, particularly under stressful conditions. A key aspect of this regulatory role involves the recycling process of autophagy, which helps to sustain energy homeostasis. Autophagy, a lysosome-dependent degradation pathway, plays a fundamental role in maintaining cellular homeostasis by degrading damaged organelles and misfolded proteins. In the context of tumor formation, autophagy significantly influences cancer metabolism and chemotherapy resistance, contributing to both tumor suppression and surveillance. This review focuses on the relationship between mitochondria and autophagy, specifically in the context of cancer progression. Investigating the interaction between autophagy and mitochondria reveals new possibilities for cancer treatments and may result in the development of more effective therapies targeting mitochondria, which could have significant implications for cancer treatment. Additionally, this review highlights the increasing understanding of autophagy's role in tumor development, with a focus on modulating mitochondrial function and autophagy in both pre-clinical and clinical cancer research. It also explores the potential for developing more-targeted and personalized therapies by investigating autophagy-related biomarkers.

Pancreatic cancer is an aggressive cancer with a poor prognosis. Metabolic abnormalities are one of the hallmarks of pancreatic cancer, and pancreatic cancer cells can adapt to biosynthesis, energy intake, and redox needs through metabolic reprogramming to tolerate nutrient deficiency and hypoxic microenvironments. Pancreatic cancer cells can use glucose, amino acids, and lipids as energy to maintain malignant growth. Moreover, they also metabolically interact with cells in the tumour microenvironment to change cell fate, promote tumour progression, and even affect immune responses. Importantly, metabolic changes at the body level deserve more attention. Basic research and clinical trials based on targeted metabolic therapy or in combination with other treatments are in full swing. A more comprehensive and in-depth understanding of the metabolic regulation of pancreatic cancer cells will not only enrich the understanding of the mechanisms of disease progression but also provide inspiration for new diagnostic and therapeutic approaches.

Over the past decade, cancer immunotherapy has significantly advanced through the introduction of immune checkpoint inhibitors and the augmentation of adoptive cell transfer to enhance the innate cancer defense mechanisms. Despite these remarkable achievements, some cancers exhibit resistance to immunotherapy, with limited patient responsiveness and development of therapy resistance. Metabolic adaptations in both immune cells and cancer cells have emerged as central contributors to immunotherapy resistance. In the last few years, new insights emphasized the critical role of cancer and immune cell metabolism in animal models and patients. During therapy, immune cells undergo important metabolic shifts crucial for their acquired effector function against cancer cells. However, cancer cell metabolic rewiring and nutrient competition within tumor microenvironment (TME) alters many immune functions, affecting their fitness, polarization, recruitment, and survival. These interactions have initiated the development of novel therapies targeting tumor cell metabolism and favoring antitumor immunity within the TME. Furthermore, there has been increasing interest in comprehending how diet impacts the response to immunotherapy, given the demonstrated immunomodulatory and antitumor activity of various nutrients. In conclusion, recent advances in preclinical and clinical studies have highlighted the capacity of immune-based cancer therapies. Therefore, further exploration into the metabolic requirements of immune cells within the TME holds significant promise for the development of innovative therapeutic approaches that can effectively combat cancer in patients.

