Two new natural brominated allenes named as nipponallene 1 and neonipponallene 2 were isolated fr... more Two new natural brominated allenes named as nipponallene 1 and neonipponallene 2 were isolated from the red alga Laurencia nipponica, collected near the Russian shore of the Sea of Japan (Troitsa Bay). The structures and absolute stereochemistry of 1 and 2 were elucidated using NMR spectroscopy, chemical transformations, modified Mosher's method and on the basis of biogenetic understanding.
A simple and practical approach for the synthesis of the marine sponge pigment fascaplysin was us... more A simple and practical approach for the synthesis of the marine sponge pigment fascaplysin was used for the total syntheses of its natural derivatives, the marine alkaloids 3-bromofascaplysin, 10-bromofascaplysin, and 3,10-dibromofascaplysin. The conditions of each step were revised, and as a result these compounds were produced by identical procedures with total yields of 40-43%.
Rhizochalin [(2R,3R,26R,27R)-2,27-diamino-3-hydroxy-26-[(2R,3R,4S,6R)-3,4,5-trihydroxy-6-(hydroxy... more Rhizochalin [(2R,3R,26R,27R)-2,27-diamino-3-hydroxy-26-[(2R,3R,4S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy]octacosan-11-one], an antimicrobial and cytotoxic marine two-headed sphingolipid-like natural product, isolated from the sponge Rhizochalina incrustata, and some related compounds were studied as anticarcinogenic and proapoptotic agents. The corresponding effects were tested on the mouse skin epidermal JB6 P+ Cl 41 cell line, its stable transfectants, THP-1, HeLa, and SNU-C4 human tumor cells using a variety of assessments, including cell viability (MTS), flow cytometry, anchorage-independent soft agar, and luciferase assays. At 5–10 μM concentrations, rhizochalin was effective as an inhibitor of the malignant transformation of JB6 P+ Cl 41 cells or colony formation of human tumor cells, which exerted its action, at least in part, through the induction of p53-dependent apoptosis. Structure–activity relationship study showed aglycon of rhizochalin to be the most active while peracetylated aglycon was the least active among the compounds studied.
Two novel triterpene holostane glycosides, synaptosides A (1) and A 1 (2), have been isolated fro... more Two novel triterpene holostane glycosides, synaptosides A (1) and A 1 (2), have been isolated from the Vietnamese sea cucumber Synapta maculata (Synaptida, Apodida). Their structures were elucidated by spectroscopic methods (NMR and MS) and chemical transformations. Glycosides 1 and 2 have rare branched pentasaccharide carbohydrate chains featuring a 3-O-methylglucuronic acid residue not previously reported in glycosides from sea cucumbers and a 6-Osulfated glucose. Glycoside 2 has an oxo group at C-7 and a 8(9)-double bond. All these structural features are unknown in glycosides from sea cucumbers. Glycoside 1 has moderate cytotoxic activity (IC 50 8.6 µg/mL) and glycoside 2 is inactive against HeLa tumor cells.
Purpose. Polycarpine from ascidian Polycarpa aurata was previously found to be active against dif... more Purpose. Polycarpine from ascidian Polycarpa aurata was previously found to be active against different human tumor cells. In this study, we investigated the antitumor mechanisms of polycarpine and its synthetic derivative, desmethoxyethoxy-polycarpine (dimethylpolycarpine), through the induction of apoptosis. This new knowledge regarding the proapoptotic action of polycarpine and dimethylpolycarpine should lead to a better understanding of their effects and development of a new class of anticancer drugs. Methods. Apoptosis was clearly observed by flow cytometry and Western blotting using an antibody against cleaved caspase-3 as an apoptotic marker. Results. Polycarpines differentially activated p38 kinase, JNKs, and ERKs in JB6 Cl 41 cells. The polycarpines-induced apoptosis was decreased in cells expressing a dominant-negative mutant of JNK. Both compounds stimulated p53-dependent transcriptional activity and phosphorylation. Induction of p53-phosphorylation at serine 15 was suppressed in JNK1 and JNK2 knockout cells. Furthermore, polycarpines were unable to induce apoptosis in p53-deficient MEFs in contrast to a strong induction of apoptosis in wild type MEFs, suggesting that p53 is involved in apoptosis induced by polycarpines. The p53 phosphorylation in turn was mediated by activated JNKs. Conclusions. These results indicate that all three MAPK signaling pathways are involved in the response of JB6 cells to treatment with polycarpines. Evidence also supports a proapoptotic role of the JNKs signaling pathway in vivo and clearly indicates that JNKs are required for phosphorylation of c-Jun, activation of p53, and subsequent apoptosis induced by polycarpines.
