F16

F16 is a mitochondrial permeability transition pore (PTP) modulator with an EC₅₀ of 30 μM in mice. F16 promotes PTP opening, accumulates in cancer cell mitochondria, and induces mitochondrial depolarization, swelling, cristae disruption, outer membrane rupture, ATP depletion, reactive oxygen species (ROS) production, cytochrome c release and mitochondrial uncoupling. F16 induces cell cycle arrest at the G1 (occasionally G2) phase, reduces the phosphotyrosine content of Neu, as well as the levels of phosphorylated PKB/Akt and phosphorylated MAP kinase, downregulates the protein expression levels of Neu and PKB, triggers apoptosis in cells with moderate Bcl-2 expression, and induces necrosis in cells with overexpressed Bcl-2. F16 can be used in research related to breast cancer and gastric cancer^[1][2][3]. In Vitro:F16 (100 nM-15 μM; 36-40 h) selectively inhibits proliferation of EpH4-A6 neu-overexpressing mouse mammary epithelial cells, with partial inhibition observed at concentrations as low as 100 nM^[1].
F16 (3 μM; 3-7 days) inhibits proliferation of neu-, v-Ha-ras-, and β-catenin-initiated mouse mammary tumor cell lines and most human breast cancer cell lines^[1].
F16 (3 μM; 36 h-3 days) induces cell cycle arrest (primarily G1 arrest) in EpH4-A6 neu-overexpressing mouse mammary epithelial cells and sensitive mouse and human breast tumor cell lines^[1].
F16 (24 h) induces S phase cell cycle arrest in SGC-7901 cells after 24 h of incubation^[3].
F16 (3 μM; 15-72 h) induces apoptosis in EpH4-A6 neu-overexpressing mouse mammary epithelial cells, characterized by oligonucleosomal DNA fragmentation, Annexin V positivity, and cytochrome c release, but does not induce apoptosis in EpH4-EV control cells^[1].
F16 (0.3-3 μM; 48 h) induces oligonucleosomal DNA fragmentation (apoptosis) in apoptosis-sensitive EpH4-A6 and SMF cells, but not in apoptosis-resistant EpH4, Bcl-2-overexpressing EpH4-A6.C13, EpH4-A6.C18, SMF-Bcl-2, or NF324-1C cells^[2].
F16 (3 μM; 18-36 h) induces cytochrome c release (an apoptotic marker) in apoptosis-sensitive EpH4-A6 cells within 18 h, but not in apoptosis-resistant Bcl-2-overexpressing EpH4-A6.C13 and EpH4-A6.C18 cells, where delayed cytochrome c localization changes are associated with mitochondrial breakdown rather than apoptosis^[2].
F16 (3 μM; 24 h) induces caspase-3 activation (an apoptotic marker) in apoptosis-sensitive EpH4-A6 and SMF cells, but not in apoptosis-resistant Bcl-2-overexpressing EpH4-A6.C13, EpH4-A6.C18, SMF-Bcl-2, or NF324-1C cells^[2].
F16 (Various concentrations; 24 h) induces apoptosis in SGC-7901 cells in a concentration-dependent manner after 24 h of incubation^[3].
F16 (3 μM; 2-24 h) accumulates selectively in mitochondria of sensitive mouse and human mammary tumor/transformed epithelial cell lines, but not in resistant normal or tumor cell lines^[1].
F16 (3 μM; 1 h) accumulation in mitochondria is driven and retained by the mitochondrial transmembrane potential (ΔΨ_m), and lack of accumulation in resistant cell lines is not mediated by MDR-1 or MRP-1 pumps^[1].
F16 (1 μM; 1 h) does not alter accumulation in EpH4-A6 cells due to Bcl-2 overexpression, with F16-sensitive cell lines showing higher mitochondrial accumulation than F16-resistant cell lines^[2].
F16 (3-50 μM; 15-72 h) compromises mitochondrial structure and function in sensitive cells, causing swelling, ATP depletion, superoxide production, permeability transition pore opening, and altered respiration, leading to cytotoxicity^[1].