Cancer cellular heterogeneity and therapy resistance arise substantially from metabolic and transcriptional adaptations, but how these are interconnected is poorly understood. Here, we show that, in melanoma, the cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) forms an enzymatic partnership with acetyl-coenzyme A (CoA) synthetase 2 (ACSS2) in the nucleus to couple high glucose metabolic flux with acetyl-histone H3 modification of neural crest (NC) lineage and glucose metabolism genes. Importantly, we show that acetaldehyde is a metabolite source for acetyl-histone H3 modification in an ALDH1A3-dependent manner, providing a physiologic function for this highly volatile and toxic metabolite. In a zebrafish melanoma residual disease model, an ALDH1-high subpopulation emerges following BRAF inhibitor treatment, and targeting these with an ALDH1 suicide inhibitor, nifuroxazide, delays or prevents BRAF inhibitor drug-resistant relapse. Our work reveals that the ALDH1A3-ACSS2 couple directly coordinates nuclear acetaldehyde-acetyl-CoA metabolism with specific chromatin-based gene regulation and represents a potential therapeutic vulnerability in melanoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive form of pancreatic cancer, known for its challenging diagnosis and limited treatment options. The focus on metabolic reprogramming as a key factor in tumor initiation, progression, and therapy resistance has gained prominence. In this review we focus on the impact of metabolic changes on the interplay among stromal, immune, and tumor cells, as glutamine and branched-chain amino acids (BCAAs) emerge as pivotal players in modulating immune cell functions and tumor growth. We also discuss ongoing clinical trials that explore metabolic modulation for PDAC, targeting mitochondrial metabolism, asparagine and glutamine addiction, and autophagy inhibition. Overcoming challenges in understanding nutrient effects on immune-stromal-tumor interactions holds promise for innovative therapeutic strategies.

Impairing the BET family coactivator BRD4 with small-molecule inhibitors (BETi) showed encouraging preclinical activity in treating acute myeloid leukemia (AML). However, dose-limiting toxicities and limited clinical activity dampened the enthusiasm for BETi as a single agent. BETi resistance in AML myeloblasts was found to correlate with maintaining mitochondrial respiration, suggesting that identifying the metabolic pathway sustaining mitochondrial integrity could help develop approaches to improve BETi efficacy. Herein, we demonstrated that mitochondria-associated lactate dehydrogenase allows AML myeloblasts to utilize lactate as a metabolic bypass to fuel mitochondrial respiration and maintain cellular viability. Pharmacologically and genetically impairing lactate utilization rendered resistant myeloblasts susceptible to BET inhibition. Low-dose combinations of BETi and oxamate, a lactate dehydrogenase inhibitor, reduced in vivo expansion of BETi-resistant AML in cell line and patient-derived murine models. These results elucidate how AML myeloblasts metabolically adapt to BETi by consuming lactate and demonstrate that combining BETi with inhibitors of lactate utilization may be useful in AML treatment.

Lactate utilization allows AML myeloblasts to maintain metabolic integrity and circumvent antileukemic therapy, which supports testing of lactate utilization inhibitors in clinical settings to overcome BET inhibitor resistance in AML. See related commentary by Boët and Sarry, p. 950.

Traditional Chinese medicine Qingfengteng primarily acquired from the dried canes of Sinomenium acutum (Thunb.) Rehd. et Wils. var. cinereum Rehd. et Wils. and S. acutum (Thunb.) Rehd. et Wils. For the therapeutic treatment of rheumatism, acute arthritis, and rheumatoid arthritis based on Qingfengteng, sinomenine hydrochloride was recently made the principal active ingredient in various dosage forms. 8-Bis(benzylthio)octanoic acid (CPI-613) was an orphan medicine that the FDA and EMA approved orphan for the treatment of certain resistant malignancies. Its unique mode of action and minimal toxicity toward normal tissues made for an apt pharmacophore. In order to expand the field of sinomenine anticancer structures, sinomenine/8-Bis(benzylthio)octanoic acid derivatives were designed and synthesized. Among them, target hybrids e4 stood out for having notable cytotoxic effects against cancer cell lines, especially for K562 cells, with IC50 values of 2.45 μM and high safety. In-depth investigations demonstrated that e4 caused apoptosis by stopping the cell cycle at G1 phase, and doing so by altering the morphology of the nucleus and causing membrane potential of the in mitochondria to collapse. These results indicated e4 exerted an antiproliferative effect through apoptosis induction via mitochondrial pathway.

Our increased understanding of how key metabolic pathways are activated and regulated in malignant cells has identified metabolic vulnerabilities of cancers. Translating this insight to the clinics, however, has proved challenging. Roadblocks limiting efficacy of drugs targeting cancer metabolism may lie in the nature of the metabolic ecosystem of tumors. The exchange of metabolites and growth factors between cancer cells and nonmalignant tumor-resident cells is essential for tumor growth and evolution, as well as the development of an immunosuppressive microenvironment. In this Review, we will examine the metabolic interplay between tumor-resident cells and how targeted inhibition of specific metabolic enzymes in malignant cells could elicit pro-tumorigenic effects in non-transformed tumor-resident cells and inhibit the function of tumor-specific T cells. To improve the efficacy of metabolism-targeted anticancer strategies, a holistic approach that considers the effect of metabolic inhibitors on major tumor-resident cell populations is needed.

