• colorectal cancer
• epigenetics
• genetics
• molecular mechanisms
• targeted therapy
• tumor metabolism

• Shanghai Rising‐Star Program
• National Natural Science Foundation of China

• Lewis lung carcinoma (LLC)
• bortezomib
• chemotherapy-induced peripheral neuropathy (CIPN)
• dichloroacetate
• metabolic interventions
• metformin
• oxamate
• sex differences

• R01 CA249939 NCI NIH HHS

• cancer
• dichloroacetate
• glioma
• lactic acidosis
• pyruvate dehydrogenase
• pyruvate dehydrogenase kinase
• pyruvate dehydrogenase phosphatase

• 4-O-methlyascochlorin
• 5-fluorouracil
• drug-resistance
• synergistic effects
• β-catenin

• Humans
• Fluorouracil/pharmacology
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/pathology
• Wnt Signaling Pathway/drug effects
• Apoptosis/drug effects
• Drug Synergism
• beta Catenin/metabolism
• beta Catenin/genetics
• Cell Proliferation/drug effects
• Cell Line, Tumor
• Drug Resistance, Neoplasm/drug effects
• TOR Serine-Threonine Kinases/metabolism

• 2022R1A4A5032702 National Research Foundation of Korea (NRF) Korean government (MSIT)

• Glycolysis
• Inhibitor
• Metabolic reprogramming
• Pyruvate dehydrogenase kinase
• Structure-activity relationship

• Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism
• Protein Serine-Threonine Kinases
• Pyruvate Dehydrogenase Complex/metabolism
• Glycolysis
• Binding Sites

• Chemotherapy
• Drug resistance
• Fluorouracil
• Metabolism
• Tumor

• Humans
• Fluorouracil/pharmacology
• Neoplasms/drug therapy
• Antimetabolites, Antineoplastic/pharmacology
• Antimetabolites, Antineoplastic/therapeutic use
• Drug Resistance, Neoplasm
• Cell Line, Tumor

• 3D spheroids model
• 5-fluorouracil (5-FU) codrugs
• Organ-on Chip
• anticancer drugs
• dichloroacetate (DCA)
• mutual prodrugs

• Humans
• Fluorouracil/pharmacology
• Prodrugs/pharmacology
• Antineoplastic Agents/pharmacology
• Acetates
• Cell Line
• Hydrocarbons, Chlorinated

• Docetaxel
• Drug combination
• JS-K
• Nasopharyngeal carcinoma
• Nitric oxide

• Animals
• Apoptosis
• Cell Line, Tumor
• Cell Proliferation
• Docetaxel/pharmacology
• Docetaxel/therapeutic use
• Humans
• Mice
• Nasopharyngeal Carcinoma/drug therapy
• Nasopharyngeal Neoplasms/drug therapy
• Nasopharyngeal Neoplasms/metabolism
• Nasopharyngeal Neoplasms/pathology
• Xenograft Model Antitumor Assays

• 56MESS
• PHENSS
• ROS
• chemotherapy
• cisplatin
• cytotoxicity
• lipophilicity
• phenylacetate
• platinum(II)
• platinum(IV)

• Humans
• Female
• Platinum
• Cisplatin/chemistry
• Cell Line, Tumor
• Reactive Oxygen Species
• Glioblastoma
• Ovarian Neoplasms
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/chemistry
• Phenylacetates

Background: Inhalation of asbestos fibers is the most common cause of malignant pleural mesothelioma (MPM). In 2004, the United States Food and Drug Administration approved a combination of cisplatin with pemetrexed to treat unresectable MPM. Nonetheless novel treatment is urgently needed. The objective of this study is to report the combination effect of dichloroacetate (DCA) or niclosamide (Nic) Nic in MPM.