F16 (3 μM; 24-48 h) downregulates Neu-dependent signaling in EpH4-A6 neu-overexpressing mouse mammary epithelial cells, reducing phosphorylation of Neu, PKB, and MAPK, and decreasing Neu and PKB protein levels^[1].
F16 (3 μM; 24-96 h) induces a time-dependent reduction in cell number in apoptosis-sensitive EpH4-A6 and SMF cells, as well as apoptosis-resistant Bcl-2-overexpressing EpH4-A6.C13, EpH4-A6.C18, SMF-Bcl-2, and NF324-1C cells, with a 3 μM concentration causing up to 32-fold reduction in cell number over 96 h in EpH4-A6 cells^[2].
F16 (3 μM; 24-48 h) induces apoptosis in EpH4-A6 cells and necrosis in Bcl-2-overexpressing EpH4-A6.C13 and EpH4-A6.C18 cells; caspase inhibition reduces F16-induced death in EpH4-A6 cells, while buffering ATP levels and neutralizing superoxide reduces necrotic death in Bcl-2-overexpressing cells^[2].
F16 (3 μM; 48 h) induces apoptotic morphological changes in EpH4-A6 cells and necrotic morphological changes in Bcl-2-overexpressing EpH4-A6.C13 cells after 48 h of incubation^[2].
F16 (3 μM; 15-48 h) induces a time-dependent decrease in cellular ATP levels in both apoptosis-sensitive EpH4-A6 and SMF cells, and apoptosis-resistant Bcl-2-overexpressing EpH4-A6.C13, EpH4-A6.C18, SMF-Bcl-2, and NF324-1C cells, with a 50-60% reduction in ATP levels observed after treatment in SMF-derived and NF324-1C cells^[2].
F16 (48 h) has its cytotoxicity on SGC-7901 cells almost completely reversed by ATP pre-treatment 0.5 h before F16, indicating that decreased intracellular ATP availability is a major factor in F16-mediated cytotoxicity^[3].
F16 (3 μM; 15-72 h) induces a time-dependent increase in superoxide anion levels in apoptosis-sensitive EpH4-A6 cells and apoptosis-resistant Bcl-2-overexpressing EpH4-A6.C13 and EpH4-A6.C18 cells, but not in F16-resistant EpH4-EV cells^[2].
F16 (48 h) potently inhibits proliferation of SGC-7901 and MCF-7 cancer cells with over 10-fold selectivity for SGC-7901 cells over non-tumor GES-1 cells^[3].
F16 (48 h) increases intracellular ROS levels in SGC-7901 cells after 48 h of incubation, with partial reversal by pre-treatment with reductants^[3].
F16 (3 µM; 24 h) selectively accumulates in the mitochondria of SGC-7901 cells after 24 h of incubation at 3 µM^[3].
F16 (48 h) reduces intracellular ATP levels in SGC-7901 cells after 48 h of incubation, with no additional effect at higher concentrations^[3].
F16 (10 µM; higher concentrations) induces dose-dependent structural damage to isolated rat liver mitochondria, including swelling at 10 µM and membrane rupture at higher concentrations^[3].
F16 enhances H⁺ and K⁺ permeabilization of the inner membrane of isolated rat liver mitochondria in a concentration-dependent manner^[3].
F16 immediately increases the membrane fluidity of isolated rat liver mitochondria, as measured by reduced fluorescence anisotropy of HP-labeled mitochondria^[3].
F16 (75 µM) increases state 4 oxygen consumption rate of isolated rat liver mitochondria in a dose-dependent manner, with a 3-fold increase at 75 µM, indicating an uncoupling effect^[3].
F16 (20 µM) increases the metabolic thermogenic output of isolated rat liver mitochondria at 20 µM, consistent with an uncoupling effect on oxidative phosphorylation^[3].
F16 causes a concentration-dependent decrease in mitochondrial membrane potential (ΔΨ_m) in isolated rat liver mitochondria, which is mediated by mitochondrial permeability transition (MPT)^[3].
F16 (1 h) induces concentration-dependent release of cytochrome c from isolated rat liver mitochondria after 1 h of incubation at 4 °C^[3]. In Vivo:F16 (20 mg/kg; i.p.) retards the growth of EpH4-A6-derived subcutaneous breast tumors in nude mice^[1].