• Cisplatin resistance
• DLL1
• LINC00460
• Neuroblastoma
• Notch
• miR-149-5p

• Animals
• Humans
• Mice
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/administration & dosage
• Apoptosis/drug effects
• Calcium-Binding Proteins/genetics
• Calcium-Binding Proteins/metabolism
• Carcinogenesis/drug effects
• Carcinogenesis/genetics
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cisplatin/pharmacology
• Drug Resistance, Neoplasm/genetics
• Intercellular Signaling Peptides and Proteins/genetics
• Intercellular Signaling Peptides and Proteins/metabolism
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs/genetics
• Neuroblastoma/genetics
• Neuroblastoma/drug therapy
• Neuroblastoma/metabolism
• Receptors, Notch/metabolism
• Receptors, Notch/genetics
• RNA, Long Noncoding/genetics
• Signal Transduction/drug effects
• Xenograft Model Antitumor Assays

• 2021Y9118 The Joint Fund Project of Science and Technology Innovation in Fujian Province

• B7‐H3
• NR1D1
• NUTM2A‐AS1
• cisplatin
• neuroblastoma

• Humans
• Neuroblastoma/genetics
• Neuroblastoma/pathology
• Neuroblastoma/drug therapy
• Neuroblastoma/metabolism
• Drug Resistance, Neoplasm/genetics
• B7 Antigens/metabolism
• B7 Antigens/genetics
• RNA, Long Noncoding/genetics
• Cisplatin/pharmacology
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic/drug effects
• Immune Evasion
• Animals
• Proteolysis/drug effects
• Mice

• 2022CFB344 Natural Science Foundation of Hubei Province of China
• D20220059 the Scientific and Technological Project of Enshi Tujia and Miao Autonomous Prefecture of Hubei Province
• 82060539 the National Natural Science Foundation of China
• 82360477 the National Natural Science Foundation of China
• the National Natural Science Foundation of China

• Humans
• Child
• Neuroblastoma/drug therapy
• Monensin/pharmacology
• Monensin/therapeutic use
• Annexin A5/pharmacology
• Annexin A5/therapeutic use
• Apoptosis
• Cell Line, Tumor
• Cell Proliferation

• Scientific and Technological Research Council of Turkey

• Biological sciences
• Cancer
• Cancer systems biology

• anti-cancer
• cancer metabolism
• cardiotoxicity
• perhexiline
• repurposing

• NA The Hospital Research Foundation
• NA Cancer Council SA

• AKI-to-CKD transition
• CPT2
• EP4
• lipophagy
• macrophages

• National Natural Science Foundation of China
• Chongqing Science and Technology Innovation Leading Talent Support Program
• Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission

• insulin resistance
• nitric oxide
• perhexiline
• type 2 diabetes

• 1075767; 1162356 National Health and Medical Research Council
• 102126 National Heart Foundation of Australia

Cancer is one of the most frequently diagnosed diseases, and despite the continuous efforts in searching for new and more effective treatments, its morbidity and mortality remain a significant health problem worldwide. Calorie restriction, a dietary manipulation that consists in a reduction of the calorie intake, is gaining attention as a potential adjuvant intervention for preventing and/or fighting cancer. Several forms of energy reduction intake, which includes caloric restriction tout-court, dietary restrictions, and intermittent fasting, are being explored for their ability to prevent or slow down cancer progression. Additionally, another anti-cancer approach being under investigation relies on the use of nutraceuticals known as “Caloric Restriction Mimetics” that can provide caloric restriction-mediated benefits without subjecting the patients to a strict diet. Preclinical in vitro and in vivo studies consistently show that diet modifiers reducing the calorie have impact on tumor microenvironment and cancer metabolism, resulting in reduced growth and progression of cancer. Preliminary clinical studies show that patients subjected to a reduced nutrient/energy intake experience improved outcomes from chemo- and radiotherapy while better tolerating the side effects. Here, we review the state of the art on the therapeutic potential of calorie restriction and of caloric restriction mimetics in preventing or retarding tumor development by modulating a subset of cellular processes. The most recent clinical progresses with caloric restriction mimetics in the clinical practice are also discussed.