Materials and methods: The effect of a combination of DCA and Nic was studied using a panel of MPM cell lines (H28, MSTO-211H, H226, H2052, and H2452). Cell viability was monitored by MTT assay. Glycolysis, oxidative phosphorylation, glucose, glycogen, pyruvate, lactate, citrate, succinate and ATP levels were determined by corresponding ELISA. Apoptosis, mitochondrial transmembrane potential, cell cycle analysis, hydrogen peroxide and superoxide were investigated by flow cytometry. Cell migration and colony formation were investigated by transwell migration and colony formation assays respectively. The in vivo effect was confirmed using 211H and H226 nude mice xenograft models.

Results and conclusion: Cell viability was reduced. Disturbance of glycolysis and/or oxidative phosphorylation resulted in downregulation of glycogen, citrate and succinate. DCA and/or Nic increased apoptosis, mitochondrial transmembrane depolarization, G2/M arrest and reactive oxygen species. Moreover, DCA and/or Nic suppressed cell migration and colony formation. Furthermore, a better initial tumor suppressive effect was induced by the DCA/Nic combination compared with either drug alone in both 211H and H226 xenograft models. In H226 xenografts, DCA/Nic increased median survival of mice compared with single treatment. Single drug and/or a combination disturbed the Warburg effect and activated apoptosis, and inhibition of migration and proliferation in vivo. In conclusion, dichloroacetate and/or niclosamide showed a tumor suppressive effect in MPM in vitro and in vivo, partially mediated by disturbance of glycolysis/oxidative phosphorylation, apoptosis, ROS production, G2/M arrest, and suppression of migration and proliferation.

The promising results of immunotherapy in tumors have changed the current treatment modality for cancer. However, the remarkable responses are limited to a minority of patients, which is due to immune suppression in the tumor microenvironment (TME). These include the pre-exists of suppressive immune cells, physical barriers to immune infiltration, antigen and antigen presentation deficiency, and expression of inhibitory immune checkpoint molecules. Recently, increasing evidence reveal that tumor metabolism, especially abnormal glucose metabolism of tumors, plays an essential role in tumor immune escape and is a potential target to combine with immunotherapy. By glucose uptake, tumor cells alter their metabolism to facilitate unregulated cellular proliferation and survival and regulate the expression of inhibitory immune checkpoint molecules. Meanwhile, glucose metabolism also regulates the activation, differentiation, and functions of immunocytes. In addition, tumor mainly utilizes glycolysis for energy generation and cellular proliferation, which cause the TME to deplete nutrients for infiltrating immune cells such as T cells and produce immunosuppressive metabolites. Thus, therapeutics that target glucose metabolism, such as inhibiting glycolytic activity, alleviating hypoxia, and targeting lactate, have shown promise as combination therapies for different types of cancer. In this review, we summarized the functions of glucose metabolism in the tumor cells, immune cells, and tumor microenvironment, as well as strategies to target glucose metabolism in combination with immune checkpoint blockade for tumor therapy.

• National Natural Science Foundation of China
• China Postdoctoral Science Foundation

Metabolic reprogramming has been recognized as an essential emerging cancer hallmark. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been reported to have anti-cancer effects by reversing tumor-associated glycolysis. This study was performed to explore the anti-cancer potential of DCA in lung cancer alone and in combination with chemo- and targeted therapies using two non-small cell lung cancer (NSCLC) cell lines, namely, A549 and LNM35. DCA markedly caused a concentration- and time-dependent decrease in the viability and colony growth of A549 and LNM35 cells in vitro. DCA also reduced the growth of tumor xenografts in both a chick embryo chorioallantoic membrane and nude mice models in vivo. Furthermore, DCA decreased the angiogenic capacity of human umbilical vein endothelial cells in vitro. On the other hand, DCA did not inhibit the in vitro cellular migration and invasion and the in vivo incidence and growth of axillary lymph nodes metastases in nude mice. Treatment with DCA did not show any toxicity in chick embryos and nude mice. Finally, we demonstrated that DCA significantly enhanced the anti-cancer effect of cisplatin in LNM35. In addition, the combination of DCA with gefitinib or erlotinib leads to additive effects on the inhibition of LNM35 colony growth after seven days of treatment and to synergistic effects on the inhibition of A549 colony growth after 14 days of treatment. Collectively, this study demonstrates that DCA is a safe and promising therapeutic agent for lung cancer.