Purpose 3-Demethylubiquinone Q2 (1) was isolated from the ascidian Aplidium glabrum. The cancer-p... more Purpose 3-Demethylubiquinone Q2 (1) was isolated from the ascidian Aplidium glabrum. The cancer-preventive properties and the structure–activity relationship for 3-demethylubiquinone Q2 (1) and 12 of its synthetic analogs (3–14) are reported. Methods Compounds 3–14, having one or several di- or triprenyl substitutions and quinone moieties with methoxyls in different positions, were synthesized. The cancer-preventive properties of compounds 1 and 3–14 were tested in JB6 Cl41 mouse skin cells, using a variety of assessments, including the methanethiosulfonate (MTS) assay, flow cytometry, and soft agar assay. Statistical nonparametric methods were used to confirm statistical significance. Results All quinones tested were shown to inhibit JB6 Cl41 cell transformation, to induce apoptosis, AP-1, and NF-κB activity, and to inhibit p53 activity. The most promising effects were indicated for compounds containing two isoprene units in a side chain and a methoxyl group at the para-position to a polyprenyl substitution. Conclusions Quinones 1 and 3–14 demonstrated cancer-preventive activity in JB6 Cl41 cells, which may be attributed to the induction of p53-independent apoptosis. These activities depended on the length of side chains and on the positions of the methoxyl groups in the quinone part of the molecule.
a b s t r a c t 3-and 10-Bromofascaplysins was previously found to possess cytotoxic activity. In... more a b s t r a c t 3-and 10-Bromofascaplysins was previously found to possess cytotoxic activity. In this study, we investigated their cancer preventive and proapoptotic properties. These effects were tested on mouse skin epidermal JB6 P + Cl41 cell line, its stable transfectants, and human tumor HL-60, THP-1, SNU-C4, SK-MEL-28, DLD-1, MDA-MB-231, and HeLa cells using a variety of assessments, including a cell viability (MTS) assay, flow cytometry, anchorage-independent soft agar assay, luciferase assay, mitochondrial permeability assay, and Western blotting. 3-and 10-Bromofascaplysins were effective at submicromolar concentrations as the anticancer agents, which exerted their action, at least in part, through the induction of caspase-8, -9, -3-dependent apoptosis.
Frondoside A is a pentaoside having an acetyl moiety at the aglycon ring and xylose as a third mo... more Frondoside A is a pentaoside having an acetyl moiety at the aglycon ring and xylose as a third monosaccharide residue. Cucumarioside A 2 -2 is a pentaoside having glucose as a third monosaccahride unit. We compared the effects of frondoside A and A 2 -2 for cell death-inducing capability with close attention paid to structure-activity relationships. Both frondoside A and A 2 -2 strongly induced apoptosis of leukemic cells. Frondoside A-induced apoptosis was more potent and rapid than A 2 -2-induced apoptosis. A 2 -2-induced but not frondoside A-induced apoptosis was caspase-dependent. This suggests that holothurians may induce apoptosis of leukemic cells caspase-dependently or -independently, depending on the holothurian structure.
