• Breast Cancer
• Electron transport chain
• Mitochondrial respiration
• Oxidative phosphorylation

• Humans
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Energy Metabolism
• Mitochondria/metabolism
• Female

• ATP/ADP exchanging
• Parkinson's disease
• adenine nucleotide translocases
• cancer
• heart disease
• human diseases
• mitochondria
• post-translational modifications

• 2022JH2/101300084 Applied Basic Research Foundation of Liaoning Province

• PENAO
• SAHA
• SLC25A5
• neuroblastoma

• Animals
• Mice
• Antineoplastic Agents/pharmacology
• Apoptosis
• Cell Line, Tumor
• Histone Deacetylase Inhibitors/pharmacology
• Histones/metabolism
• Hydroxamic Acids/therapeutic use
• Mitochondria/metabolism
• Neuroblastoma/drug therapy
• Vorinostat/pharmacology
• Adenine Nucleotide Translocator 2/antagonists & inhibitors

• Cancer Council NSW
• Cancer Institute NSW

• Breast cancer fear
• breast cancer knowledge
• early detection
• mammography

• Bacterial metabolite
• Breast cancer
• Inflammation
• Metastasis
• Oncobiome
• Oncobiosis

• Animals
• Bacteria/metabolism
• Breast Neoplasms/pathology
• Dysbiosis/microbiology
• Estrogens/metabolism
• Female
• Humans
• Mice
• Microbiota
• Tumor Microenvironment

• NKFIH
• University of Debrecen

• breast neoplasms
• clinical trials as topic
• guidelines as topic
• immunotherapy

• Female
• Guidelines as Topic
• Humans
• Immunotherapy/methods
• Societies, Medical
• Triple Negative Breast Neoplasms/therapy
• United States
• United States Food and Drug Administration

• DCA
• metabolism
• toxoplasmosis

• Antiprotozoal Agents/pharmacology
• Apoptosis/drug effects
• Dichloroacetic Acid/chemistry
• Dichloroacetic Acid/pharmacology
• Fibroblasts/drug effects
• Fibroblasts/parasitology
• Humans
• Metabolic Networks and Pathways/drug effects
• Mitochondria/metabolism
• Oxidation-Reduction
• Oxidoreductases
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase/antagonists & inhibitors
• Pyruvates/metabolism
• Toxoplasma/drug effects
• Toxoplasmosis/drug therapy

• Fundacao Araucaria
• MCTI | Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
• Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
• Fundação Oswaldo Cruz (FIOCRUZ)

Mitochondrial metabolism is an attractive target for cancer therapy. Reprogramming metabolic pathways can potentially sensitize tumors with limited treatment options, such as triple-negative breast cancer (TNBC), to chemo- and/or radiotherapy. Dichloroacetate (DCA) is a specific inhibitor of the pyruvate dehydrogenase kinase (PDK), which leads to enhanced reactive oxygen species (ROS) production. ROS are the primary effector molecules of radiation and an increase hereof will enhance the radioresponse. In this study, we evaluated the effects of DCA and radiotherapy on two TNBC cell lines, namely EMT6 and 4T1, under aerobic and hypoxic conditions. As expected, DCA treatment decreased phosphorylated pyruvate dehydrogenase (PDH) and lowered both extracellular acidification rate (ECAR) and lactate production. Remarkably, DCA treatment led to a significant increase in ROS production (up to 15-fold) in hypoxic cancer cells but not in aerobic cells. Consistently, DCA radiosensitized hypoxic tumor cells and 3D spheroids while leaving the intrinsic radiosensitivity of the tumor cells unchanged. Our results suggest that although described as an oxidative phosphorylation (OXPHOS)-promoting drug, DCA can also increase hypoxic radioresponses. This study therefore paves the way for the targeting of mitochondrial metabolism of hypoxic cancer cells, in particular to combat radioresistance.

• breast cancer
• dichloroacetate
• hypoxic radiosensitivity
• reactive oxygen species

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer associated with poor prognosis, early recurrence, and the lack of durable chemotherapy responses and specific targeted treatments. The recent FDA approval for immune checkpoint inhibition in combination with nab-paclitaxel for the treatment of metastatic TNBC created opportunity to advocate for immunotherapy in TNBC patients. However, improving the current low response rates is vital. Most cancers, including TNBC tumors, display metabolic plasticity and undergo reprogramming into highly glycolytic tumors through the Warburg effect. Consequently, accumulation of the metabolic byproduct lactate and extracellular acidification is often observed in several solid tumors, thereby exacerbating tumor cell proliferation, metastasis, and angiogenesis. In this review, we focus on the role of lactate acidosis in the microenvironment of glycolytic breast tumors as a major driver for immune evasion with a special emphasis on TNBCs. In particular, we will discuss the role of lactate regulators such as glucose transporters, lactate dehydrogenases, and lactate transporters in modulating immune functionality and checkpoint expression in numerous immune cell types. This review aims to spark discussion on interventions targeting lactate acidosis in combination with immunotherapy to provide an effective means of improving response to immune checkpoint inhibitors in TNBC, in addition to highlighting challenges that may arise from TNBC tumor heterogeneity.

