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Cancer Science Sep 2019Recurrence and chemoresistance in colorectal cancer remain important issues for patients treated with conventional therapeutics. Metformin and phenformin, previously...
Recurrence and chemoresistance in colorectal cancer remain important issues for patients treated with conventional therapeutics. Metformin and phenformin, previously used in the treatment of diabetes, have been shown to have anticancer effects in various cancers, including breast, lung and prostate cancers. However, their molecular mechanisms are still unclear. In this study, we examined the effects of these drugs in chemoresistant rectal cancer cell lines. We found that SW837 and SW1463 rectal cancer cells were more resistant to ionizing radiation and 5-fluorouracil than HCT116 and LS513 colon cancer cells. In addition, metformin and phenformin increased the sensitivity of these cell lines by inhibiting cell proliferation, suppressing clonogenic ability and increasing apoptotic cell death in rectal cancer cells. Signal transducer and activator of transcription 3 and transforming growth factor-β/Smad signaling pathways were more activated in rectal cancer cells, and inhibition of signal transducer and activator of transcription 3 expression using an inhibitor or siRNA sensitized rectal cancer cells to chemoresistant by inhibition of the expression of antiapoptotic proteins, such as X-linked inhibitor of apoptosis, survivin and cellular inhibitor of apoptosis protein 1. Moreover, metformin and phenformin inhibited cell migration and invasion by suppression of transforming growth factor β receptor 2-mediated Snail and Twist expression in rectal cancer cells. Therefore, metformin and phenformin may represent a novel strategy for the treatment of chemoresistant rectal cancer by targeting signal transducer and activator of transcription 3 and transforming growth factor-β/Smad signaling.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemoradiotherapy; Colon; Colonic Neoplasms; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Fluorouracil; Humans; Male; Metformin; Mice; Mice, Nude; Neoplasm Recurrence, Local; Phenformin; Rectal Neoplasms; STAT3 Transcription Factor; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Xenograft Model Antitumor Assays
PubMed: 31278880
DOI: 10.1111/cas.14124 -
International Journal of Molecular... Jul 2019Currently, there is increasing evidence linking diabetes mellitus (especially type 2 diabetes mellitus) with carcinogenesis through various biological processes, such as... (Review)
Review
Currently, there is increasing evidence linking diabetes mellitus (especially type 2 diabetes mellitus) with carcinogenesis through various biological processes, such as fat-induced chronic inflammation, hyperglycemia, hyperinsulinemia, and angiogenesis. Chemotherapeutic agents are used in the treatment of cancer, but in most cases, patients develop resistance. Phenformin, an oral biguanide drug used to treat type 2 diabetes mellitus, was removed from the market due to a high risk of fatal lactic acidosis. However, it has been shown that phenformin is, with other biguanides, an authentic tumor disruptor, not only by the production of hypoglycemia due to caloric restriction through AMP-activated protein kinase with energy detection (AMPK) but also as a blocker of the mTOR regulatory complex. Moreover, the addition of phenformin eliminates resistance to antiangiogenic tyrosine kinase inhibitors (TKI), which prevent the uncontrolled metabolism of glucose in tumor cells. In this review, we evidence the great potential of phenformin as an anticancer agent. We thoroughly review its mechanism of action and clinical trial assays, specially focusing on current challenges and future perspectives of this promising drug.
Topics: Animals; Antineoplastic Agents; Diabetes Mellitus, Type 2; Humans; Models, Biological; Neoplasms; Phenformin; Risk Factors
PubMed: 31284513
DOI: 10.3390/ijms20133316 -
Clinical Cancer Research : An Official... Sep 2023Oncogene-driven macropinocytosis fuels nutrient scavenging in some cancer types, yet whether this occurs in thyroid cancers with prominent MAPK-ERK and PI3K pathway...
PURPOSE
Oncogene-driven macropinocytosis fuels nutrient scavenging in some cancer types, yet whether this occurs in thyroid cancers with prominent MAPK-ERK and PI3K pathway mutations remains unclear. We hypothesized that understanding links between thyroid cancer signaling and macropinocytosis might uncover new therapeutic strategies.