Other natural products U 0800 Desmethylubiquinone Q 2 from the Far-Eastern Ascidian Aplidium glab... more Other natural products U 0800 Desmethylubiquinone Q 2 from the Far-Eastern Ascidian Aplidium glabrum: Structure and Synthesis. -(SHUBINA, L. K.; FEDOROV, S. N.; RADCHENKO, O. S.; BALANEVA, N. N.; KOLESNIKOVA, S. A.; DMITRENOK, P. S.; BODE, A.; DONG, Z.; STONIK*, V. A.; Tetrahedron Lett. 46 (2005) 4, 559-562; Pac. Inst.
New asterosaponins archasterosides A (1), B (2), and the known regularoside A (3) were isolated f... more New asterosaponins archasterosides A (1), B (2), and the known regularoside A (3) were isolated from the Vietnamese starfish Archaster typicus and structurally elucidated by extensive NMR techniques and chemical transformations. Compounds 1-3 showed moderate cytotoxic activities against HeLa and mouse JB6 P + Cl41 cell lines. The most active, 2, induced basal AP-1-and p53-, but not NF-jB-transcriptional activations in JB6 Cl41 cells.
The marine natural chamigrane-type sesquiterpenoid, dactylone, is closely related to secondary me... more The marine natural chamigrane-type sesquiterpenoid, dactylone, is closely related to secondary metabolites of some edible species of red algae. In the present study, the effect of dactylone was tested on the mouse skin epidermal JB6 P + Cl41 cell line and its stable transfectants as well as on several human tumor cell lines, including lung (H460), colon (HCT-116), and skin melanomas (SK-MEL-5 and SK-MEL-28). This natural product was effective at nontoxic doses as a cancerpreventive agent, which exerted its actions, at least in part, through the inhibition of cyclin D3 and Cdk4 expression and retinoblastoma tumor suppressor protein (Rb) phosphorylation. The inhibition of these cell cycle components was followed by cell cycle arrest at the G 1 -S transition with subsequent p53-independent apoptosis. Therefore, these data showed that application of dactylone and related compounds may lead to decreased malignant cell transformation and/or decreased tumor cell proliferation. [Cancer Res 2007;67(12):5914-20]
Three new triterpene oligoglycosides, okhotosides B 1 (1), B 2 (2), and B 3 (3), have been isolat... more Three new triterpene oligoglycosides, okhotosides B 1 (1), B 2 (2), and B 3 (3), have been isolated from the sea cucumber Cucumaria okhotensis along with the known compounds frondoside A (4), frondoside A 1 , cucumarioside A 2 -5, and koreoside A. The structures of 1-3 were elucidated on the basis of their spectroscopic data (2D NMR and MS). Compounds 1-3 were moderately toxic against HeLa tumor cells. Frondoside A (4) showed more potent cytotoxicity against THP-1 and HeLa tumor cell lines (with IC 50 values of 4.5 and 2.1 µg/mL, respectively) and decreased both the AP-1-dependent trascriptional activities induced by UVB, EGF, or TPA in JB6-LucAP-1 cells and the EGF-induced NF-κB-dependent transcriptional activity in JB6-LucNF-kB cells at doses of about 1 µg/mL. At the same doses, it increased the p53dependent transcriptional activity in nonactivated JB6-Lucp53 cells and inhibited the colony formation of JB6 P + Cl 41 cells activated with EGF (INCC 50 ) 0.8 µg/mL).
Frondoside A is a pentaoside having an acetyl moiety at the aglycon ring and xylose as a third mo... more Frondoside A is a pentaoside having an acetyl moiety at the aglycon ring and xylose as a third monosaccharide residue. Cucumarioside A 2 -2 is a pentaoside having glucose as a third monosaccahride unit. We compared the effects of frondoside A and A 2 -2 for cell death-inducing capability with close attention paid to structure-activity relationships. Both frondoside A and A 2 -2 strongly induced apoptosis of leukemic cells. Frondoside A-induced apoptosis was more potent and rapid than A 2 -2-induced apoptosis. A 2 -2-induced but not frondoside A-induced apoptosis was caspase-dependent. This suggests that holothurians may induce apoptosis of leukemic cells caspase-dependently or -independently, depending on the holothurian structure.
