[Research on anticancer activity of isocorydine and its derivatives].

Isocorydine and its analogs were extracted from Dicranostigma leptopodum and Stephania yunnanensis through the method of natural products chemistry. Its derivatives were prepared by chemical structure modifications from isocorydine. MTT method was used to study the inhibitory effect of those compounds on the growth of HepG2, HeLa and MGC-803 cancer cell lines in vitro. The results showed that isocorydine and its analogs all have the growth inhibition for those cancer cell lines. This paper investigated the structure-activity relationship of isocorydine and its derivatives with anticancer activity in the aspect of stereochemical structure, functional groups positions of the compounds and the electron density of aromatic rings based on the single crystal diffraction structure and the molecular docking of EGFR and isocorydine.

Design, synthesis, and biological evaluation of novel spin-labeled derivatives of podophyllotoxin as potential antineoplastic agents. Part XII.

Five novel nitroxyl spin-labeled ester derivatives of podophyllotoxin (11a-11e) have been prepared and their structural information on these nitroxyl spin-labeled ester derivatives of podophyllotoxin (11a-11e) using (1)HNMR spectroscopy was efficiently obtained by application of the in situ reduction of representative nitroxyl spin-labeled ester derivative of podophyllotoxin 11e with phenylhydrazine for the preparation of N-hydroxylamine 12 in the NMR tube. These novel derivatives were further evaluated for their in vitro cytotoxic activity against five neoplastic cell lines (K562, HL-60, SPCA-1, Lewis, and L-1210) using MTT assay. Most of the target compounds (except for all these compounds against SPCA-1) exhibited more pronounced cytotoxicity against several neoplastic cell lines than that of the prototypical inhibitor etoposide.

Proanthocyanidin from grape seeds enhances doxorubicin-induced antitumor effect and reverses drug resistance in doxorubicin-resistant K562/DOX cells.

With the aim of enhancing the efficacy of chemotherapeutic agents, we investigated the antitumor actions and reversal effect on drug resistance of proanthocyanidin plus doxorubicin. The results showed that proanthocyanidin 12.5-200 mg/L significantly inhibited proliferation of K562, K562/DOX, SPC-A-1, and Lewis cells in vitro in a time- and concentration-dependent manner, as determined by microculture tetrazolium assay. A combination of proanthocyani din 12.5, or 25 mg/L and doxorubicin treatment synergistically inhibited cell proliferation with decreased IC50 values. Proanthocyanidin reverses drug resistance in doxorubicin-resistant K562/DOX cells, and IC50 values were decreased by 9.19 (3.64-23.19), 2.56 (1.48-.44), and 0.94 (0.81-1.09) mg/L, respectively, after 24 h treatment with doxorubicin 0.1-9.0 mg/L alone or in combination with proanthocyanidin 12.5 or 25 mg/L; the proanthocyanidin reversal fold was 3.6 and 9.8, respectively. Under confocal laser scanning microscope, the combination of proanthocyanidin 25 or 50 mg/L with doxorubicin 3 mg/L significantly increased the accumulation of intracellular doxorubicin, Ca2+, and Mg2+, and reduced the pH value and mitochondrial membrane potential in K562/DOX cells as compared with doxorubicin alone (p < 0.01). Additionally, the apoptosis rate was increased by 11.3% +/- 3.3%, 14.2% +/- 5.4%, and 23.8% +/- 2.8%, respectively, for doxorubicin 3 mg/L alone or with proanthocyanidin 12.5 or 25 mg/L, as compared with controls (3.0% +/- 1.4%), as demonstrated by flow cytometry. In vivo experiments demonstrated that i.p. administration of proanthocyanidin 10 mg/kg with doxorubicin 2 mg/kg had an inhibitory effect on the growth of transplantation tumor sarcoma 180 and hepatoma 22 in mice as compared with doxorubicin alone (p < 0.05). These results suggest that proanthocyanidin enhances doxorubicin-induced antitumor effect and reverses drug resistance, and its mechanism is attributed partially to the promotion of doxorubicin-induced apoptosis through an elevation of intracellular doxorubicin, and Ca2+, Mg2+ concentration, and a reduction of pH value and mitochondrial membrane potential.

Antioxidative activity of spin labeled derivatives of podophyllic acid hydrazide.

AIM: To study the relationship between structure and antioxidation activity of spin labeled derivatives of podophyllic acid hydrazide (GP) in tissues and red blood cells (RBC) from rats. METHODS: The homogenate of liver, heart, and kidneys of rats was used to measure malondialdehyde (MDA) spontaneous generated and induced by hydroxyl free radical generation system (Fe2+-ascorbic acid, FRGS) or doxorubicin (DOX) by TBA colorimetric method. H2O2-caused hemolysis was determined spectrophotometrically. Superoxide anion from zymosan-stimulated neutrophils of rats was evaluated by NBT-reduction assay. RESULTS: GP1 and GP1OH obviously inhibited MDA formation either spontaneously or induced by FRGS and DOX and antagonized hemolysis induced by H2O2, but GP and GP1H showed less potent activity. GP1 also inhibited the formation of superoxide anion from activated neutrophils of rats. CONCLUSION: Introduction of nitroxyl radical moieties into GP generated potent derivatives with antioxidative activity. The essential antioxidation active groups of spin labeled derivative of GP are NO or NOH group in nitroxyl radical moieties.

Anti-inflammatory effect of recombinant human superoxide dismutase in rats and mice and its mechanism.

AIM: To investigate the anti-inflammatory effects and mechanism of recombinant human superoxide dismutase (rhSOD). METHODS: Inflammation models such as croton oil-induced ear swelling and carrageenan-induced hind paw edema in mice and rats were prepared. The nitric oxide synthase (NOS ) activity was measured by NADPH-diaphoras stain assay, N-acetyl-beta-D-glucosaminidase (beta-NAG) activity by spectrophotography, malondialdehyde (MDA) content by thiobarbituric acid (TBA) fluorescence technique, and interleukin-1beta (IL -1beta), tumor necrosis factor alpha (TNF alpha), and IL-8 content by radioimmunoassay (RIA). RESULTS: rhSOD 20-80 mg/kg ip, 40-80 mg/kg im, and 80 mg/kg ip significantly inhibited carrageenan-induced paw edema in rats, croton oil-induced ear swelling in mice, and carrageenan-induced hind paw edema in mice, respectively. In the rat arthritis induced by carrageenan, rhSOD 40 mg/kg reduced MDA content in inflamed paws, inhibited NOS activity, and lowered the content of IL-1beta and TNFalpha in exudate significantly. The inhibitory effect of rhSOD 40 mg/kg ip on IL-1beta production was more evident than that of dexamethasone 2 mg/kg ip. Also rhSOD obviously inhibited neutrophil infiltration; However, rhSOD had no effect on beta-NAG activity in exudate. CONCLUSION: rhSOD has anti-inflammatory effect on experimental inflammation in rats and mice, and its mechanisms are relevant to oxygen free radical scavenging, anti-lipid peroxidation, inhibition of neutrophil infiltration, and formation of inflammatory cytokines.