Inhibitory effect of liriopesides B in combination with gemcitabine on human pancreatic cancer cells.

Gemcitabine (GEM) is a standard chemotherapeutic agent for patients with pancreatic cancer; however, GEM-based chemotherapy has a high rate of toxicity. A combination of GEM and active constituents from natural products may enhance its therapeutic efficacy and reduce its toxicity. This study investigated the synergistic effects of the combination of liriopesides B (LirB) from Liriope spicata var. prolifera and GEM on human pancreatic cancer cells. The results of our study showed that the combination of LirB and GEM synergistically decreased the viability of pancreatic cancer cells. The combination also caused a strong increase in apoptosis and a strong decrease in cell migration and invasion. Furthermore, LirB combined with GEM had potent inhibitory effects on pancreatic cancer stem cells (CSCs). Studies on the mechanisms of action showed that the combination more potently inhibited protein kinase B (Akt) and nuclear factor kappa B (NF-κB), as well as the downstream antiapoptotic molecules B-cell lymphoma 2 (Bcl-2) and survivin than either agent used alone. The results of this study suggest that the combination of LirB with GEM may improve the efficacy of GEM for the treatment of pancreatic cancer.

Controllable antibacterial and bacterially anti-adhesive surface fabricated by a bio-inspired beetle-like macromolecule.

Drug resistance to bacteria becomes an emerging intractable problem, therefore, developing novel antibacterial agents has become urgently needed. Herein, a bio-inspired design strategy was adopted to synthesize a series of beetle-like macromolecule of multiple quaternary ammonium salts (QASs), which was designed with different cationic charge densities and numbers of hexadecane chains by adjusting their different quaternization degree (QD). It was found that the fabricated fabric surface with them exhibited controllable and outstanding antibacterial and bacterially anti-adhesive properties. More importantly, the antibacterial efficiency was demonstrated to be enhanced with the increasing of QD, and related to the zeta potential, and surface tension. Additionally, the proposed bacterially anti-adhesive model of action revealed the "resisting effect" of hydration layer which greatly resisted the adhesion of bacteria.

Metal-free synthesis of imidazo[1,5-a]pyridines via elemental sulfur mediated sequential dual oxidative Csp3-H amination.

A simple and efficient approach has been developed for the synthesis of imidazo[1,5-a]pyridines using the elemental sulfur mediated sequential dual oxidative Csp3-H amination of 2-pyridyl acetates and amines under metal- and peroxide-free conditions. Broad substrate scope, operational simplicity and gram-scale ability make this chemistry very practical.

The formation of zein-chitosan complex coacervated particles: Relationship to encapsulation and controlled release properties.

The complex coacervation between zein and chitosan (CS) as well as the relationship with the controlled release properties of their complex nanoparticles were studied. The factors influencing the nanoparticle formation between zein and CS, including solid to liquid ratio, zein to CS ratio and pH, were systematically investigated. The isothermal titration calorimetry (ITC) showed that zein-CS interaction was spontaneous exothermic process. The pH the higher was, the stronger the interaction between zein and CS. The mean particle sizes of ZCNPs were increased by enhanced turbidity between zein and CS (from 90.89 nm to 1368.77 nm). The morphology study showed that spherical particles and coacervate were obtained with the increased interaction between zein and CS. The release profiles of curcumin in vitro indicated that slight burst effect followed by slow release was observed after interacting CS. The ZCNPs at pH 4.0 exhibited smaller particle size (162.07 nm), more stable ζ-potential (49.7 mV), higher encapsulation efficiency (94.67%) and slower release rate. In conclusion, the stronger the interaction was, the lower the curcumin released from the nanoparticles in vitro, and the ZCNPs at pH 4.0 had better potential in oral delivery application.

Synthesis and evaluation of curcumin-related compounds containing inden-2-one for their effects on human cancer cells.

Indanones are very useful molecules as starting building blocks for the synthesis of biologically active compounds. A series of novel curcumin-related compounds containing indan-2-one were synthesized and screened for anticancer activities. The structures were confirmed by spectral data (IR, NMR, and Mass). Inhibitory effects of these compounds on the growth of prostate cancer PC-3 cells, pancreatic cancer BxPC-3 cells, colon cancer HT-29 cells, lung cancer H1299 cells and non-tumorigenic human prostate epithelial RWPE-1 cells were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The IC50 for compound IND-4 was lower than 1 µM in the four cancer cell lines. The present study indicates that IND-4 may have useful effects on human cancer cells.