EXPERIMENTAL DESIGN
Macropinocytosis was assessed across cells derived from papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), non-malignant follicular thyroid, and aggressive anaplastic thyroid cancer (ATC), by imaging fluorescent dextran and serum albumin. The impacts of ectopic BRAFV600E and mutant RAS, genetic PTEN silencing, and inhibitors targeting RET, BRAF, and MEK kinases were quantified. BrafV600E p53-/- ATC tumors in immunocompetent mice were used to measure efficacy of an albumin-drug conjugate comprising microtubule-destabilizing monomethyl auristatin E (MMAE) linked to serum albumin via a cathepsin-cleavable peptide (Alb-vc-MMAE).
RESULTS
FTC and ATC cells showed greater macropinocytosis than non-malignant and PTC cells. ATC tumors accumulated albumin at 8.8% injected dose per gram tissue. Alb-vc-MMAE, but not MMAE alone, reduced tumor size by >90% (P < 0.01). ATC macropinocytosis depended on MAPK/ERK activity and nutrient signaling, and increased by up to 230% with metformin, phenformin, or inhibition of IGF1Ri in monoculture but not in vivo. Macrophages also accumulated albumin and express the cognate IGF1R ligand, IGF1, which reduced ATC responsiveness to IGF1Ri.
CONCLUSIONS
These findings identify regulated oncogene-driven macropinocytosis in thyroid cancers and demonstrate the potential of designing albumin-bound drugs to efficiently treat them.
Topics: Mice; Animals; Phosphatidylinositol 3-Kinases; Mutation; Proto-Oncogene Proteins B-raf; Thyroid Neoplasms; Thyroid Carcinoma, Anaplastic; Oncogenes; Thyroid Cancer, Papillary; Serum Albumin
PubMed: 37289199
DOI: 10.1158/1078-0432.CCR-22-2976 -
Cells Aug 2022The treatment of many skin inflammation diseases, such as psoriasis and atopic dermatitis, is still a challenge and inflammation plays important roles in multiple stages...
The treatment of many skin inflammation diseases, such as psoriasis and atopic dermatitis, is still a challenge and inflammation plays important roles in multiple stages of skin tumor development, including initiation, promotion and metastasis. Phenformin, a biguanide drug, has been shown to play a more efficient anti-tumor function than another well-known biguanide drug, metformin, which has been reported to control the expression of pro-inflammatory cytokines; however, little is known about the effects of phenformin on skin inflammation. This study used a mouse acute inflammation model, ex vivo skin organ cultures and in vitro human primary keratinocyte cultures to demonstrate that phenformin can suppress acute skin inflammatory responses induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in vivo and significantly suppresses the pro-inflammatory cytokines IL-1β, IL-6 and IL-8 in human primary keratinocytes in vitro. The suppression of pro-inflammatory cytokine expression by phenformin was not directly through regulation of the MAPK or NF-κB pathways, but by controlling the expression of c-Myc in human keratinocytes. We demonstrated that the overexpression of c-Myc can induce pro-inflammatory cytokine expression and counteract the suppressive effect of phenformin on cytokine expression in keratinocytes. In contrast, the down-regulation of c-Myc produces effects similar to phenformin, both in cytokine expression by keratinocytes in vitro and in skin inflammation in vivo. Finally, we showed that phenformin, as an AMPK activator, down-regulates the expression of c-Myc through regulation of the AMPK/mTOR pathways. In summary, phenformin inhibits the expression of pro-inflammatory cytokines in keratinocytes through the down-regulation of c-Myc expression to play an anti-inflammation function in the skin.
Topics: AMP-Activated Protein Kinases; Animals; Cytokines; Dermatitis, Atopic; Humans; Inflammation; Keratinocytes; Mice; Phenformin; Proto-Oncogene Proteins c-myc
PubMed: 35954273
DOI: 10.3390/cells11152429 -
RSC Chemical Biology Apr 2021Rising bacterial antibiotic resistance is a global threat. To deal with it, new antibacterial agents and antiseptic materials need to be developed. One alternative in... (Review)
Review
Rising bacterial antibiotic resistance is a global threat. To deal with it, new antibacterial agents and antiseptic materials need to be developed. One alternative in this quest is the organometallic derivatization of well-established antibacterial drugs and also the fabrication of advanced metal-based materials having antibacterial properties. Metal-based agents and materials often show new modes of antimicrobial action which enable them to overcome drug resistance in pathogenic bacterial strains. This review summarizes recent (2017-2020) progress in the field of organometallic-derived antibacterial drugs and metal-based materials having antibacterial activity. Specifically, it covers organometallic derivatives of antibacterial drugs including β-lactams, ciprofloxacin, isoniazid, trimethoprim, sulfadoxine, sulfamethoxazole, and ethambutol as well as non-antibacterial drugs like metformin, phenformin and aspirin. Recent advances and reported clinical trials in the use of metal-based nanomaterials as antibiofouling coatings on medical devices, as photocatalytic agents in indoor air pollutant control, and also as photodynamic/photothermal antimicrobial agents are also summarized.