• Caloric restriction mimetics
• Drug therapy
• Ketogenic diet
• Tumor microenvironment
• Warburg effect

• CPT1A
• carboplatin
• fatty acid oxidation
• ovarian cancer
• oxidative phosphorylation
• proteogenomic
• proteomic
• reactive oxygen species
• resistance

• Acetyl-CoA Carboxylase/genetics
• Acetyl-CoA Carboxylase/metabolism
• Animals
• Apoptosis/drug effects
• Carboplatin/pharmacology
• Carboplatin/therapeutic use
• Carnitine O-Palmitoyltransferase/antagonists & inhibitors
• Carnitine O-Palmitoyltransferase/genetics
• Carnitine O-Palmitoyltransferase/metabolism
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cystadenocarcinoma, Serous/drug therapy
• Cystadenocarcinoma, Serous/metabolism
• Cystadenocarcinoma, Serous/pathology
• DNA Damage
• Drug Resistance, Neoplasm/drug effects
• Fatty Acids/metabolism
• Female
• Gene Expression Regulation, Neoplastic/drug effects
• Genomics
• Humans
• Mice, SCID
• Molecular Targeted Therapy
• Neoplasm Grading
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/pathology
• Oxidation-Reduction/drug effects
• Oxidative Phosphorylation/drug effects
• Phosphoproteins/metabolism
• Proteomics
• Reactive Oxygen Species/metabolism
• Mice

• U24 CA210954 NCI NIH HHS
• S10 OD028685 NIH HHS
• R50 CA211499 NCI NIH HHS
• P30 CA015083 NCI NIH HHS
• U24 CA210993 NCI NIH HHS
• U01 CA214114 NCI NIH HHS
• P50 CA136393 NCI NIH HHS

• Cancer stem cells
• Neural crest
• Neuroblastoma
• Polyploid giant cancer cells molecular mechanisms
• Therapeutic targeting
• Tumour microenvironment

High-risk neuroblastoma (HR-NB) still remains the most dangerous tumor in early childhood. For this reason, the identification of new therapeutic approaches is of fundamental importance. Recently, we combined the conventional pharmacological approach to NB, represented by cisplatin, with fendiline hydrochloride, an inhibitor of several transporters involved in multidrug resistance of cancer cells, which demonstrated an enhancement of the ability of cisplatin to induce apoptosis. In this work, we co-administrated acetazolamide, a carbonic anhydrase isoform IX (CAIX) inhibitor which was reported to increase chemotherapy efficacy in various cancer types, to the cisplatin/fendiline approach in SKNBE2 xenografts in NOD-SCID mice with the aim of identifying a novel and more effective treatment. We observed that the combination of the three drugs increases more than twelvefold the differences in the cytotoxic activity of cisplatin alone, leading to a remarkable decrease of the expression of malignancy markers. Our conclusion is that this approach, based on three FDA-approved drugs, may constitute an appropriate improvement of the pharmacological approach to HR-NB.

• CAIX
• acetazolamide
• drug repositioning
• fendiline hydrochloride
• neuroblastoma
• non-coding RNAs