Curcumin analogues with high activity for inhibiting human prostate cancer cell growth and androgen receptor activation.

The androgen receptor (AR) has a critical role in prostate cancer development and progression. Several curcumin analogues (A10, B10, C10, E10 and F10) with different linker groups were investigated for their effects in human prostate cancer CWR­22Rv1 and LNCaP cell lines. The ability of these compounds to inhibit testosterone (TT)­ or dihydrotestosterone (DHT)­induced AR activity was determined by an AR­linked luciferase assay and by TT­ or DHT­induced expression of prostate specific antigen. Compounds F10 and E10 had stronger inhibitory effects on the growth of cultured CWR­22Rv1 and LNCaP cell lines, and they also had enhanced stimulatory effects on apoptosis compared with curcumin and other curcumin analogues (A10, B10, C10) in CWR­22Rv1 cells. E10 and F10 were more potent inhibitors of AR activity than curcumin, A10 and B10. The higher activities of E10 and F10 may be correlated with a heteroatom linker. The results indicate that one of the potential mechanisms for the anticancer effect of the curcumin analogues was inhibition of AR pathways in human prostate cancer cells.

Effects of curcumin analogues for inhibiting human prostate cancer cells and the growth of human PC-3 prostate xenografts in immunodeficient mice.

Four curcumin analogues ((2E,6E)-2,6-bis(thiophen-3-methylene) cyclohexanone (AS), (2E,5E)-2,5-bis(thiophen-3-methylene) cyclopentanone (BS), (3E,5E)-3,5-bis(thiophen-3-methylene)-tetrahydropyran-4-one (ES) and (3E,5E)-3,5-bis(thiophen-3-methylene)-tetrahydrothiopyran-4-one (FS) as shown in Fig. 1) with different linker groups were investigated for their effects in human prostate cancer CWR-22Rv1 and PC-3 cells. Compounds FS and ES had stronger inhibitory effects than curcumin, AS and BS on the growth of cultured CWR-22Rv1 and PC-3 cells, as well as on the androgen receptor (AR) and nuclear factor kappa B (NF-κB) activity. The strong activities of ES and FS may be correlated with a heteroatom linker. In animal studies, severe combined immunodeficient (SCID) mice were injected subcutaneously (s.c.) with PC-3 cells in Matrigel. After 4 to 6 weeks, mice with PC-3 tumors (about 0.6 cm wide and 0.6 cm long) received daily intraperitoneal (i.p.) injections of vehicle, ES and FS (10 µg/g body weight) for 31 d. FS had a potent effect in inhibiting the growth and progression of PC-3 tumors. Our results indicate that FS may be useful for inhibiting human prostate tumors growth.

A triple combination of atorvastatin, celecoxib and tipifarnib strongly inhibits pancreatic cancer cells and xenograft pancreatic tumors.

Because K-Ras mutation and cyclooxygenase-2 (COX-2) overexpression are hallmarks of majority of pancreatic cancer patients, an approach to inhibit the progression and growth of pancreatic cancer using the simultaneous administration of agents that inhibit the function of both targets, should be considered. In the present study, we assessed the effects of atorvastatin (Lipitor), celecoxib (Celebrex) and tipifarnib (Zarnestra) on the growth of human pancreatic cancer. In the in vitro studies, we found that treatment of human pancreatic tumor cells with a combination of atorvastatin, celecoxib and tipifarnib had a stronger inhibitory effect on growth and a stronger stimulatory effect on apoptosis than each drug alone or for any combination of two drugs. We also found that treatment of Panc-1 cells with a combination of all three drugs strongly decreased the levels of phosphorylated Erk1/2 and Akt. In an animal model of xenograft tumors in severe combined immunodeficient (SCID) mice, we found that daily i.p. injections of a combination of atorvastatin, celecoxib and tipifarnib had a stronger inhibitory effect on the growth of the tumors in mice than each drug alone or for any combination of two drugs. The results of our study indicate that a combination of atorvastatin, celecoxib and tipifarnib may be an effective strategy for the treatment of pancreatic cancer.

Anti-proliferative, anti-inflammatory and antioxidant effects of curcumin analogue A2.

