-
Proceedings of the National Academy of... Mar 2022SignificanceMetformin is the most commonly prescribed drug for the treatment of type 2 diabetes mellitus, yet the mechanism by which it lowers plasma glucose...
SignificanceMetformin is the most commonly prescribed drug for the treatment of type 2 diabetes mellitus, yet the mechanism by which it lowers plasma glucose concentrations has remained elusive. Most studies to date have attributed metformin's glucose-lowering effects to inhibition of complex I activity. Contrary to this hypothesis, we show that inhibition of complex I activity in vitro and in vivo does not reduce plasma glucose concentrations or inhibit hepatic gluconeogenesis. We go on to show that metformin, and the related guanides/biguanides, phenformin and galegine, inhibit complex IV activity at clinically relevant concentrations, which, in turn, results in inhibition of glycerol-3-phosphate dehydrogenase activity, increased cytosolic redox, and selective inhibition of glycerol-derived hepatic gluconeogenesis both in vitro and in vivo.
Topics: Animals; Electron Transport Complex IV; Gluconeogenesis; Glucose; Glycerol; Glycerolphosphate Dehydrogenase; Guanidines; Hypoglycemic Agents; Liver; Metformin; Oxidation-Reduction; Phenformin; Pyridines
PubMed: 35238637
DOI: 10.1073/pnas.2122287119 -
Cancer Research Communications Dec 2023Preclinical studies show that activation of AMP kinase by phenformin can augment the cytotoxic effect and RAF inhibitors in BRAF V600-mutated melanoma. We conducted a...
PURPOSE
Preclinical studies show that activation of AMP kinase by phenformin can augment the cytotoxic effect and RAF inhibitors in BRAF V600-mutated melanoma. We conducted a phase Ib dose-escalation trial of phenformin with standard dose dabrafenib/trametinib in patients with metastatic BRAF V600-mutated melanoma.
EXPERIMENTAL DESIGN
We used a 3+3 dose-escalation design which explored phenformin doses between 50 and 200 mg twice daily. Patients also received standard dose dabrafenib/trametinib. We measured phenformin pharmacokinetics and assessed the effect of treatment on circulating myeloid-derived suppressor cells (MDSC).
RESULTS
A total of 18 patients were treated at dose levels ranging from 50 to 200 mg twice daily. The planned dose-escalation phase had to be cancelled because of the COVID 19 pandemic. The most common toxicities were nausea/vomiting; there were two cases of reversible lactic acidosis. Responses were seen in 10 of 18 patients overall (56%) and in 2 of 8 patients who had received prior therapy with RAF inhibitor. Pharmacokinetic data confirmed drug bioavailability. MDSCs were measured in 7 patients treated at the highest dose levels and showed MDSC levels declined on study drug in 6 of 7 patients.
CONCLUSIONS
We identified the recommended phase II dose of phenformin as 50 mg twice daily when administered with dabrafenib/trametinib, although some patients will require short drug holidays. We observed a decrease in MDSCs, as predicted by preclinical studies, and may enhance immune recognition of melanoma cells.
SIGNIFICANCE
This is the first trial using phenformin in combination with RAF/MEK inhibition in patients with BRAF V600-mutated melanoma. This is a novel strategy, based on preclinical data, to increase pAMPK while blocking the MAPK pathway in melanoma. Our data provide justification and a recommended dose for a phase II trial.
Topics: Humans; Melanoma; Skin Neoplasms; Phenformin; Proto-Oncogene Proteins B-raf
PubMed: 37930123
DOI: 10.1158/2767-9764.CRC-23-0296 -
Seminars in Nephrology May 2023The good old days were not good, at least in terms of treating patients with type 2 diabetes. In the 1960s, the development of a radioimmunoassay for insulin permitted... (Review)
Review
The good old days were not good, at least in terms of treating patients with type 2 diabetes. In the 1960s, the development of a radioimmunoassay for insulin permitted determination of the distinguishing features of type 1 and type 2 diabetes. The latter was treated with sulfonylureas and then phenformin, although the mechanisms of action at the time were unknown. The University Group Diabetes Program was a randomized controlled trial experienced by my medical generation, and the results were dramatic, both medically and legally. Next came the thiazolidinediones. All compounds were associated with weight gain and any end point benefits were uncertain. Nevertheless, basic science explained how glucose is sensed and even found a home for sulfonylureas in some patients. Next came the boom in renin-angiotensin-aldosterone system blockade, sacred ground for many, albeit the benefits were less than astounding. Other wonder drugs came and went. Over the decades, great strides were made in defining the pathology of diabetic renal disease, which is appropriate because the condition has become a primary cause of end-stage renal failure. Nonetheless, recent advances have turned around a depressing situation and are reasons for optimism. We now have compounds that actually could help patients with type 2 diabetes. One hundred years after insulin's introduction, it is high time.