Neuroblastoma (NB) is a heterogeneous developmental tumor occurring in childhood, which arises from the embryonic sympathoadrenal cells of the neural crest. Although the recent progress that has been done on this tumor, the mechanisms involved in NB are still partially unknown. Despite some genetic aberrations having been identified, the sporadic cases represent the majority. Due to its wide heterogeneity in clinical behavior and etiology, NB represents a challenge in terms of prevention and treatment. Since a definitive therapy is lacking so far, there is an urgent necessity to unveil the molecular mechanisms behind NB onset and progression to develop new therapeutic approaches. Long non-coding RNAs (lncRNAs) are a group of RNAs longer than 200 nucleotides. Whether lncRNAs are destined to become a protein or not, they exert multiple biological functions such as regulating gene expression and functions. In recent decades, different research has highlighted the possible role of lncRNAs in the pathogenesis of many diseases, including cancer. Moreover, lncRNAs may represent potential markers or targets for diagnosis and treatment of diseases. This mini-review aimed to briefly summarize the most recent findings on the involvement of some lncRNAs in NB disease by focusing on their mechanisms of action and possible role in unveiling NB onset and progression.

• cancer
• lncRNAs
• neuroblastoma

• Animals
• Gene Expression Regulation, Neoplastic
• Humans
• Neuroblastoma/genetics
• Neuroblastoma/metabolism
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism

Despite significant improvement of neuroblastoma (NB) patients’ survival due to recent treatment advancements in recent years, NB is still associated with high mortality rate. In search of novel strategies to increase NB’s susceptibility to pharmacological treatments, we investigated the in vitro and in vivo effects of fendiline hydrochloride as an enhancer of cisplatin antitumor activity. To assess the modulation of fendiline treatment on cisplatin responses, we used in vitro (evaluating NB cell proliferation by XCELLigence technology and colony formation, and gene expression by RT-PCR) and in vivo (NB cell grafts in NOD-SCID mice) models of NB. NB cell treatment with fendiline induced the expression of the ncRNA NDM29, leading to cell differentiation and to the reduction of the expression of MDRs/ABC transporters linked to multidrug resistance. These events were correlated to higher NB cell susceptibility to cisplatin and, consequently, increased its cytotoxic potency. In vivo, this drug interaction causes an enhanced ability of cisplatin to induce apoptosis in NB masses, resulting in tumor growth reduction and prolonged animal survival rate. Thus, the administration of fendiline might be a possible novel therapeutic approach to increase cisplatin efficacy in aggressive and poorly responsive NB cases.

• GD2
• NDM29
• fendiline hydrochloride
• neuroblastoma
• non-coding RNA

• Animals
• Antineoplastic Agents/administration & dosage
• Antineoplastic Combined Chemotherapy Protocols/administration & dosage
• Apoptosis
• Brain Neoplasms/drug therapy
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival/drug effects
• Cisplatin/administration & dosage
• Drug Synergism
• Fendiline/administration & dosage
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplasm Transplantation
• Neuroblastoma/drug therapy
• RNA, Untranslated/metabolism

• MCM2
• acetazolamide
• carbonic anhydrase 9
• ciprofloxacin
• neuroblastoma

Cancer cells reprogram their metabolism to meet bioenergetics and biosynthetic demands. The first observation of metabolic reprogramming in cancer cells was made a century ago (“Warburg effect” or aerobic glycolysis), leading to the classical view that cancer metabolism relies on a glycolytic phenotype. There is now accumulating evidence that most cancers also rely on mitochondria to satisfy their metabolic needs. Indeed, the current view of cancer metabolism places mitochondria as key actors in all facets of cancer progression. Importantly, mitochondrial metabolism has become a very promising target in cancer therapy, including for refractory cancers such as Pancreatic Ductal AdenoCarcinoma (PDAC). In particular, mitochondrial oxidative phosphorylation (OXPHOS) is an important target in cancer therapy. Other therapeutic strategies include the targeting of glutamine and fatty acids metabolism, as well as the inhibition of the TriCarboxylic Acid (TCA) cycle intermediates. A better knowledge of how pancreatic cancer cells regulate mitochondrial metabolism will allow the identification of metabolic vulnerabilities and thus novel and more efficient therapeutic options for the benefit of each patient.