Head and neck squamous cell carcinoma (HNSCC) is among the most prevalent cancer worldwide, with the most severe impact on quality of life of patients. Despite the development of multimodal therapeutic approaches, the clinical outcomes of HNSCC are still unsatisfactory, mainly caused by relatively low responsiveness to treatment and severe drug resistance. Metabolic reprogramming is currently considered to play a pivotal role in anticancer therapeutic resistance. This review aimed to define the specific metabolic programs and adaptations in HNSCC therapy resistance. An extensive literature review of HNSCC was conducted via the PubMed including metabolic reprogramming, chemo- or immune-therapy resistance. Glucose metabolism, fatty acid metabolism, and amino acid metabolism are closely related to the malignant biological characteristics of cancer, anti-tumor drug resistance, and adverse clinical results. For HNSCC, pyruvate, lactate and almost all lipid categories are related to the occurrence and maintenance of drug resistance, and targeting amino acid metabolism can prevent tumor development and enhance the response of drug-resistant tumors to anticancer therapy. This review will provide a better understanding of the altered metabolism in therapy resistance of HNSCC and promote the development of new therapeutic strategies against HNSCC, thereby contribute to a more efficacious precision medicine.

Treatment of advanced pancreatic adenocarcinoma remains suboptimal. Therapeutic agents with a novel mechanism of action are desperately needed; one such novel agent is CPI-613 targets. We here analyze the outcomes of 20 metastatic pancreatic cancer patients treated with CPI-613 and FOLFIRINOX in our institution and evaluate their outcomes to borderline-resectable patients treated with curative surgery.

A post hoc analysis was performed of the phase I CPI-613 trial data (NCT03504423) comparing survival outcomes to borderline-resectable cases treated with curative resection at the same institution. Survival was measured by overall survival (OS) for all study cases and disease-free survival (DFS) for resected cases with progression-free survival for CPI-613 cases.

There were 20 patients in the CPI-613 cohort and 60 patients in the surgical cohort. Median follow-up times were 441 and 517 days for CPI-613 and resected cases, respectively. There was no difference in survival times between CPI-613 and resected cases with a mean OS of 1.8 versus 1.9 year (p = 0.779) and mean PFS/DFS of 1.4 versus 1.7 years (p = 0.512). There was also no difference in 3-year survival rates for OS (hazard ratio [HR] = 1.063, 95% confidence interval [CI] 0.302-3.744, p = 0.925) or DFS/PFS (HR = 1.462, 95% CI 0.285-7.505, p = 0.648).

The first study to evaluate the survival between metastatic patients treated with CPI-613 versus borderline-resectable cases undergoing curative resection. Analysis revealed no significant differences in survival outcomes between the cohorts. Study results are suggestive that there may be potential utility with the addition of CPI-613 to potentially resectable pancreatic adenocarcinoma, although additional research with more comparable study groups are required.

anti-Programmed Death-1 (anti-PD-1) immunotherapy has shown promising manifestation in improving the survival rate of patients with advanced melanoma, with its efficacy closely linked to Programmed cell death-Ligand 1 (PD-L1) expression. However, low clinical efficacy and drug resistance remain major challenges. Although the metabolic alterations from tricarboxylic acid (TCA) cycle to glycolysis is a hallmark in cancer cells, accumulating evidence demonstrating TCA cycle plays critical roles in both tumorigenesis and treatment.