• angiogenesis
• dichloroacetate
• erlotinib
• gefitinib
• lung cancer
• pyruvate dehydrogenase kinase inhibitor
• tumor growth

• A549 Cells
• Animals
• Cellular Reprogramming/genetics
• Dichloroacetic Acid/pharmacology
• Glycolysis/drug effects
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Lung Neoplasms/pathology
• Mice
• Neoplasm Metastasis
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase/antagonists & inhibitors
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase/genetics
• Xenograft Model Antitumor Assays

• Cancer metabolism
• Gastrointestinal tumors
• Glucose metabolism
• Lipid metabolism

5-Fluorouracil (5-FU) is regarded as the first line treatment for colorectal cancer; however, its effectiveness is limited by drug resistance. The ultimate goal of cancer therapy is induction of cancer cell death to achieve an effective outcome with minimal side effects. The present work aimed to assess the anti-cancer activities of mitocans which can be considered as an effective anticancer drug due to high specificity in targeting cancer cells.

MTT (3–4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide) assay was performed to determine the effects of our mitocans on cell viability and cell death. Apoptosis and necrosis, caspase 3 activity, mitochondrial membrane potential and ROS production in HT29 cell lines were analyzed by ApopNexin™ FITC/PI Kit, Caspase- 3 Assay Kit, MitoTracker Green and DCFH-DA, respectively. Moreover, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression level of pro-apoptotic (Bax) and anti-apoptotic (Bcl-2) genes in HT29 cell lines.

Treatment with mitocans (3Br-P + DCA) inhibited the growth of HT29. Moreover, 3Br-P + DCA significantly induced apoptosis and necrosis, activation of caspase 3 activity, depolarize the mitochondrial membrane potential, and ROS production. At a molecular level, 3Br-P + DCA treatment remarkably down-regulated the expression of Bcl-2, while up-regulated the expression of Bax.

Mitocans, in particular the combined drug, 3Br-P + DCA, could be regarded and more evaluated as a safe and effective compound for CRC treatment. Targeting hexokinase and pyruvate dehydrogenase kinase enzymes may be an option to overcome 5-FU -mediated chemo-resistant in colorectal cancer.

The online version contains supplementary material available at 10.1186/s12885-021-08564-3.

• 3-Bromopyruvate
• 5-fluorouracil
• Apoptosis
• Colorectal cancer cells
• Dichloroacetate

• Dichloroacetate
• Warburg effect
• glioblastoma
• metformin

• Non-small cell lung cancers (NSCLCs)
• chemotherapy
• curcumin
• multi-drug resistance
• pleiotropic actions
• polyphenolic compound

Diphenyltin(IV) diallyldithiocarbamate compound (Compound 1) and triphenyltin(IV) diallyldithiocarbamate compound (Compound 2) are two newly synthesised compounds of organotin(IV) with diallyldithiocarbamate ligands.

To assess the cytotoxic effects of two synthesised compounds against HT-29 human colon adenocarcinoma cells and human CCD-18Co normal colon cells.

Two successfully synthesised compounds were characterised using elemental (carbon, hydrogen, nitrogen, and sulphur) analysis, Fourier-Transform Infrared (FTIR), and ¹H, ¹³C ¹¹⁹Sn Nucleus Magnetic Resonance (NMR) spectroscopies. The single-crystal structure of both compounds was determined by X-ray single-crystal analysis. The cytotoxicity of the compounds was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazholium bromide (MTT) assay upon 24 h of treatment. While the mode of cell death was determined based on the externalisation of phosphatidylserine using a flow cytometer.