• OXPHOS
• biguanides
• cancer metabolism
• energetic metabolism
• metabolic heterogeneity
• mitochondria
• mitochondrial complex I
• mitochondrial metabolism
• pancreatic ductal adenocarcinoma
• therapeutic strategy

Long noncoding RNA small nucleolar RNA host gene 16 (lncRNA SNHG16) has been revealed to be involved in the tumorigenesis of neuroblastoma. However, the role of SNHG16 in regulating cisplatin sensitivity in neuroblastoma remains largely unknown.

The expression of SNHG16, microRNA (miR)-338-3p and polo-like kinase 4 (PLK4) mRNA was measured using quantitative real-time polymerase chain reaction. The protein levels of PLK4, multidrug resistance protein 1 (MRP1), multidrug-resistance gene 1-type p-glycoprotein (P-gp) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway-related proteins were detected by Western blot. The half maximal inhibitory concentration (IC50) value, cell proliferation, migration and invasion were analyzed using Cell Counting Kit-8 assays or Transwell assay. Apoptotic cells were measured by Flow cytometry. The interaction between miR-338-3p and SNHG16 or PLK4 was confirmed by dual-luciferase reporter and RNA immunoprecipitation assay. In vivo experiments were conducted through the murine xenograft model.

SNHG16 was up-regulated, while miR-338-3p was down-regulated in cisplatin-resistant neuroblastoma tissues and cells. SNHG16 silencing weakened cisplatin resistance, reflected by the reduction of IC50 value, down-regulation of MRP-1 and P-gp protein expression, suppression of proliferation, migration and invasion, as well as enhancement of apoptosis in SNHG16 deletion cisplatin-resistant neuroblastoma cells. Besides that, SNHG16 could regulate PLK4 expression by sponging miR-338-3p and SNHG16/miR-338-3p/PLK4 axis could affect the activation of PI3K/AKT pathway in cisplatin-resistant neuroblastoma cells. MiR-338-3p inhibition attenuated SNHG16 deletion-mediated impairment on cisplatin resistance and PLK4 overexpression reversed the decrease of cisplatin-resistance induced by miR-338-3p re-expression. Furthermore, SNHG16 knockdown contributed to the anti-tumor effect of cisplatin in neuroblastoma in vivo.

SNHG16 contributed to the tumorigenesis and cisplatin resistance in neuroblastoma possibly through miR-338-3p/PLK4 pathway, indicating a novel insight for overcoming chemoresistance in neuroblastoma patients.

• Cisplatin resistance
• Neuroblastoma
• PLK4
• SNHG16
• miR-338-3p

Cervical cancer (CC) remains a major disease burden on the female population worldwide. Chemotherapy with cisplatin (cis-diamminedichloroplatinum (II); CDDP) and related drugs are the main treatment option for CC; however, their efficacy is limited by the development of drug resistance. Noncoding RNAs (ncRNAs) have been found to play critical roles in numerous physiological and pathological cellular processes, including drug resistance of cancer cells. In this review, we describe some of the ncRNAs, including miRNAs, lncRNAs and circRNAs, that are involved in the sensitivity/resistance of CC to CDDP-based chemotherapy and discuss their mechanisms of action. We also describe some ncRNAs that could be therapeutic targets to improve the sensitivity of CC to CDDP-based chemotherapy.

• Cervical cancer
• Circular RNA
• Cisplatin resistance
• Long non-coding RNA
• MicroRNA
• Noncoding RNAs

• Cancer stem cells
• Drug repurposing
• Low-grade glioma
• Medulloblastoma
• Pediatric brain tumors

• Antineoplastic Agents/pharmacology
• Brain Neoplasms/drug therapy
• Brain Neoplasms/pathology
• Child
• Drug Repositioning
• Glioma/drug therapy
• Glioma/pathology
• Humans
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/pathology
• Pediatrics/methods

• Cancer
• Cathepsins
• Cationic amphiphilic drugs
• Cell death
• Lysosome
• SMPD1
• pH

