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Drug Development Research Jun 2020Diabetes mellitus is a serious metabolic disorder affecting millions of people worldwide. Phenformin and metformin are biguanide antidiabetic agents that are... (Comparative Study)
Comparative Study Review
Diabetes mellitus is a serious metabolic disorder affecting millions of people worldwide. Phenformin and metformin are biguanide antidiabetic agents that are conveniently synthesized in a single-step chemical reaction. Phenformin was once used to lower blood glucose levels, but later withdrawn from the market in several countries because it was frequently associated with lactic acidosis. Metformin is still a widely prescribed medication for the treatment of type 2 diabetes despite the introduction of several newer antidiabetic agents. Metformin is administered orally and has desirable pharmacokinetics. Incidence of metformin-induced lactic acidosis is serious but very rare. Imeglimin, a novel molecule being investigated by Poxel and Sumitomo Dainippon Pharma in Japan, is currently in clinical trials for the treatment of type 2 diabetes. Unlike metformin, imeglimin is a cyclic molecule containing a triazine ring. However, like metformin, imeglimin is also a basic small molecule. Imeglimin is synthesized from metformin as a precursor via a single step chemical reaction. Recent mechanism of action studies suggests that imeglimin improves mitochondria function, when given in combination with metformin it helps achieve better glycemic control in patients with type 2 diabetes. We herein describe and compare the current status, synthesis, physicochemical properties, pharmacokinetic parameters, mechanism of action, and preclinical/clinical studies of metformin and imeglimin.
Topics: Acidosis, Lactic; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Phenformin; Triazines
PubMed: 31916629
DOI: 10.1002/ddr.21636 -
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 -
The Journal of Investigative Dermatology Jan 2021The results in the article by Zhou et al. (2020) demonstrate that the antidiabetic drug phenformin inhibits skin tumor growth and promotes keratinocyte differentiation,...
The results in the article by Zhou et al. (2020) demonstrate that the antidiabetic drug phenformin inhibits skin tumor growth and promotes keratinocyte differentiation, and an underlying mechanism is also defined. In this commentary, additional potential mechanisms through which phenformin may exert its antitumorigenic effect are described. Thus, the proposed repurposing of phenformin to treat skin cancer has merit.
Topics: Adenosine Monophosphate; Drug Repositioning; Humans; Hypoglycemic Agents; Neoplasms; Phenformin
PubMed: 33342506
DOI: 10.1016/j.jid.2020.06.008 -
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 -
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 -
Cell Reports Feb 2020The antidiabetic drug phenformin displays potent anticancer activity in different tumors, but its mechanism of action remains elusive. Using Shh medulloblastoma as...
The antidiabetic drug phenformin displays potent anticancer activity in different tumors, but its mechanism of action remains elusive. Using Shh medulloblastoma as model, we show here that at clinically relevant concentrations, phenformin elicits a significant therapeutic effect through a redox-dependent but complex I-independent mechanism. Phenformin inhibits mitochondrial glycerophosphate dehydrogenase (mGPD), a component of the glycerophosphate shuttle, and causes elevations of intracellular NADH content. Inhibition of mGPD mimics phenformin action and promotes an association between corepressor CtBP2 and Gli1, thereby inhibiting Hh transcriptional output and tumor growth. Because ablation of CtBP2 abrogates the therapeutic effect of phenformin in mice, these data illustrate a biguanide-mediated redox/corepressor interplay, which may represent a relevant target for tumor therapy.
Topics: Animals; Antineoplastic Agents; Co-Repressor Proteins; Hedgehog Proteins; Humans; Hypoglycemic Agents; Mice; Neoplasms; Phenformin
PubMed: 32049007
DOI: 10.1016/j.celrep.2020.01.024 -
Journees Annuelles de Diabetologie de... 1967
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The New England Journal of Medicine Oct 1962
Topics: Acidosis; Diabetes Mellitus; Humans; Phenformin
PubMed: 13949484
DOI: 10.1056/NEJM196210182671604 -
Science (New York, N.Y.) Apr 1979
Topics: Humans; Phenformin; United States; United States Food and Drug Administration
PubMed: 432643
DOI: 10.1126/science.432643 -
The Journal of Emergency Medicine 1998Phenformin was removed from the U.S. market 20 years ago because of a high incidence of lactic acidosis. Unfortunately, this medication is still available from foreign... (Review)
Review
Phenformin was removed from the U.S. market 20 years ago because of a high incidence of lactic acidosis. Unfortunately, this medication is still available from foreign sources. Another biguanide, metformin, was reintroduced to the United States market for the treatment of diabetes. Biguanide-induced lactic acidosis should be included in the differential diagnosis of elevated anion gap metabolic acidosis. We present a case of phenformin-induced lactic acidosis in which we were consulted at the local poison control center. We also review its pathophysiology, presentation, and treatment. A review of the actions of phenformin illustrates the mechanism of pathology that may also occur with metformin. Risk factors for the development of lactic acidosis include renal deficiency, hepatic disease, cardiac disease, and drug interaction such as cimetidine.
Topics: Acidosis, Lactic; Aged; Diabetes Mellitus, Type 2; Humans; Incidence; Male; Phenformin; Prognosis; Risk Factors
PubMed: 9848705
DOI: 10.1016/s0736-4679(98)00103-6