The elemental analysis data of the two compounds showed an agreement with the suggested formula of (C₆H₅)₂Sn[S₂CN(C₃H₅)₂]₂ for Compound 1 and (C₆H₅)₃Sn[S₂CN(C₃H₅)₂] for Compound 2. The two major peaks of infrared absorbance, i.e., ν(C = N) and ν(C = S) were detected at the range of 1475–1479 cm⁻¹ and 972–977 cm⁻¹, respectively. The chemical shift of carbon in NCS₂ group for Compound 1 and 2 were found at 200.82 and 197.79 ppm. The crystal structure of Compound 1 showed that it is six coordinated and crystallised in monoclinic, P2₁/c space group. While the crystal structure of Compound 2 is five coordinated and crystallised in monoclinic, P2₁/c space group. The cytotoxicity (IC₅₀) of the two compounds against HT-29 cell were 2.36 μM and 0.39 μM. Meanwhile, the percentage of cell death modes between 60% and 75% for compound 1 and compound 2 were mainly due to apoptosis, suggesting that both compounds induced growth arrest.

Our study concluded that the synthesised compounds showed potent cytotoxicity towards HT-29 cell, with the triphenyltin(IV) compound showing the highest effect compared to diphenyltin(IV).

• Apoptosis
• CCD-18Co
• Cytotoxicity
• Diallyldithiocarbamate
• HT-29
• Organotin(IV)

Targeting altered tumour metabolism is an emerging therapeutic strategy for cancer treatment. The metabolic reprogramming that accompanies the development of malignancy creates targetable differences between cancer cells and normal cells, which may be exploited for therapy. There is also emerging evidence regarding the role of stromal components, creating an intricate metabolic network consisting of cancer cells, cancer-associated fibroblasts, endothelial cells, immune cells, and cancer stem cells. This metabolic rewiring and crosstalk with the tumour microenvironment play a key role in cell proliferation, metastasis, and the development of treatment resistance. In this review, we will discuss therapeutic opportunities, which arise from dysregulated metabolism and metabolic crosstalk, highlighting strategies that may aid in the precision targeting of altered tumour metabolism with a focus on combinatorial therapeutic strategies.

• cancer cell metabolism
• immunotherapy
• metabolic reprogramming
• targeted therapy
• tumour microenvironment

• Antineoplastic Agents/chemistry
• Antineoplastic Agents/therapeutic use
• Cancer-Associated Fibroblasts/drug effects
• Cell Proliferation/drug effects
• Energy Metabolism/drug effects
• Humans
• Metabolic Networks and Pathways/drug effects
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/metabolism
• Tumor Microenvironment/drug effects

• anticancer
• cytotoxicity
• drug delivery
• metal-organic frameworks
• microporous materials

• Alendronate/chemistry
• Alendronate/pharmacology
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Catalysis
• Coumaric Acids/chemistry
• Coumaric Acids/pharmacology
• Dichloroacetic Acid/chemistry
• Dichloroacetic Acid/pharmacology
• Drug Compounding
• Drug Therapy, Combination
• Humans
• Ibuprofen/chemistry
• Ibuprofen/pharmacology
• MCF-7 Cells
• Metal-Organic Frameworks/chemistry
• Nanocapsules/chemistry
• Porosity
• Zirconium/chemistry

• H2020 European Research Council

Trichosanthis semen, the seeds of Trichosanthes kirilowii Maxim. or Trichosanthes rosthornii Harms, has long been used in Korean medicine to loosen bowels and relieve chronic constipation. Although the fruits and radixes of this medicinal herb and their constituents have been reported to exhibit therapeutic effects in various cancers, the anti-cancer effects of its seeds have been relatively less studied. In this study, we investigated the effects of an ethanolic extract of T. kirilowii seeds (TKSE) against colorectal cancer and its mechanism.

The anti-tumor effects of the TKSE were evaluated in HT-29 and CT-26 colorectal cancer cells and in a CT-26 tumor-bearing mouse model.