PubMed: 34458790
DOI: 10.1039/d0cb00218f -
FEBS Open Bio May 2021Inhibitors of ataxia-telangiectasia mutated (ATM), such as KU-55933 (Ku), represent a promising class of novel anticancer drugs. In addition, the biguanide derivative...
Inhibitors of ataxia-telangiectasia mutated (ATM), such as KU-55933 (Ku), represent a promising class of novel anticancer drugs. In addition, the biguanide derivative phenformin exhibits antitumor activity superior to that of the AMPK activator metformin. Herein, we assessed the potential combinatorial therapeutic efficacy of phenformin and Ku when used to inhibit the growth of liver cancer cells, and we assessed the mechanisms underlying such efficacy. The Hep-G2 and SMMC-7721 liver cancer cell lines were treated with phenformin and Ku either alone or in combination, after which the impact of these drugs on cellular proliferation was assessed via 3-(4,5-dimethylthiazol) 2, 5-diphenyltetrazolium and colony formation assays, whereas Transwell assays were used to gauge cell migratory activity. The potential synergy between these two drugs was assessed using the CompuSyn software, while flow cytometry was employed to evaluate cellular apoptosis. In addition, western blotting was utilized to measure p-ATM, p-AMPK, p-mTOR, and p-p70s6k expression, while mitochondrial functionality was monitored via morphological analyses, JC-1 staining, and measurements of ATP levels. Phenformin and Ku synergistically impacted the proliferation, migration, and apoptotic death of liver cancer cells. Together, these compounds were able to enhance AMPK phosphorylation while inhibiting the phosphorylation of mTOR and p70s6k. These data also revealed that phenformin and Ku induced mitochondrial dysfunction as evidenced by impaired ATP synthesis, mitochondrial membrane potential, and abnormal mitochondrial morphology. These findings suggest that combination treatment with phenformin and Ku may be an effective approach to treating liver cancer via damaging mitochondria within these tumor cells.
Topics: AMP-Activated Protein Kinases; Apoptosis; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; China; Drug Synergism; Drug Therapy, Combination; Humans; Liver Neoplasms; Mitochondria; Morpholines; Phenformin; Phosphorylation; Pyrones; Ribosomal Protein S6 Kinases, 70-kDa; TOR Serine-Threonine Kinases
PubMed: 33742560
DOI: 10.1002/2211-5463.13152 -
The Journal of Investigative Dermatology Jan 2021Phenformin is a drug in the biguanide class that was previously used to treat type 2 diabetes. We have reported the antitumor activities of phenformin to enhance the...
Phenformin is a drug in the biguanide class that was previously used to treat type 2 diabetes. We have reported the antitumor activities of phenformin to enhance the efficacy of BRAF-MAPK kinase-extracellular signal-regulated kinase pathway inhibition and to inhibit myeloid-derived suppressor cells in various melanoma models. Here we demonstrate that phenformin suppresses tumor growth and promotes keratinocyte differentiation in the 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate two-stage skin carcinogenesis mouse model. Moreover, phenformin enhances the suspension-induced differentiation of mouse and human keratinocytes. Mechanistically, phenformin induces the nuclear translocation of NFATc1 in keratinocytes in an AMPK-dependent manner. Pharmacologic or genetic inhibition of calcineurin and NFAT signaling reverses the effects of phenformin on keratinocyte differentiation. Taken together, our study reveals an antitumor activity of phenformin to promote keratinocyte differentiation that warrants future translational efforts to repurpose phenformin for the treatment of cutaneous squamous cell carcinomas.
