Phellodendrine

Phellodendrine is an orally active plant alkaloid. Phellodendrine inhibits the proliferation of KRAS-mutated pancreatic cancer cells by suppressing macropinocytosis and glutamine metabolism, inducing ROS accumulation and mitochondrial apoptosis. Phellodendrine promotes autophagy by activating the AMPK/mTOR pathway, alleviating intestinal damage in ulcerative colitis. Phellodendrine can alleviate gouty arthritis by inhibiting the IL-6/STAT3 signaling pathway. Phellodendrine suppresses allergic reactions by altering the conformation of MRGPRB3/MRGPRX2 protein, thereby inhibiting the activation of PKC and subsequent downstream MAPK and NF-κB signaling. Phellodendrine inhibits the AKT/NF-κB pathway and down-regulates the expression of COX-2, thereby protecting zebrafish embryos from oxidative stress. Phellodendrine has an anti-major depressive disorder (MDD) effect by down-regulating CHRM1, HTR1A, and the PI3K/Akt signaling pathway^{[1][2][3][4][5][6]}. In Vitro:Phellodendrine (0.6-80 μM, 24 h-14 d) significantly inhibits the proliferation and colony formation ability of KRAS-mutated PANC-1 and MiaPaCa-2 cells and its driven macropinocytosis, while showing no obvious toxicity to KRAS wild-type BxPC-3 cells and normal pancreatic cells HPDE6-c7^[1].
Phellodendrine (10-40 μM, 12-24 h) diminishes the albumin (Alb) driven intracellular glutamine level, induces reactive oxygen species generation and causes mitochondrial membrane potential (MMP) depolarization in PANC-1 cells^[1].
Phellodendrine (5-40 μM, 0-48 h) induces apoptosis cell death in PANC-1 cells through caspase-dependent mitochondrial intrinsic pathway^[1].
Phellodendrine (5-20 μM) activates the p-AMPK/mTOR signalling pathway, as well as autophagy in Caco-2 cells stimulated by H₂O₂^[2].
Phellodendrine (5 μM) attenuates Monosodium urate (MSU) (HY-B2130A)-induced MMP3 production and proteoglycan degradation by inhibiting IL-6/STAT3 pathway in rabbit primary chondrocytes and C28/I2 cells (human normal chondrocytes)^[3].
Phellodendrine (0-50 μM) reduces the mRNA expression of MRGPRB3 and responsiveness of MRGPRX2 by altering its structure, is able to decrease Ca²⁺ levels, phosphorylation levels of CaMK, PLCβ1, PKC, ERK, JNK, p38, and p65, and inhibits the degradation of IκB-α in RBL-2H3 cells^[4].
Phellodendrine (25-200 μg/mL, 37 h) increases the survival rate of zebrafish embryos and restores the abnormal heart rate levels^[5].
Phellodendrine (50-200 μg/mL, 13 h) reduces the ROS level in zebrafish embryos and inhibits lipid peroxidation^[5].
Phellodendrine (100 μg/mL) reverses the expression of AKT and NF-κB3, IKK, COX-2 which were abnormally changed by AAPH (HY-Y0525)-induced oxidative stress in zebrafish embryos^[5].
Phellodendrine (2.5-160 μg/mL, 24-48 h) has an anti-MDD effect by regulating the mRNA levels of CHRM1, HTR1A and key targets of the PI3K/Akt signalling pathway (PI3K, Akt, mTOR) in PC12 cells^[6].
In Vivo:Phellodendrine (30-60 mg/kg, i.p., once daily for 2 weeks) inhibits macropinocytosis in mice and effectively reduces the growth of PANC-1 xenograft tumors^[1].
Phellodendrine (30 mg/kg, p.o., once daily for 7 days) reduces the intestinal damage of ulcerative colitis (UC) in mice^[2].
Phellodendrine (40 mg/kg, i.p., mice single dose or rats once daily for 5 days) alleviated Uric acid sodium (MSU) (HY-B2130A)-induced acute peritonitis in mice and arthritis in rats^[3].
Phellodendrine (0.3-3 mg/kg, i.v.) protects against C48/80 (HY-130592)-induced foot swelling and Evans blue exudation in mice, and suppresses C48/80-induced RBL-2H3 rat basophilic leukemia cells degranulation, and β-HEX, HIS, IL-4, and TNF-α release^[4].