The plasma levels of metabolites in patients with melanoma were measured by nuclear magnetic resonance (NMR) spectroscopy. The effect of pyruvate dehydrogenase subunit 1 (PDHA1) and oxoglutarate dehydrogenase (OGDH) on immunotherapy was performed by B16F10 tumor-bearing mice. Flow cytometry analyzed the immune microenvironment. RNA sequencing analyzed the global transcriptome alterations in CPI613-treated melanoma cells. The regulation of PD-L1 and glycolysis by PDHA1/OGDH-ATF3 signaling were confirmed by Quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, dual-luciferase reporter gene, Chromatin immunoprecipitation (ChIP)-quantitative PCR and Seahorse assay. The relationship between PDHA1/OGDH-ATF3-glycolysis and the efficacy of melanoma anti-PD-1 immunotherapy was verified in the clinical database and single-cell RNA-seq (ScRNA-Seq).

In our study, the results showed that significant alterations in metabolites associated with glycolysis and the TCA cycle in plasma of patients with melanoma through NMR technique, and then, PDHA1 and OGDH, key enzymes for regulation TCA cycle, were remarkable raised in melanoma and negatively related to anti-PD-1 efficacy through clinical database analysis as well as ScRNA-Seq. Inhibition of PDHA1 and OGDH by either shRNA or pharmacological inhibitor by CPI613 dramatically attenuated melanoma progression as well as improved the therapeutic efficacy of anti-PD-1 against melanoma. Most importantly, suppression of TCA cycle remarkably raises PD-L1 expression and glycolysis flux through AMPK-CREB-ATF3 signaling.

Taken together, our results demonstrated the role of TCA cycle in immune checkpoint blockade and provided a novel combination strategy for anti-PD-1 immunotherapy in melanoma treatment.

A common approach to studying thiamine pyrophosphate (TPP)-dependent enzymes is by chemical inhibition with thiamine/TPP analogues which feature a neutral aromatic ring in place of the positive thiazolium ring of TPP. These are potent inhibitors but their preparation generally involves multiple synthetic steps to construct the central ring. We report efficient syntheses of novel, open-chain thiamine analogues which potently inhibit TPP-dependent enzymes and are predicted to share the same binding mode as TPP. We also report some open-chain analogues that inhibit pyruvate dehydrogenase E1-subunit (PDH E1) and are predicted to occupy additional pockets in the enzyme other than the TPP-binding pockets. This opens up new possibilities for increasing the affinity and selectivity of the analogues for PDH, which is an established anti-cancer target.

Cancer cells exhibit metabolic reprogramming and bioenergetic alteration, utilizing glucose fermentation for energy production, known as the Warburg effect. However, there are a lack of comprehensive reviews summarizing the metabolic reprogramming, bioenergetic alteration, and their oncogenetic links in gastrointestinal (GI) cancers. Furthermore, the efficacy and treatment potential of emerging anticancer drugs targeting these alterations in GI cancers require further evaluation. This review highlights the interplay between aerobic glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS) in cancer cells, as well as hypotheses on the molecular mechanisms that trigger this alteration. The role of hypoxia-inducible transcription factors, tumor suppressors, and the oncogenetic link between hypoxia-related enzymes, bioenergetic changes, and GI cancer are also discussed. This review emphasizes the potential of targeting bioenergetic regulators for anti-cancer therapy, particularly for GI cancers. Emphasizing the potential of targeting bioenergetic regulators for GI cancer therapy, the review categorizes these regulators into aerobic glycolysis/ lactate biosynthesis/transportation and TCA cycle/coupled OXPHOS. We also detail various anti-cancer drugs and strategies that have produced pre-clinical and/or clinical evidence in treating GI cancers, as well as the challenges posed by these drugs. Here we highlight that understanding dysregulated cancer cell bioenergetics is critical for effective treatments, although the diverse metabolic patterns present challenges for targeted therapies. Further research is needed to comprehend the specific mechanisms of inhibiting bioenergetic enzymes, address side effects, and leverage high-throughput multi-omics and spatial omics to gain insights into cancer cell heterogeneity for targeted bioenergetic therapies.

Devimistat (CPI-613) is a novel inhibitor of tumoral mitochondrial metabolism. We investigated the effect of devimistat in vitro and in a phase Ib clinical trial in patients with advanced biliary tract cancer (BTC).