Topics: Animals; Calcineurin; Cell Differentiation; Humans; Hypoglycemic Agents; Keratinocytes; Melanoma; Mice; Neoplasms, Experimental; Nitrofurans; Phenformin; Signal Transduction; Skin; Skin Neoplasms
PubMed: 32619504
DOI: 10.1016/j.jid.2020.05.114 -
American Journal of Translational... 2023Glucose 6 phosphatase dehydrogenase (G6PD) is a key regulator of the pentose phosphate pathway (PPP). However, the exact role of G6PD in gastrointestinal cancers remains...
BACKGROUND
Glucose 6 phosphatase dehydrogenase (G6PD) is a key regulator of the pentose phosphate pathway (PPP). However, the exact role of G6PD in gastrointestinal cancers remains unclear. The purpose of this study is to explore the correlation of G6PD with clinical features, pathological stages, diagnosis and prognosis of gastrointestinal cancers, as well as uncover possible mechanisms of G6PD on mutations, immunity and signaling pathways.
METHODS
G6PD mRNA expression data were downloaded from TCGA and GEO databases. Protein expression was examined by the HPA database. The correlation of G6PD expression with clinical and pathological characteristics was explored. The pROC package in R language was used to evaluate the diagnostic value of G6PD expression in gastrointestinal cancers. We accessed the correlation of disease-free survival (DFS) with G6PD online by Kaplan-Meier plotter. Univariate Cox regression and stepwise multiple Cox regression analysis were performed to determine the association between G6PD and patient's overall survival. In addition, genomic alterations, mutation profiles, immune infiltration, drug sensitivity and enrichment analysis related with G6PD were visualized.
RESULTS
After a pan-cancerous genomic analysis, we found that G6PD expression was the highest in African American esophageal carcinoma (ESCA) patients (<0.05). G6PD was correlated with age, weight, disease stage, lymph node metastasis and pathological grade. Notably, G6PD showed an excellent predictive diagnosis ability for liver hepatocellular carcinoma (LIHC) (AUC=0.949, 95% CI=0.925-0.973, <0.001). G6PD can improve the DFS of esophageal adenocarcinoma (EAC) and pancreatic adenocarcinoma (PAAD) patients (<0.05). Both Univariate Cox regression and stepwise multiple Cox regression analysis in R language determined that G6PD expression was closely related with LIHC (<0.001). G6PD was found to have a high mutation rate in colon adenocarcinoma and ESCA and gene amplification in ESCA, Cholangiocarcinoma, PAAD and LIHC. Copy number of G6PD was missing in LIHC. G6PD was also related to mutation of TP53 (<0.05). Particularly, it was positively correlated with CD276 in all gastrointestinal cancers and negatively with HERV-H LTR-associating 2 in ESCA and stomach adenocarcinoma. The abnormal expression of G6PD was related to the increase of CD4+ Th2 subsets and the decrease of CD4+ (non-regulatory) of T cells. G6PD was sensitive to FK866, Phenformin, AICAR etc., while resistant to RO-3306, CGP-082996, TGX221 etc. G6PD was found to closely interact with TALDO1, GAPDH and TP53. G6PD related biological processes included aging, nutritional response and daunorubicin metabolism, and related pathways included PPP, cytochrome P450 metabolism of exogenous substances and glutathione metabolism.
CONCLUSION
G6PD is highly expressed in gastrointestinal cancers. It is a carcinogenic indicator related to prognosis and can be used as a potential diagnostic marker of gastrointestinal cancers, so as to provide new strategy for cancer treatment.
PubMed: 37193179
DOI: No ID Found -
The Laryngoscope Jul 2021Iatrogenic laryngotracheal stenosis (iLTS) is the pathological narrowing of the glottis, subglottis, and/or trachea due to scar tissue. Patients with type 2 diabetes...
OBJECTIVES
Iatrogenic laryngotracheal stenosis (iLTS) is the pathological narrowing of the glottis, subglottis, and/or trachea due to scar tissue. Patients with type 2 diabetes mellitus (T2DM) are over 8 times more likely to develop iLTS and represent 26% to 53% of all iLTS patients. In this investigation, we compared iLTS scar-derived fibroblasts in patients with and without T2DM.
STUDY DESIGN
Controlled ex vivo study.