Four isoforms of actinoporins were isolated in 2002-2004 from the tropical sea anemone Heteractis... more Four isoforms of actinoporins were isolated in 2002-2004 from the tropical sea anemone Heteractis crispa (=Radianthus macrodactylus). Their potent hemolytic activities and effects on Ehrlich ascites carcinoma bearing mice were also studied. In this study, the individual actinoporin (RTX-A) demonstrated potential cancer-preventive activity at extremely low and non-cytotoxic concentrations. The substance suppressed the malignant transformation of mouse JB6 P + Cl41 cells stimulated by epidermal growth factor (EGF) in soft agar with the inhibition of number of the colonies C 50 (INCC 50 ) = 0.034 nM. Actinoporin RTX-A also was shown to inhibit the phenotype expression of HeLa human cancer cells with an INCC 50 = 0.03 nM. The cytotoxic effect of RTX-A against JB6 P + Cl41 cells and HeLa, THP-1, MDA-MB-231, and SNU-C4 human tumor cell lines was high (IC 50 = 0.57, 2.26, 1.11, 30.0 and 4.66 nM), but significantly less than their capacity to suppress tumor cell colony formation or phenotype expression. RTX-A also induced apoptosis and inhibited basal AP-1, NF-κB, and p53-dependent transcriptional activity in JB6 Cl41 cells. These results confirmed that actinoporin RTX-A from H. crispa, at least partially, might exhibit cancer-preventive and anticancer cytotoxic properties through the induction of p53-independent apoptosis and inhibition of the oncogenic AP-1 and NF-κB nuclear factors activity.
Recently, we have shown that two biologically active, disulfated polyhydroxysteroids from the Pac... more Recently, we have shown that two biologically active, disulfated polyhydroxysteroids from the Pacific brittle star Ophiopholis aculeata stimulate Ca 2+ influx into different cell types. In the present study, 45 Ca 2+ and two fluorescent calcium probes, quin-2/AM and fura-2/AM, were employed to investigate the course and amplitude of calcium signals induced in different mouse cells using an radio-isotope, spectrofluorimetry, and microcytofluorimetry techniques. The cytotoxic and hemolytic effects were not observed for both steroids at the wide range of concentrations. Steroids did not influence [ 3 H]-uridine incorporation in a variety of cells. The investigated steroids stimulated a rapid increase in cytosolic Ca 2+ content in Ehrlich mouse carcinoma cells, mouse spleen lymphocytes, and mouse peritoneal macrophages in the concentration range 1-100 g/ml on a dose-dependent basis. Blockers of L-type calcium channels, such as verapamil, diltiazem, nifedipine (1 × 10 −7 M), and 1 mM EGTA, inhibited this process and reduced the response of cells to steroid application. The stimulatory effect of steroids on human fibroblast proliferation and mouse macrophage lysosome activity was observed also. It is suggested that the investigated compounds may act as Ca 2+ -agonists and increase Ca 2+ -transport across cell membranes.
... and Valentin A. Stonik* . Pacific Institute of Bioorganic Chemistry and Institute of Chemist... more ... and Valentin A. Stonik* . Pacific Institute of Bioorganic Chemistry and Institute of Chemistry of the Far-Eastern Division of the Russian Academy of Sciences 690022, Prospect 100-letya Vladivostoka 159c and 159b, Vladivostok, Russia. ... Michaud, DP; Schmidt, PG J. Am. Chem. ...
Two new natural brominated allenes named as nipponallene 1 and neonipponallene 2 were isolated fr... more Two new natural brominated allenes named as nipponallene 1 and neonipponallene 2 were isolated from the red alga Laurencia nipponica, collected near the Russian shore of the Sea of Japan (Troitsa Bay). The structures and absolute stereochemistry of 1 and 2 were elucidated using NMR spectroscopy, chemical transformations, modified Mosher's method and on the basis of biogenetic understanding.