• Glutamine
• Krebs cycle
• Oxidative phosphorylation
• Pentose phosphate pathway
• Reductive carboxylation
• Serine

Neuroblastoma (NB) is the most common extracranial solid tumor often diagnosed in childhood. Despite intense efforts to develop a successful treatment, current available therapies are still challenged by high rates of resistance, recurrence and progression, most notably in advanced cases and highly malignant tumors. Emerging evidence proposes that this might be due to a subpopulation of cancer stem cells (CSCs) or tumor-initiating cells (TICs) found in the bulk of the tumor. Therefore, the development of more targeted therapy is highly dependent on the identification of the molecular signatures and genetic aberrations characteristic to this subpopulation of cells. This review aims at providing an overview of the key molecular players involved in NB CSCs and focuses on the experimental evidence from NB cell lines, patient-derived xenografts and primary tumors. It also provides some novel approaches of targeting multiple drivers governing the stemness of CSCs to achieve better anti-tumor effects than the currently used therapeutic agents.

• cancer stem cells
• genetic aberrations
• molecular signatures
• neuroblastoma
• therapeutic targets

Aberrant fatty acid (FA) metabolism is a unique vulnerability of cancer cells and may present a promising target for cancer therapy. Our study aims to elucidate the molecular mechanisms by which NKX2–8 deletion reprogrammed FA metabolism-induced chemoresistance in epithelial ovarian cancer (EOC).

The deletion frequency and expression of NKX2–8 in 144 EOC specimens were assayed using Fluorescence in situ hybridization and immunochemical assays. The effects of NKX2–8 deletion and the fatty acid oxidation (FAO) antagonist Perhexiline on chemoresistance were examined by Annexin V and colony formation in vitro, and via an intraperitoneal tumor model in vivo. The mechanisms of NKX2–8 deletion in reprogrammed FA metabolism was determined using Chip-seq, metabolomic analysis, FAO assays and immunoprecipitation assays.

NKX2–8 deletion was correlated with the overall and relapse-free survival of EOC patients. NKX2–8 inhibited the FAO pathway by epigenetically suppressing multiple key components of the FAO cascade, including CPT1A and CPT2. Loss of NKX2–8 resulted in reprogramming of FA metabolism of EOC cells in an adipose microenvironment and leading to platinum resistance. Importantly, pharmacological inhibition of FAO pathway using Perhexiline significantly counteracted NKX2–8 deletion-induced chemoresistance and enhanced platinum's therapeutic efficacy in EOC.

Our results demonstrate that NKX2–8 deletion-reprogrammed FA metabolism contributes to chemoresistance and Perhexiline might serve as a potential tailored treatment for patients with NKX2–8-deleted EOC.

This work was supported by Natural Science Foundation of China; Guangzhou Science and Technology Plan Projects; Natural Science Foundation of Guangdong Province; The Fundamental Research Funds for the Central Universities.

• Chemoresistance
• Epithelial ovarian cancer
• Fatty acid oxidation
• Metabolic reprogram
• NKX2–8

• AMPK
• NAD
• acetyl-CoA
• acetyltransferases
• aspirin
• deacetylases
• fasting
• hydroxycitric acid
• mTOR
• metformin
• nicotine adenine dinucleotide precursors
• polyphenols
• rapamycin
• resveratrol
• sirtuins
• spermidine

• LncRNAs
• diabetic Alzheimer’s disease
• inflammation
• insulin resistance
• long noncoding RNAs
• synaptic dysfunction

• Alzheimer’s disease
• Amyloid β peptide
• Long non-coding RNAs
• Neurotoxicity
• Regulatory factors

• NAD(P)H
• SHG
• cancer cell
• chemotherapy
• collagen
• early response

• cancer metabolism
• glutaminolysis
• glycolysis
• growth factors
• mitochondrial transmembrane potential
• systems biology

• Autophagy
• Carcinogenesis/pathology
• Citric Acid Cycle
• Humans
• Neoplasms/pathology
• Oxidation-Reduction
• Warburg Effect, Oncologic