TKSE suppressed the growth of HT-29 and CT-26 cells (both colorectal cancer cell lines) and the cytotoxic effect of TKSE was greater than that of 5-fluorouracil (5-Fu) in HT-29 cells. TKSE significantly induced mitochondrial membrane potential loss in HT-29 and CT-26 cells and dose-dependently inhibited Bcl-2 expression and induced the cleavages of caspase-3 and PARP. In particular, TKSE at 300 µg/mL induced nuclear condensation and fragmentation in HT-29 cells. Furthermore, TKSE dose-dependently inhibited activations of the Akt/mTOR and ERK pathways, and markedly induced the phosphorylation of AMPK. An AMPKα inhibitor (compound C) effectively blocked the TKSE-induced mitochondrial dysfunction. In addition, TKSE attenuated the hypoxia-inducible factor-1α/vascular endothelial growth factor signaling pathway in HT-29 cells under hypoxic-mimic conditions and inhibited migration and invasion. Oral administration of TKSE (100 or 300 mg/kg) inhibited tumor growth in a mouse CT-26 allograft model but was not as effective as 5-Fu (the positive control), which was administered intraperitoneally. In the same model, 5-Fu caused significant body weight loss, but no such loss was observed in TKSE-treated mice.

Taken together, these results suggest TKSE has potent anti-tumor effects which might be partly due to the activation of AMPK, and the induction mitochondrial-mediated apoptosis in colorectal cancer cells. These findings provide scientific evidence supporting the potential use of TKSE as a complementary and alternative medicine for the treatment of colorectal cancer.

• Anti-cancer
• Anti-tumor
• Apoptosis
• Colorectal cancer
• Trichosanthis semen

Chemotherapy-induced painful peripheral neuropathy (CIPN) is the most common toxicity associated with widely used chemotherapeutics. CIPN is the major cause of dose reduction or discontinuation of otherwise life-saving treatment. Unfortunately, CIPN can persist in cancer survivors, which adversely affects their quality of life. Moreover, available treatments are vastly inadequate, warranting a better understanding of the biochemical and metabolic mechanisms that occur in response to chemotherapeutics which would be critical for the development of novel therapies for CIPN. Using extracellular flux analysis, this study demonstrated that the proteasome inhibitor, bortezomib, enhanced glycolysis while suppressing oxidative phosphorylation in the sensory neurons of mice. This metabolic phenotype is known as aerobic glycolysis. Bortezomib upregulated lactate dehydrogenase A and pyruvate dehydrogenase kinase 1, which consequently enhanced the production of lactate and repressed pyruvate oxidation, respectively. Moreover, lactate dehydrogenase A- and pyruvate dehydrogenase kinase 1-driven aerobic glycolysis was associated with increased extracellular acidification, augmented calcium responses, and pain in bortezomib-induced CIPN. Remarkably, pharmacological blockade and in vivo knockdown of lactate dehydrogenase A or pyruvate dehydrogenase kinase 1 reversed the metabolic phenotype, attenuated calcium responses, and alleviated pain induced by bortezomib. Collectively, these results elucidate the mechanisms by which bortezomib induces aerobic glycolysis. Moreover, these findings establish aerobic glycolysis as a metabolic phenotype that underpins bortezomib-induced CIPN.

• CIPN
• DRG
• Neuropathy
• aerobic glycolysis
• metabolism
• mitochondria

• Antimetabolites, Antineoplastic/administration & dosage
• Antimetabolites, Antineoplastic/pharmacology
• Colorectal Neoplasms/drug therapy
• Delayed-Action Preparations/chemistry
• Fluorouracil/administration & dosage
• Fluorouracil/pharmacology
• Galactans/chemistry
• HT29 Cells
• Humans
• Infrared Rays
• Mannans/chemistry
• Nanocomposites/chemistry
• Nanoparticles/chemistry
• Photochemotherapy
• Plant Gums/chemistry
• Rose Bengal/administration & dosage
• Rose Bengal/pharmacology
• Silicon Dioxide/chemistry

• MOF-Fe2+
• antitumor treatment
• dichloroacetic acid
• liposomes
• oxidative stress