Cell viability assays of devimistat ± gemcitabine and cisplatin (GC) were performed and the effect of devimistat on mitochondrial respiration via oxygen consumption rate (OCR) was evaluated. A phase Ib/II trial was initiated in patients with untreated advanced BTC. In phase Ib, devimistat was infused over 2 hours in combination with GC on days 1 and 8 every 21 days with a primary objective to determine the recommended phase II dose (RP2D). Secondary objectives included safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).

In vitro, devimistat with GC had a synergistic effect on two cell lines. Devimistat significantly decreased OCR at higher doses and in arms with divided dosing. In the phase Ib trial, 20 patients received a median of nine cycles (range, 3-19). One DLT was observed, and the RP2D of devimistat was determined to be 2,000 mg/m2 in combination with GC. Most common grade 3 toxicities included neutropenia (n = 11, 55%), anemia (n = 4, 20%), and infection (n = 3, 15%). There were no grade 4 toxicities. After a median follow-up of 15.6 months, ORR was 45% and median PFS was 10 months (95% confidence interval, 7.1-14.9). Median OS is not yet estimable.

Devimistat in combination with GC is well tolerated and has an acceptable safety profile in patients with untreated advanced BTC.

Upon antigen-specific T cell receptor (TCR) engagement, human CD4+ T cells proliferate and differentiate, a process associated with rapid transcriptional changes and metabolic reprogramming. Here, we show that the generation of extramitochondrial pyruvate is an important step for acetyl-CoA production and subsequent H3K27ac-mediated remodeling of histone acetylation. Histone modification, transcriptomic, and carbon tracing analyses of pyruvate dehydrogenase (PDH)-deficient T cells show PDH-dependent acetyl-CoA generation as a rate-limiting step during T activation. Furthermore, T cell activation results in the nuclear translocation of PDH and its association with both the p300 acetyltransferase and histone H3K27ac. These data support the tight integration of metabolic and histone-modifying enzymes, allowing metabolic reprogramming to fuel CD4+ T cell activation. Targeting this pathway may provide a therapeutic approach to specifically regulate antigen-driven T cell activation.

Many types of differentiated cells can reenter the cell cycle upon injury or stress. The underlying mechanisms are still poorly understood. Here, we investigated how quiescent cells are reactivated using a zebrafish model, in which a population of differentiated epithelial cells are reactivated under a physiological context. A robust and sustained increase in mitochondrial membrane potential was observed in the reactivated cells. Genetic and pharmacological perturbations show that elevated mitochondrial metabolism and ATP synthesis are critical for cell reactivation. Further analyses showed that elevated mitochondrial metabolism increases mitochondrial ROS levels, which induces Sgk1 expression in the mitochondria. Genetic deletion and inhibition of Sgk1 in zebrafish abolished epithelial cell reactivation. Similarly, ROS-dependent mitochondrial expression of SGK1 promotes S phase entry in human breast cancer cells. Mechanistically, SGK1 coordinates mitochondrial activity with ATP synthesis by phosphorylating F1Fo-ATP synthase. These findings suggest a conserved intramitochondrial signaling loop regulating epithelial cell renewal.

Boosting the metabolism of immune cells while restricting cancer cell metabolism is challenging. Herein, we report that using biomaterials for the controlled delivery of succinate metabolite to phagocytic immune cells activates them and modulates their metabolism in the presence of metabolic inhibitors. In young immunocompetent mice, polymeric microparticles, with succinate incorporated in the backbone, induced strong pro-inflammatory anti-melanoma responses. Administration of poly(ethylene succinate) (PES MP)-based vaccines and glutaminase inhibitor to young immunocompetent mice with aggressive and large, established B16F10 melanoma tumors increased their survival three-fold, a result of increased cytotoxic T cells expressing RORγT (Tc17). Mechanistically, PES MPs directly modulate glutamine and glutamate metabolism, upregulate succinate receptor SUCNR1, activate antigen presenting cells through and HIF-1alpha, TNFa and TSLP-signaling pathways, and are dependent on alpha-ketoglutarate dehydrogenase for their activity, which demonstrates correlation of succinate delivery and these pathways. Overall, our findings suggest that immunometabolism-modifying PES MP strategies provide an approach for developing robust cancer immunotherapies.

