Phenformin

Phenformin (Phenethylbiguanide) is an orally active biguanide hypoglycemic agent. Phenformin inhibits mitochondrial respiratory chain complex I, leading to an increased AMP/ATP ratio, activation of AMPK, and subsequent inhibition of the mTOR pathway, thereby suppressing cell proliferation, inducing apoptosis and autophagy. Phenformin inhibits cancer stem cells (CSCs) and possesses potent antitumor potential. In Vitro:Phenformin induces cell death in HPV⁺ head and neck cancer cells, with an EC₅₀ that is 840-fold lower than that of metformin^[1].
Phenformin induces G0/G1 cell cycle arrest, reduces the proportion of S-phase cells in a dose-dependent manner, inhibits CDK4 and D-glycine in SKOV3, IGROV-1 and Hey ovarian cancer cell lines, and activates p21 protein in the above-mentioned cell lines^[1].
Phenformin significantly reduces the viability, proliferation and invasion ability of melanoma cells by inducing apoptosis, and decreases the expression of cancer stem cell (CSC)-specific markers in both 2D and 3D spheroid models^[1].
Phenformin inhibits the self-renewal of glioblastoma stem cells and induces their cell death, and these stem cells are more sensitive to Phenformin than glioma cells^[1].
Phenformin and SCH772984 synergistically inhibit proliferation, synergistically induce apoptosis, and completely suppress the mTOR signaling pathway in NF1-mutant melanoma cells^[1].
Phenformin (0.5-5 mM; 24-72 h) reduces the viability and promotes apoptosis of SET2 JAK2^V617F cells, with corresponding IC₅₀ values of 2 mM, 1.79 mM, and 0.79 mM at 24 h, 48 h, and 72 h, respectively^[2].
Phenformin (2 mM; 12-48 h) inhibits the proliferation of human cholangiocarcinoma cell lines RBE and Huh28 in a time-dependent manner, with significant effects observed at 12, 24, and 48 h^[3].
Phenformin (2 mM; 10 d) inhibits the colony-forming ability of human cholangiocarcinoma cell lines RBE and Huh28^[3].
Phenformin (2 mM; 24 h) induces apoptosis in human cholangiocarcinoma cell lines RBE and Huh28^[3].
Phenformin (2 mM; 24 h) upregulates the mRNA expression of autophagy-related genes (BECN1, ATG5, ATG7) in human cholangiocarcinoma cell lines RBE and Huh28^[3].
Compared to cells transfected with negative control siRNA, Phenformin (2 mM; 12-48 h) reduces the viability of LKB1-knockdown RBE and Huh28 human cholangiocarcinoma cell lines to a greater extent at 12, 24, and 48 h^[3].
Phenformin (2 mM; 24 h) upregulates autophagy-related genes (BECN1, ATG5, ATG7) in human cholangiocarcinoma cell lines RBE and Huh28, and this effect is reversed by LKB1 knockdown^[3]. In Vivo:Phenformin (40 mg/kg; i.p.; daily; 45 days) increases the percentages of LSK, myeloid progenitor, and multipotent progenitor populations but does not reduce disease burden in Jak2^V617F-knockin MPN mice^[2].
Phenformin (2 mM; intratumoral injection; every 4 days; 30 days) significantly inhibits RBE tumor volume in a subcutaneous cholangiocarcinoma xenograft mouse model^[3].