• Animals
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Dichloroacetic Acid/administration & dosage
• Dichloroacetic Acid/pharmacology
• Drug Synergism
• Ferrous Compounds/administration & dosage
• Ferrous Compounds/chemistry
• Ferrous Compounds/pharmacology
• Humans
• Liposomes/pharmacology
• Metal-Organic Frameworks/administration & dosage
• Metal-Organic Frameworks/pharmacology
• Mice
• Mice, Inbred BALB C
• Mice, Inbred ICR
• Mice, Nude
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/pathology
• Oxidative Stress/drug effects
• Oxidative Stress/physiology
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays

• common signaling pathways
• drug resistance
• non-small cell lung cancer
• transcriptome microarray data

• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/pathology
• Drug Resistance
• Early Detection of Cancer
• Gene Expression Profiling/methods
• Humans
• Lung Neoplasms/genetics
• Lung Neoplasms/pathology
• Signal Transduction

Investigation of the cytotoxic potential of imidazole-derived thiosemicarbazones and their copper(ii) complexes with CHCl₂CO₂⁻ as a co-ligand.

• Acetate
• Anticancer mechanisms
• Dichloroacetate

• Acetates/antagonists & inhibitors
• Acetates/chemistry
• Acetyl Coenzyme A
• Animals
• Antineoplastic Agents/pharmacology
• Brain Neoplasms/metabolism
• Brain Neoplasms/pathology
• Chlorides
• Dichloroacetic Acid/analysis
• Dichloroacetic Acid/toxicity
• Evidence-Based Medicine
• Glioblastoma/pathology
• Heart/drug effects
• Humans
• Ketones
• Lactic Acid/chemistry
• Models, Theoretical
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Oxygen/chemistry
• Perfusion
• Rats

• coordination modulation
• dichloroacetate
• drug delivery
• endocytosis pathways
• immune system response
• metal−organic frameworks
• surface modification

• Animals
• Cell Survival/drug effects
• Drug Delivery Systems
• Fumarates/chemistry
• HEK293 Cells
• HeLa Cells
• Humans
• Immune System/drug effects
• MCF-7 Cells
• Metal-Organic Frameworks/chemistry
• Metal-Organic Frameworks/pharmacology
• Metal-Organic Frameworks/toxicity
• Zirconium/chemistry

• apoptosis
• dichloroacetate
• pyruvate dehydrogenase kinase-1
• phosphatidylinositol 3-kinase/protein kinase b/glycogen synthase kinase-3β
• hypoxia inducible factor-1
• hexokinase-2

• Apoptosis/drug effects
• Cells, Cultured
• Dichloroacetic Acid/pharmacology
• Glycogen Synthase Kinase 3 beta/metabolism
• Humans
• Microscopy, Confocal
• Myocytes, Smooth Muscle/drug effects
• Myocytes, Smooth Muscle/metabolism
• Phosphatidylinositol 3-Kinase/metabolism
• Platelet-Derived Growth Factor/pharmacology
• Protein Serine-Threonine Kinases/metabolism
• Proto-Oncogene Proteins c-akt/metabolism
• Pulmonary Artery/cytology
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Signal Transduction/drug effects

• alkaloid
• apoptosis
• caspase-3
• cell cycle
• gastric carcinoma
• lily

• T-lymphocyte metabolism
• immune checkpoints
• immunotherapy
• metabolic checkpoints
• tumor cell metabolism
• tumor microenvironment

• Animals
• Antibodies, Monoclonal/therapeutic use
• Antigens, Neoplasm/immunology
• Cellular Reprogramming
• Costimulatory and Inhibitory T-Cell Receptors/immunology
• Humans
• Immunization
• Immunotherapy/methods
• Neoplasms/immunology
• Neoplasms/metabolism
• Neoplasms/therapy
• T-Lymphocytes/immunology
• T-Lymphocytes/transplantation
• Tumor Escape
• Tumor Microenvironment