The transcriptional co-activator Yes-associated protein (YAP) is essential for Hippo pathway-driven tumorigenesis in various cancers. However, the expression and function of YAP in neuroblastoma remains elusive. Here, we show that YAP was highly expressed in Neuroblastoma (NB) and expression levels correlated with advanced tumor staging. Knockdown of YAP significantly impaired neuroblastoma proliferation, tumorigenesis, and invasion in vitro. Injection of the YAP inhibitor, Peptide 17, dramatically prevented neuroblastoma subcutaneous tumor growth by efficiently downregulating YAP expression in tumors. Additionally, less proliferative and more apoptotic cells were found in the Peptide 17 treatment group. Furthermore, YAP inhibition significantly inhibited cisplatin-resistant neuroblastoma proliferation, tumorigenesis, and invasion in vitro. The combination of Peptide 17 with low-dose cisplatin efficiently impaired cisplatin-resistant NB subcutaneous tumor growth, being as effective as high-dose cisplatin. Notably, the combination therapy caused lesser liver toxicity in mice compared to the high-dose cisplatin treatment group. Collectively, this work identifies YAP as a novel regulator of neuroblastoma proliferation, tumorigenesis, and invasion and indicates that YAP is a potential therapeutic target for cisplatin-resistant neuroblastoma.

• YAP
• cisplatin resistance
• neuroblastoma

• Alzheimer's disease
• SH-SY5Y
• lncRNA EBF3-AS
• neurons apoptosis

• ECI2
• androgen receptor
• cell cycle
• lipid degradation
• metabolism

• Biomarkers, Tumor/analysis
• Cell Death/drug effects
• Cell Line, Tumor
• Cell Survival/drug effects
• Dodecenoyl-CoA Isomerase/metabolism
• Gene Expression Regulation, Neoplastic
• Humans
• Kaplan-Meier Estimate
• Lipid Metabolism/drug effects
• Lipid Metabolism/physiology
• Male
• Perhexiline/pharmacology
• Prostatic Neoplasms/metabolism
• Prostatic Neoplasms/mortality
• Prostatic Neoplasms/pathology
• Receptors, Androgen/metabolism

• P01 CA077739 NCI NIH HHS
• P30 CA016056 NCI NIH HHS
• R01 CA166440 NCI NIH HHS

Neuroblastoma (NB) is the most common and aggressive pediatric cancer, characterized by a remarkable phenotypic diversity and high malignancy. The heterogeneous clinical behavior, ranging from spontaneous remission to fatal metastatic disease, is attributable to NB biology and genetics. Despite major advances in therapies, NB is still associated with a high morbidity and mortality. Thus, novel diagnostic, prognostic, and therapeutic approaches are required, mainly to improve treatment outcomes of high-risk NB patients. Among neuroepithelial cancers, NB is the most studied tumor as far as PPAR ligands are concerned. PPAR ligands are endowed with antitumoral effects, mainly acting on cancer stem cells, and constitute a possible add-on therapy to antiblastic drugs, in particular for NB with unfavourable prognosis. While discussing clinical background, this review will provide a synopsis of the major studies about PPAR expression in NB, focusing on the potential beneficial effects of hypoglycemic drugs, thiazolidinediones and metformin, to reduce the occurrence of relapses as well as tumor regrowth in NB patients.

• Cancer
• Human neuronal network
• Multi-electrode array (MEA)
• NDM29
• Neuroblastoma
• SKNBE2-S1.1

• Alzheimer’s disease
• BACE1
• BACE1-AS
• BC200
• amyloid β peptide
• lncRNA
• ncRNAs

• Aged
• Alzheimer Disease/genetics
• Amyloid beta-Peptides/genetics
• Gene Expression
• Humans
• RNA, Long Noncoding/genetics
• RNA, Untranslated/genetics