Chelerythrine Chloride (NSC 646662)

Chelerythrine interacts with the catalytic domain of PKC, is a competitive inhibitor with respect to the phosphate acceptor (histone IIIS) with Ki value of 0.7 μM and a non-competitive inhibitor with respect to ATP. Chelerythrine shows potent cytotoxic effects against L-1210 cells with IC50 of 0.53 μM. Chelerythrine does not alter any activity of PKA, TPK and Ca/CM-PK, and the Chelerythrine inhibitory effect on PKC activity does not vary among the various substrates including GS, MLC, MBP and Fibrinogen. ^[1] Chelerythrine inhibits PKC activity in crude cell extracts from SQ-20B cells in a dose dependent manner. Chelerythrine decreases cell viability as determined by the MTT assay in a dose-dependent manner in SCC35, JSQ3, SQ20B and SCC61 cells. ^[2] Chelerythrine chloride (5 μM) suppresses VEGF-induced expression of ICAM-1, VCAM-1, and E-selectin in HUVECs. Chelerythrine chloride (5 μM) suppresses VEGF-induced NF-κB activity in HUVECs. Chelerythrine chloride (5 μM) all suppresses basal and VEGF-induced leukocyte adhesiveness in HUVECs. ^[3] Chelerythrine (6 mM-30 mM) rapidly induces pyknosis, shrinkage and subsequent cell death in cardiac myocytes. Chelerythrine(30 μM)-induced myocyte death is accompanied by nuclear fragmentation and activation of caspase-3 and -9 in primary culture of neonatal rat ventricular myocytes. Chelerythrine (10 μM) causes cytochrome c release from mitochondria, suggesting that ROS mediates chelerythrine-induced cytochrome c release in cardiac myocytes. ^[4] Chelerythrine displaces the fluorescently labeled BH3 domain peptide from a recombinant GST-BcLXL fusion protein with IC50 of 1.5 μM. Chelerythrine at 2.5 μM and 5 μM for 16 hours induces a substantial decrease in mitochondrial potential as indicated by an increase in JC-1 green fluorescence in human neuroblastoma SH-SY5Y cells. Chelerythrine (5 μM) also induces the appearance of sub-G1 DNA that is indicative of apoptosis in SH-SY5Y cells. Chelerythrine (10 μM) induces mitochondrial potential change, CytC release from the mitochondria in SH-SY5Y cells. ^[5]

The lymphocytic mouse leukemia L1210 cells are plated sparsely at 1×10⁴ cells per well in 24-well cluster plates in RPMI 1640 medium containing 10% foetal calf serum, 4 mM glutamine, 100 U/mL penicillin, 100 pg/mL streptomycin sulphate and Chelerythrine to be tested (solubilized in dimethylsulphoxyde ). After a 2 day incubation period at 37 ℃ in a humidified atmosphere (5% CO₂ in air), growth is monitored by counting cell numbers in a coulter-counter. IC50 values are calculated on the basis of the linear regression lines established for Chelerythrine tested.

Chelerythrine (5 mg/kg i.p.) results in tumor growth delay in mice bearing SQ-20B xenografts. ^[2] Chelerythrine (5 mg/kg) treatment significantly increases TUNEL-positive nuclei in the myocardium as well as cleaved forms of caspase-3 and -9 in adult rat. ^[4]