• lipid metabolism
• metabolic reprogramming
• pentose phosphate pathway
• transketolase-like 1
• tumor metabolism

• Anticancer agents
• Colorectal cancer
• Cytotoxicity
• Pyrazoline
• Spirooxindoles

• Akt-mTOR
• TE-1
• autophagy
• dichloroacetate

• BCC
• Cancer biomarker
• Carcinoma
• Melanoma
• Mitochondria
• SCC
• Targeted therapy
• Warburg effect

B-chronic lymphocytic leukemia (B-CLL) patients harboring p53 mutations are invariably refractory to therapies based on purine analogues and have limited treatment options and poor survival. Having recently demonstrated that the mitochondria-targeting small molecule sodium dichloroacetate (DCA) exhibits anti-leukemic activity in p53^wild-type B-CLL cells, the aim of this study was to evaluate the effect of DCA in p53^mutated B-CLL cells and in p53^mutated/null leukemic cell lines. DCA exhibited comparable cytotoxicity in p53^wild-type and p53^mutated B-CLL patient cell cultures, as well as in p53^mutated B leukemic cell lines (MAVER, MEC-1, MEC-2). At the molecular level, DCA promoted the transcriptional induction of p21 in all leukemic cell types investigated, including p53^null HL-60. By using a proteomic approach, we demonstrated that DCA up-regulated the ILF3 transcription factor, which is a known regulator of p21 expression. The role of the ILF3/p21 axis in mediating the DCA anti-leukemic activity was underscored by knocking-down experiments. Indeed, transfection with ILF3 and p21 siRNAs significantly decreased both the DCA-induced p21 expression and the DCA-mediated cytotoxicity. Taken together, our results emphasize that DCA is a small molecule that merits further evaluation as a therapeutic agent also for p53^mutated leukemic cells, by acting through the induction of a p53-independent pathway.

• 5-Fluorouracil
• Autophagy
• Cancer therapy
• Glucose metabolism
• Mitochondrial dysfunction
• Platinum-dichloroacetate conjugates

Colon cancers develop adaptive mechanisms to survive under extreme conditions and display hallmarks of unlimited proliferation and resistance to cell death. The deregulation of cell death is a key factor that contributes to chemoresistance in tumors. In a physiological context, balance between cell proliferation and death, and protection against cell damage are fundamental processes for maintaining gut epithelial homeostasis. The mechanisms underlying anti-death cytoprotection and tumor resistance often bear common pathways, and although distinguishing them would be a challenge, it would also provide an opportunity to develop advanced anti-cancer therapeutics. This review will outline cell death pathways (i.e., apoptosis, necrosis, and necroptosis), and discuss cytoprotective strategies in normal intestinal epithelium and death resistance mechanisms of colon tumor. In colorectal cancers, the intracellular mechanisms of death resistance include the direct alteration of apoptotic and necroptotic machinery and the upstream events modulating death effectors such as tumor suppressor gene inactivation and pro-survival signaling pathways. The autocrine, paracrine and exogenous factors within a tumor microenvironment can also instigate resistance against apoptotic and necroptotic cell death in colon cancers through changes in receptor signaling or transporter uptake. The roles of cyclooxygenase-2/prostaglandin E2, growth factors, glucose, and bacterial lipopolysaccharides in colorectal cancer will be highlighted. Targeting anti-death pathways in the colon cancer tissue might be a promising approach outside of anti-proliferation and anti-angiogenesis strategies for developing novel drugs to treat refractory tumors.

• Colon cancer
• Tumorigenesis
• Anti-apoptosis
• Chemoresistance
• Anti-necroptosis
• Cytoprotection

• Animals
• Antineoplastic Agents/therapeutic use
• Apoptosis/drug effects
• Apoptosis Regulatory Proteins/metabolism
• Cell Cycle Proteins
• Cell Proliferation/drug effects
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/physiopathology
• Drug Resistance, Neoplasm
• Humans
• Necrosis
• Signal Transduction/drug effects
• Tumor Microenvironment

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