• Warburg effect
• anti-tumor immunity
• immunosuppression
• immunotherapy
• lactate acidosis
• metabolic reprogramming
• triple negative breast cancer
• tumor metabolism

• Animals
• Basic Helix-Loop-Helix Transcription Factors/metabolism
• Biomarkers, Tumor/metabolism
• Breast Neoplasms/blood supply
• Breast Neoplasms/metabolism
• Breast Neoplasms/therapy
• Female
• Humans
• Hypoxia/metabolism
• Hypoxia/therapy
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Models, Biological
• Neovascularization, Pathologic
• Prognosis
• Signal Transduction
• Tumor Microenvironment

• 18974 Cancer Research UK
• A18974 Cancer Research UK

• anticancer drug
• breast cancer
• cancer
• chemoresistance
• glucose metabolism
• resistance
• sensitization
• triple-negative breast cancer

• NPRP 11S-1214-170101 Qatar Foundation

Our group previously demonstrated that sarcoma cell lines were insensitive to epidermal growth factor receptor (EGFR) inhibitor gefitinib monotherapy. PENAO, an anti-tumour metabolic compound created in our laboratory, is currently in clinical trials. Considering the positive regulation of tumour energy production by both the EGFR signalling and tumour metabolism pathways, this study aimed to investigate the effect and mechanisms of combination therapy using gefitinib and PENAO in sarcoma cell lines in vitro and in vivo.

PENAO monotherapy reduced proliferation in 12 sarcoma cell lines. Combining gefitinib and PENAO resulted in synergistic inhibition in both a time- and dose-dependent manner in 3 sarcoma cell lines with less prominent monotherapy effects. Combined treatment significantly enhanced cell death and perturbed mitochondrial function. In vivo combination therapy with PENAO and gefitinib was non-toxic to mice and significantly delayed tumour growth and prolonged survival. At 20 days after treatment, tumours from the combination treated mice were significantly smaller than those from untreated and single drug treated mice. The survival curves also showed significant difference across and between groups.

The combination of PENAO and gefitinib in vitro and in vivo, shows promise as a treatment pathway in this poor outcome tumour.

• EGFR-targeted therapy
• combination therapy
• mitochondria inhibitor
• sarcomas
• tumour metabolism inhibition

• Chemotherapy
• clinical pharmacology
• drug metabolism
• genetic polymorphism
• toxicology

• Administration, Oral
• Aged
• Dichloroacetic Acid/administration & dosage
• Dichloroacetic Acid/adverse effects
• Dichloroacetic Acid/pharmacokinetics
• Drug Resistance, Neoplasm/genetics
• Drugs, Investigational/administration & dosage
• Drugs, Investigational/adverse effects
• Drugs, Investigational/pharmacokinetics
• Female
• Genotype
• Glutathione Transferase/genetics
• Glutathione Transferase/metabolism
• Half-Life
• Humans
• Male
• Middle Aged
• Multiple Myeloma/blood
• Multiple Myeloma/drug therapy
• Multiple Myeloma/genetics
• Peripheral Nervous System Diseases/chemically induced
• Peripheral Nervous System Diseases/genetics
• Polymorphism, Single Nucleotide
• Promoter Regions, Genetic/genetics
• Prospective Studies
• Protein Kinase Inhibitors/administration & dosage
• Protein Kinase Inhibitors/adverse effects
• Protein Kinase Inhibitors/pharmacokinetics
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase/antagonists & inhibitors
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism

One of the remarkable metabolic characteristics of cancer cells is that they prefer glycolysis rather than oxidative phosphorylation (OXPHOS). Pyruvate dehydrogenase E1 alpha subunit (PDHA1) is an important prerequisite for OXPHOS. Our previous studies have shown that low level of PDHA1 protein expression in esophageal squamous cell cancer (ESCC) was correlated with poor prognosis. However, the effect of PDHA1 inhibition on metabolism and biological behavior of esophageal cancer cells remains unclear.