Topics: Humans; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Renin-Angiotensin System; Kidney Failure, Chronic; Insulins; Randomized Controlled Trials as Topic
PubMed: 37862743
DOI: 10.1016/j.semnephrol.2023.151426 -
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 -
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 -
Advanced Biology Jul 2023Lung cancer is one of the most fatal cancers worldwide. Resistance to conventional therapies remains a hindrance to patient treatment. Therefore, the development of more...
Lung cancer is one of the most fatal cancers worldwide. Resistance to conventional therapies remains a hindrance to patient treatment. Therefore, the development of more effective anti-cancer therapeutic strategies is imperative. Solid tumors exhibit a hyperglycolytic phenotype, leading to enhanced lactate production; and, consequently, its extrusion to the tumor microenvironment. Previous data reveals that inhibition of CD147, the chaperone of lactate transporters (MCTs), decreases lactate export in lung cancer cells and sensitizes them to phenformin, leading to a drastic decrease in cell growth. In this study, the development of anti-CD147 targeted liposomes (LUVs) carrying phenformin is envisioned, and their efficacy is evaluated to eliminate lung cancer cells. Herein, the therapeutic effect of free phenformin and anti-CD147 antibody, as well as the efficacy of anti-CD147 LUVs carrying phenformin on A549, H292, and PC-9 cell growth, metabolism, and invasion, are evaluated. Data reveals that phenformin decreases 2D and 3D-cancer cell growth and that the anti-CD147 antibody reduces cell invasion. Importantly, anti-CD147 LUVs carrying phenformin are internalized by cancer cells and impaired lung cancer cell growth in vitro and in vivo. Overall, these results provide evidence for the effectiveness of anti-CD147 LUVs carrying phenformin in compromising lung cancer cell aggressiveness.
Topics: Humans; Phenformin; Lung Neoplasms; Cell Proliferation; Lactates; Tumor Microenvironment
PubMed: 37303292
DOI: 10.1002/adbi.202300080 -
Investigational New Drugs Jun 2022Myeloproliferative neoplasms (MPN) are disorders characterized by an alteration at the hematopoietic stem cell (HSC) level, where the JAK2 mutation is the most common...
BACKGROUND
Myeloproliferative neoplasms (MPN) are disorders characterized by an alteration at the hematopoietic stem cell (HSC) level, where the JAK2 mutation is the most common genetic alteration found in classic MPN (polycythemia vera, essential thrombocythemia, and primary myelofibrosis). We and others previously demonstrated that metformin reduced splenomegaly and platelets counts in peripheral blood in JAK2 pre-clinical MPN models, which highlighted the antineoplastic potential of biguanides for MPN treatment. Phenformin is a biguanide that has been used to treat diabetes, but was withdrawn due to its potential to cause lactic acidosis in patients.
AIMS
We herein aimed to investigate the effects of phenformin in MPN disease burden and stem cell function in Jak2-knockin MPN mice.
RESULTS
In vitro phenformin treatment reduced cell viability and increased apoptosis in SET2 JAK2 cells. Long-term treatment with 40 mg/kg phenformin in Jak2 knockin mice increased the frequency of LSK, myeloid progenitors (MP), and multipotent progenitors (MPP) in the bone marrow. Phenformin treatment did not affect peripheral blood counts, spleen weight, megakaryocyte count, erythroid precursors frequency, or ex vivo clonogenic capacity. Ex vivo treatment of bone marrow cells from Jak2 knockin mice with phenformin did not affect hematologic parameters or engraftment in recipient mice.
CONCLUSIONS
Phenformin increased the percentages of LSK, MP, and MPP populations, but did not reduce disease burden in Jak2-knockin mice. Additional studies are necessary to further understand the effects of phenformin on early hematopoietic progenitors.
Topics: Animals; Bone Marrow; Disease Models, Animal; Humans; Janus Kinase 2; Mice; Mutation; Myeloproliferative Disorders; Phenformin; Polycythemia Vera
PubMed: 35015172
DOI: 10.1007/s10637-022-01212-y -
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