This review aims to describe the systemic treatment options for pancreatic ductal adenocarcinoma and includes a summary of the current treatments as well as the ongoing clinical trials which may be efficacious in the treatment of this aggressive malignancy.

A literature review was performed using MEDLINE/PubMed between August 1996 and February 2023. The reviewed studies are categorized into these categories: current standard of care treatments, targeted therapies, immunotherapy and clinical trials. The current treatment modality for the treatment of advanced pancreatic cancer is mainly systemic chemotherapy.

The introduction of polychemotherapy regimens including gemcitabine/nab-paclitaxel and FOLFIRINOX (oxaliplatin, irinotecan, folinic acid and fluorouracil) has improved the clinical outcome of advanced pancreatic cancer. For further improvement in clinical outcomes, several novel approaches have been extensively studied in pancreatic cancer. The review discusses the current standard chemotherapy regimen and the novel treatment options in the field.

While there are novel treatments being explored for metastatic pancreatic, it remains a debilitating and aggressive disease with high mortality that warrants continued efforts to advance therapeutic options.

Brown/beige adipocytes express uncoupling protein-1 (UCP1) that enables them to dissipate energy as heat. Systematic activation of this process can alleviate obesity. Human brown adipose tissues are interspersed in distinct anatomical regions including deep neck. We found that UCP1 enriched adipocytes differentiated from precursors of this depot highly expressed ThTr2 transporter of thiamine and consumed thiamine during thermogenic activation of these adipocytes by cAMP which mimics adrenergic stimulation. Inhibition of ThTr2 led to lower thiamine consumption with decreased proton leak respiration reflecting reduced uncoupling. In the absence of thiamine, cAMP-induced uncoupling was diminished but restored by thiamine addition reaching the highest levels at thiamine concentrations larger than present in human blood plasma. Thiamine is converted to thiamine pyrophosphate (TPP) in cells; the addition of TPP to permeabilized adipocytes increased uncoupling fueled by TPP-dependent pyruvate dehydrogenase. ThTr2 inhibition also hampered cAMP-dependent induction of UCP1, PGC1a, and other browning marker genes, and thermogenic induction of these genes was potentiated by thiamine in a concentration dependent manner. Our study reveals the importance of amply supplied thiamine during thermogenic activation in human adipocytes which provides TPP for TPP-dependent enzymes not fully saturated with this cofactor and by potentiating the induction of thermogenic genes.

Tumor metabolism is emerging as a potential target for cancer therapies. This new approach holds particular promise for the treatment of glioblastoma, a highly lethal brain tumor that is resistant to conventional treatments, for which improving therapeutic strategies is a major challenge. The presence of glioma stem cells is a critical factor in therapy resistance, thus making it essential to eliminate these cells for the long-term survival of cancer patients. Recent advancements in our understanding of cancer metabolism have shown that glioblastoma metabolism is highly heterogeneous, and that cancer stem cells exhibit specific metabolic traits that support their unique functionality. The objective of this review is to examine the metabolic changes in glioblastoma and investigate the role of specific metabolic processes in tumorigenesis, as well as associated therapeutic approaches, with a particular focus on glioma stem cell populations.

Metabolic rewiring and cellular reprogramming are trademarks of neoplastic initiation and progression in acute myeloid leukemia (AML). Metabolic alteration in leukemic cells is often genotype specific, with associated changes in epigenetic and functional factors resulting in the downstream upregulation or facilitation of oncogenic pathways. Targeting abnormal or disease-sustaining metabolic activities in AML provides a wide range of therapeutic opportunities, ideally with enhanced therapeutic windows and robust clinical efficacy. This review highlights the dysregulation of amino acid, nucleotide, lipid, and carbohydrate metabolism in AML; explores the role of key vitamins and enzymes that regulate these processes; and provides an overview of metabolism-directed therapies currently in use or development.