METHODS
iLTS scar fibroblasts were isolated and cultured from subglottic scar biopsies in iLTS patients diagnosed with or without type 2 diabetes (non-T2DM). Fibroblast proliferation, fibrosis-related gene expression, and metabolic utilization of oxidative phosphorylation (OXPHOS) and glycolysis were assessed. Contractility was measured using a collagen-based assay. Metabolically targeted drugs (metformin, phenformin, amobarbital) were tested, and changes in fibrosis-related gene expression, collagen protein, and contractility were evaluated.
RESULTS
Compared to non-T2DM, T2DM iLTS scar fibroblasts had increased α-smooth muscle actin (αSMA) expression (8.2× increased, P = .020), increased contractility (mean 71.4 ± 4.3% vs. 51.7 ± 16% Δ area × 90 minute , P = .016), and reduced proliferation (1.9× reduction at 5 days, P < .01). Collagen 1 (COL1) protein was significantly higher in the T2DM group (mean 2.06 ± 0.19 vs. 0.74 ±.44 COL1/total protein [pg/μg], P = .036). T2DM iLTS scar fibroblasts had increased measures of OXPHOS, including basal respiration (mean 86.7 vs. 31.5 pmol/minute/10 μg protein, P = .016) and adenosine triphosphate (ATP) generation (mean 97.5 vs. 25.7 pmol/minute/10 μg protein, P = .047) compared to non-T2DM fibroblasts. Amobarbital reduced cellular contractility; decreased collagen protein; and decreased expression of αSMA, COL1, and fibronectin. Metformin and phenformin did not significantly affect fibrosis-related gene expression.
CONCLUSION
T2DM iLTS scar fibroblasts demonstrate a myofibroblast phenotype and greater contractility compared to non-T2DM. Their bioenergetic preference for OXPHOS drives their increased contractility, which is selectively targeted by amobarbital.
LEVEL OF EVIDENCE
NA Laryngoscope, 131:1570-1577, 2021.
Topics: Adult; Aged; Amobarbital; Biopsy; Case-Control Studies; Cell Proliferation; Cells, Cultured; Cicatrix; Constriction, Pathologic; Diabetes Mellitus, Type 2; Energy Metabolism; Female; Glottis; Glycolysis; Humans; Hypoglycemic Agents; Iatrogenic Disease; Intubation, Intratracheal; Laryngostenosis; Male; Metformin; Middle Aged; Muscle Contraction; Myofibroblasts; Oxidative Phosphorylation; Phenformin; Primary Cell Culture; Trachea; Tracheal Stenosis; Tracheostomy; Young Adult
PubMed: 32857885
DOI: 10.1002/lary.29026 -
American Journal of Translational... 2021Sorafenib is a first-line drug to treat advanced hepatocellular carcinoma (HCC), which can prolong the median overall survival of patients by approximately 3 months....
Sorafenib is a first-line drug to treat advanced hepatocellular carcinoma (HCC), which can prolong the median overall survival of patients by approximately 3 months. Phenformin is a biguanide derivative that has been shown to exhibit antitumor activity superior to that of metformin. We herein explored the ability of phenformin to enhance the anti-cancer activity of sorafenib against HCC and the mechanisms underlying such synergy. The Hep-G2 and SMMC-7721 HCC cell lines were treated with sorafenib and/or phenformin, after which the proliferation of these cells was evaluated via MTT and colony formation assays, while invasion and apoptotic cell death were evaluated via Transwell and flow cytometry assays, respectively. In addition, protein levels were assessed by Western blotting, drug synergy was assessed with the CompuSyn software, and xenograft models were established by implanting Hep-G2 cells into nude mice and then assessing drug antitumor efficacy. Sorafenib and phenformin exhibited a synergistic ability to suppress HCC cell proliferation, migration, and survival. Phenformin further bolstered the ability of sorafenib to inhibit the CRAF/ERK and PI3K/AKT/mTOR pathways. Strikingly, the combination of these two drugs achieved better efficacy in a murine model system, without causing significant weight loss or hepatorenal toxicity. Sorafenib and phenformin can synergistically suppress CRAF/ERK and PI3K/AKT/mTOR pathway activation in HCC cells, and may thus represent a promising approach to treating this deadly cancer.
PubMed: 34377232
DOI: No ID Found