In this study, a KYSE450 PDHA1 knockout (KO) cell line of esophageal cancer was established by CRISPR/Cas9 technology. Then, the glycose metabolism, cell proliferation and migration abilities, chemotherapeutic tolerance and angiogenesis of the PDHA1 KO cells were investigated in vitro and in vivo. In the PDHA1 KO cells, the glycolysis and the consumption of glucose and glutamine were significantly enhanced, while the OXPHOS was significantly suppressed, implying Warburg effect in the PDHA1 KO cells. Furthermore, it was also proved in vitro experiments that the PDHA1 KO cell obtained proliferation advantage, as well as significantly greater chemotherapy tolerance and migration ability. Xenograft experiments discovered not only larger tumors but also increased angiogenesis in the PDHA1 KO cell group.

Inhibition of PDHA1 gene expression in human ESCC leads to metabolic reprogramming of Warburg effect and increased malignancies. Targeting ESCC metabolic reprogramming may become a potential therapeutic target.

• CRISPR/Cas9
• ESCC
• KYSE450
• PDHA1
• Warburg effect
• xenotransplantation

Diffuse Intrinsic Pontine Gliomas (DIPG) are the most devastating of all pediatric brain tumors. They mostly affect young children and, as there are no effective treatments, almost all patients with DIPG will die of their tumor within 12 months of diagnosis. A key feature of this devastating tumor is its intrinsic resistance to all clinically available therapies. It has been shown that glioma development is associated with metabolic reprogramming, redox state disruption and resistance to apoptotic pathways. The mitochondrion is an attractive target as a key organelle that facilitates these critical processes. PENAO is a novel anti-cancer compound that targets mitochondrial function by inhibiting adenine nucleotide translocase (ANT). Here we found that DIPG neurosphere cultures express high levels of ANT2 protein and are sensitive to the mitochondrial inhibitor PENAO through oxidative stress, while its apoptotic effects were found to be further enhanced upon co-treatment with mTOR inhibitor temsirolimus. This combination therapy was found to act through inhibition of PI3K/AKT/mTOR pathway, HSP90 and activation of AMPK. In vivo experiments employing an orthotopic model of DIPG showed a marginal anti-tumour effect likely due to poor penetration of the inhibitors into the brain. Further testing of this anti-DIPG strategy with compounds that penetrate the BBB is warranted.

• DIPG
• PDGFR
• mTOR
• mitochondria
• paediatric brain tumour

Cells generate adenosine-5′-triphosphate (ATP), the major currency for energy-consuming reactions, through mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis. One of the remarkable features of cancer cells is aerobic glycolysis, also known as the “Warburg Effect”, in which cancer cells rely preferentially on glycolysis instead of mitochondrial OXPHOS as the main energy source even in the presence of high oxygen tension. One of the main players in controlling OXPHOS is the mitochondrial gatekeeperpyruvate dehydrogenase complex (PDHc) and its major subunit is E1α (PDHA1). To further analyze the function of PDHA1 in cancer cells, it was knock out (KO) in the human prostate cancer cell line LnCap and a stable KO cell line was established. We demonstrated that PDHA1 gene KO significantly decreased mitochondrial OXPHOS and promoted anaerobic glycolysis, accompanied with higher stemness phenotype including resistance to chemotherapy, enhanced migration ability and increased expression of cancer stem cell markers. We also examined PDHA1 protein expression in prostate cancer tissues by immunohistochemistry and observed that reduced PDHA1 protein expression in clinical prostate carcinomas was significantly correlated with poor prognosis. Collectively, our results show that negative PDHA1 gene expressionis associated with significantly higher cell stemness in prostate cancer cells and reduced protein expression of this gene is associated with shorter clinical outcome in prostate cancers.

• PDHA1
• glycolysis
• prostate cancer
• stemness

Sodium dichloroacetate (DCA) has been studied as a metabolic cancer therapy since 2007, based on a publication from Bonnet et al demonstrating that DCA can induce apoptosis (programmed cell death) in human breast, lung and brain cancer cells. Classically, the response of cancer to a medical therapy in human research is measured by Response Evaluation Criterial for Solid Tumours definitions, which define “response” by the degree of tumour reduction, or tumour disappearance on imaging, however disease stabilization is also a beneficial clinical outcome. It has been shown that DCA can function as a cytostatic agent in vitro and in vivo, without causing apoptosis. A case of a 32-year-old male is presented in which DCA therapy, with no concurrent conventional therapy, resulted in regression and stabilization of recurrent metastatic melanoma for over 4 years’ duration, with trivial side effects. This case demonstrates that DCA can be used to reduce disease volume and maintain long-term stability in patients with advanced melanoma.