In the present study, we determined the anti-proliferative, anti-inflammatory and antioxidant effects of a curcumin analogue, 2,6-bis(3,4-dihydroxybenzylidene) cyclohexanone (designated as A2). In vitro studies showed that A2 had a stronger inhibitory effect on the growth of mouse macrophage RAW 264.7 cells than curcumin. A2 also showed a stronger inhibitory effect than curcumin on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced increases in NF-κB activation and IL-1ß expression as well as in aldose reductase activity. A2 was a stronger antioxidant than curcumin as determined by inhibition of lipid peroxidation, inhibition of 1,1-diphenyl-2-picryl-hydrazyl free radical formation, and inhibition of 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) radical formation. In vivo studies indicated that A2 was more potent than curcumin for inhibiting TPA-induced ear edema and TPA-induced increases in IL-1ß. In addition, oral administration of A2 at a dose of 2,000 mg/kg body weight did not cause acute toxicity in mice. Taken together, the results of our study indicate that the curcumin analogue A2 has stronger anti-proliferative, anti-inflammatory and antioxidant activities than curcumin.

Effects of pyridine analogs of curcumin on growth, apoptosis and NF-κB activity in prostate cancer PC-3 cells.

Twelve pyridine analogs of curcumin were studied for their effects on growth and apoptosis in human prostate cancer PC-3 cells. The ability of these compounds to inhibit the transcriptional activity of nuclear factor-kappa B (NF-κB) and the level of phosphorylated extracellular signal-regulated kinases (phospho-ERK1/2) in PC-3 cells was also determined. Treatment of PC-3 cells with the pyridine analogs of curcumin resulted in concentration-dependent growth inhibition and apoptosis stimulation. Only pyridine analogs of curcumin with a tetrahydrothiopyrane-4-one linker (FN compounds) exhibited a strong inhibitory effect on growth and a strong stimulatory effect on apoptosis at low concentrations (≤ 1 µM). Mechanistic studies showed that NF-κB transcriptional activity in PC-3 cells was strongly inhibited by treatment with group FN compounds. Treatment of PC-3 cells with 1 µM FN1 resulted in a decrease of activated ERK1/2. Results from the present study indicate that FN compounds warrant further in vivo studies using suitable animal models of prostate cancer.

Effects of cyclohexanone analogues of curcumin on growth, apoptosis and NF-κB activity in PC-3 human prostate cancer cells.

Curcumin is a non-nutritive yellow pigment found in the spice turmeric, which is derived from the rhizome of the plant Curcuma longa Linn. Six cyclohexanone analogues of curcumin (A(1)-A(6)) were investigated for their effects on growth and apoptosis in PC-3 human prostate cancer cells. The ability of these compounds to inhibit NF-κB activity in PC-3 cells was also determined. Five out of the six curcumin analogues (A(2)-A(6)) had stronger inhibitory effects compared to curcumin on the growth of cultured PC-3 cells. Compounds A(2)-A(6) also had stronger stimulatory effects on apoptosis in PC-3 cells than curcumin, and these curcumin analogues more potently inhibited NF-κB activity than curcumin. The inhibitory effects of these compounds on NF-κB activity correlated with their effects on growth inhibition and apoptosis stimulation in PC-3 cells. The results of the present study provide a rationale for in vivo studies with A(2)-A(6) using suitable animal models of prostate cancer.

Triterpenoid saponins from Xanthoceras sorbifolia Bunge and their inhibitory activity on human cancer cell lines.

Xanthoceras sorbifolia Bunge is widely used as healthy food material and folk medicine in China. Phytochemical investigation on its seeds oil leavings has led to the isolation and identification of seven new oleanane-type triterpenoid saponins named sorbifoliasides A-F (1-6) and bunkankasaponin F (7), along with five known ones (8-12). The structures of the new compounds were elucidated through spectroscopic analysis and chemical derivatization. Among the isolated compounds, 16-oxo-3, 28-O-bidesmosidic triterpenoid saponins (2, 3, 5) were isolated from this plant for the first time. The cytotoxicity of all compounds against the ten selected human cancer cell lines was assayed. Compounds 7 and 9 showed significant activity against all the ten cancer cell lines (IC(50) <10 µM), while compounds 8, 10 and 11 exhibited moderate activity against most of these cancer cell lines.

Synthesis and evaluation of curcumin-related compounds for anticancer activity.

Sixty-one curcumin-related compounds were synthesized and evaluated for their anticancer activity toward cultured prostate cancer PC-3 cells, pancreas cancer Panc-1 cells and colon cancer HT-29 cells. Inhibitory effects of these compounds on the growth of PC-3, Panc-1 and HT-29 cells were determined by the MTT assay. Compounds E10, F10, FN1 and FN2 exhibited exceptionally potent inhibitory effects on the growth of cultured PC-3, Panc-1 and HT-29 cells. The IC(50) for these compounds was lower than 1 µM in all three cell lines. E10 was 72-, 46- and 117-fold more active than curcumin for inhibiting the growth of PC-3, Panc-1 and HT-29 cells, respectively. F10 was 69-, 34- and 72-fold more active than curcumin for inhibiting the growth of PC-3, Panc-1 and HT-29 cells, respectively. FN1 and FN2 had about the same inhibitory effect as E10 and F10 toward Panc-1 cells but were less active than E10 and F10 toward PC-3 and HT-29 cells. The active compounds were potent stimulators of apoptosis. The present study indicates that E10, F10, FN1 and FN2 may have useful anticancer activity.

Isolation and identification of phase 1 metabolites of curcumol in rats.

Curcumol is one of the major components of the essential oil of Curcuma wenyujin with the structure of a guaiane-type sesquiterpenoid hemiketal. It exhibits clear antitumor, antihepatic fibrosis, antioxidant, and antimicrobial activities. In this article, the metabolism of curcumol in rats was investigated by characterizing metabolites excreted into urine. Sixteen phase 1 metabolites of curcumol were isolated from the urine of rats after an oral dose of 40 mg/kg, and their structures were elucidated on the basis of spectroscopic data. The metabolites were characterized as 2α-hydroxycurcumol (M-1), (11αH)-3α-hydroxy-9-en-8,13-epoxycurcumol (M-2), (11αH)-14-hydroxy-9-en-8,13-epoxycurcumol (M-3), (11ßH)-14-hydroxy-9-en-8,12-epoxycurcumol (M-4), 10α,14-dihydroxy-(1αH,7ßH)-guai-4-en-3,8-dione (M-5), 10ß,14-dihydroxy-(1αH,7ßH)-guai-4-en-3,8-dione (M-6), 10ß-hydroxy-(1αH,7ßH,11αH)-guai-8(13),8(14)-diepoxy-4-en-3-one (M-7), 10ß-hydroxy-(1αH,7ßH,11ßH)-guai-8(12),8(14)-diepoxy-4-en-3-one (M-8), 10α-hydroxy-(1αH,7ßH,11αH)-guai-8(13), 8(14)-diepoxy-4-en-3-one (M-9), 10α-hydroxy-(1αH,7ßH,11ßH)-guai-8(12),8(14)-diepoxy-4-en-3-one (M-10), 10α,14,15-trihydroxy-(1αH,7ßH)-guai-4-en-3,8-dione (M-11), 10ß-hydroxy-(1αH,7ßH)-guai-4-en-3,8-dioxo-13-oic acid (M-12), (1αH,7ßH)-guai-4,10(14)-dien-3, 8-dioxo-13-oic acid (M-13), 5ß,10ß-dihydroxy-(1αH,7ßH,11αH)-guai-8(13),8(14)-diepoxide (M-14), 10ß,14-dihydroxycurcumol (M-15), and 5ß,10ß,14-trihydroxy-(1αH,7ßH)-guai-8-one (M-16). All were newly identified compounds, among which M-3 and M-4, M-5 and M-6, and M-7, M-8, M-9, and M-10 are three groups of epimers. On the basis of the metabolite profile, the possible metabolic pathways of curcumol in rats are proposed. This is the first study of the metabolites of guaiane-type sesquiterpene in animals.

[Inhibition of extracts from Synotis erythropappa on tyrosinase].

OBJECTIVE: To study the inhibition of extracts from Synotis erythropappa on tyrosinase. METHODS: The 70% ethanol extracts were extracted by petroleum benzine, ethyl acetate and n-butanol, and the inhibitory activities against tyrosinase of every fraction were determined in vitro and the inhibitory kinetics of ethyl acetate and n-butanol fractions were investigated. RESULTS: The four fractions extracted all had inhibitory activities on tyrosinase, inhibitory activities of ethyl acetate and n-butanol fraction were higher. Their IC50 were 57.8, 140 microg/ml for monophenol oxidase activity and 41.2, 59.6 microg/ml for diphenol oxidase activity, respectively. The inhibition kinetics analyzed by Hnewaver-Burk plots showed that ethyl acetate fraction was a competitive type inhibitor, and its Ki was determined to be 19.7 microg/ml. n-butanol fraction was an uncompetitive type inhibitor, and its Ki was determined to be 60.7 microg/ml. CONCLUSION: Ethyl acetate and n-butanol fractions of extracts from Synotis erythropappa show potential inhibitory activity on tyrosinase.