• Dichloroacetate
• Cancer
• BRAF
• Melanoma
• Cytostatic

Oral dichloroacetate sodium (DCA) has been investigated as a novel metabolic therapy for various cancers since 2007, based on data from Bonnet et al that DCA can trigger apoptosis of human lung, breast and brain cancer cells. Response to therapy in human studies is measured by standard RECIST definitions, which define “response” by the degree of tumour reduction, or tumour disappearance on imaging. However, Blackburn et al have demonstrated that DCA can also act as a cytostatic agent in vitro and in vivo, without causing apoptosis (programmed cell death). A case is presented in which oral DCA therapy resulted in tumour stabilization of stage 4 colon cancer in a 57 years old female for a period of nearly 4 years, with no serious toxicity. Since the natural history of stage 4 colon cancer consists of steady progression leading to disability and death, this case highlights a novel use of DCA as a cytostatic agent with a potential to maintain long-term stability of advanced-stage cancer.

• Dichloroacetate
• Cancer
• Colon
• Colorectal
• Cytostatic
• Stabilization
• Growth inhibition
• Intravenous

• acute renal failure
• cisplatin nephrotoxicity
• renal protection

Mitochondrial metabolism greatly influences cancer cell survival, invasion, metastasis, and resistance to many anticancer drugs. Furthermore, molecular-targeted therapies (e.g., oncogenic kinase inhibitors) create a dependence of surviving cells on mitochondrial metabolism. For these reasons, inhibition of mitochondrial metabolism represents promising therapeutic pathways in cancer. This review provides an overview of mitochondrial metabolism in cancer and discusses the limitations of mitochondrial inhibition for cancer treatment. Finally, we present preclinical evidence that mitochondrial inhibition could be associated with oncogenic “drivers” inhibitors, which may lead to innovative drug combinations for improving the efficacy of molecular-targeted therapy.

• 2-deoxyglucose
• Carboxyamidotriazole
• G2/M arrest
• Glycolysis
• Oxidative phosphorylation

• Aerobic glycolysis
• Hepatocellular carcinoma
• Lactate
• Metabolic interventions
• Oxidative stress

• Arsenic-based cancer drugs
• Drug resistance
• Metabolism
• Mitochondria
• Ovarian cancer
• Oxidative stress
• PENAO
• mTOR signalling pathway

Glioblastoma (GBM) is the most common and malignant primary brain tumor. In contrast to some other tumor types, aberrant glucose metabolism is an important component of GBM growth and chemoresistance. Recent studies of human orthotopic GBM in mice and in situ demonstrated GBM cells rely on both glycolysis and mitochondrial oxidation for glucose catabolism. These observations suggest that the homeostasis of energy metabolism of GBM cells might be further disturbed by dual-inhibition of glucose metabolism. The present study aimed to evaluate the efficacy and the mechanisms of dual-targeting therapy in GBM cells.

Representative GBM cells (immortalized GBM cell lines and patient-derived GBM cells) and non-cancerous cells were treated with 4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid (PENAO), an in-house designed novel arsenic-based mitochondrial toxin, in combination with dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor. The efficacy of this combinatorial therapy was evaluated by MTS assay, clonogenic surviving assay and apoptotic assays. The underlying mechanisms of this dual-targeting treatment were unraveled by using mitochondrial membrane potential measurements, cytosol/mitochondrial ROS detection, western blotting, extracellular flux assay and mass spectrometry.

As monotherapies, both PENAO and DCA induced proliferation arrest in a panel of GBM cell lines and primary isolates. PENAO inhibited oxygen consumption, induced oxidative stress and depolarized mitochondrial membrane potential, which in turn activated mitochondria-mediated apoptosis. By combining DCA with PENAO, the two drugs worked synergistically to inhibit cell proliferation (but had no significant effect on non-cancerous cells), impair the clonogenicity, and induce mitochondria-mediated apoptosis. An oxidative stress of mitochondrial origin takes a prominent place in the mechanism by which the combination of PENAO and DCA induces cell death. Additionally, PENAO-induced oxidative damage was enhanced by DCA through glycolytic inhibition which in turn diminished acid production induced by PENAO. Moreover, DCA treatment also led to an alteration in the multidrug resistance (MDR) phenotype of GBM cells, thereby leading to an increased cytosolic accumulation of PENAO.

The findings of this study shed a new light with respect to the dual-targeting of glucose metabolism in GBM cells and the innovative combination of PENAO and DCA shows promise in expanding GBM therapies.