A simple and practical approach for the synthesis of the marine sponge pigment fascaplysin was us... more A simple and practical approach for the synthesis of the marine sponge pigment fascaplysin was used for the total syntheses of its natural derivatives, the marine alkaloids 3-bromofascaplysin, 10-bromofascaplysin, and 3,10-dibromofascaplysin. The conditions of each step were revised, and as a result these compounds were produced by identical procedures with total yields of 40-43%.
Rhizochalin [(2R,3R,26R,27R)-2,27-diamino-3-hydroxy-26-[(2R,3R,4S,6R)-3,4,5-trihydroxy-6-(hydroxy... more Rhizochalin [(2R,3R,26R,27R)-2,27-diamino-3-hydroxy-26-[(2R,3R,4S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy]octacosan-11-one], an antimicrobial and cytotoxic marine two-headed sphingolipid-like natural product, isolated from the sponge Rhizochalina incrustata, and some related compounds were studied as anticarcinogenic and proapoptotic agents. The corresponding effects were tested on the mouse skin epidermal JB6 P+ Cl 41 cell line, its stable transfectants, THP-1, HeLa, and SNU-C4 human tumor cells using a variety of assessments, including cell viability (MTS), flow cytometry, anchorage-independent soft agar, and luciferase assays. At 5–10 μM concentrations, rhizochalin was effective as an inhibitor of the malignant transformation of JB6 P+ Cl 41 cells or colony formation of human tumor cells, which exerted its action, at least in part, through the induction of p53-dependent apoptosis. Structure–activity relationship study showed aglycon of rhizochalin to be the most active while peracetylated aglycon was the least active among the compounds studied.
Two novel triterpene holostane glycosides, synaptosides A (1) and A 1 (2), have been isolated fro... more Two novel triterpene holostane glycosides, synaptosides A (1) and A 1 (2), have been isolated from the Vietnamese sea cucumber Synapta maculata (Synaptida, Apodida). Their structures were elucidated by spectroscopic methods (NMR and MS) and chemical transformations. Glycosides 1 and 2 have rare branched pentasaccharide carbohydrate chains featuring a 3-O-methylglucuronic acid residue not previously reported in glycosides from sea cucumbers and a 6-Osulfated glucose. Glycoside 2 has an oxo group at C-7 and a 8(9)-double bond. All these structural features are unknown in glycosides from sea cucumbers. Glycoside 1 has moderate cytotoxic activity (IC 50 8.6 µg/mL) and glycoside 2 is inactive against HeLa tumor cells.
Purpose. Polycarpine from ascidian Polycarpa aurata was previously found to be active against dif... more Purpose. Polycarpine from ascidian Polycarpa aurata was previously found to be active against different human tumor cells. In this study, we investigated the antitumor mechanisms of polycarpine and its synthetic derivative, desmethoxyethoxy-polycarpine (dimethylpolycarpine), through the induction of apoptosis. This new knowledge regarding the proapoptotic action of polycarpine and dimethylpolycarpine should lead to a better understanding of their effects and development of a new class of anticancer drugs. Methods. Apoptosis was clearly observed by flow cytometry and Western blotting using an antibody against cleaved caspase-3 as an apoptotic marker. Results. Polycarpines differentially activated p38 kinase, JNKs, and ERKs in JB6 Cl 41 cells. The polycarpines-induced apoptosis was decreased in cells expressing a dominant-negative mutant of JNK. Both compounds stimulated p53-dependent transcriptional activity and phosphorylation. Induction of p53-phosphorylation at serine 15 was suppressed in JNK1 and JNK2 knockout cells. Furthermore, polycarpines were unable to induce apoptosis in p53-deficient MEFs in contrast to a strong induction of apoptosis in wild type MEFs, suggesting that p53 is involved in apoptosis induced by polycarpines. The p53 phosphorylation in turn was mediated by activated JNKs. Conclusions. These results indicate that all three MAPK signaling pathways are involved in the response of JB6 cells to treatment with polycarpines. Evidence also supports a proapoptotic role of the JNKs signaling pathway in vivo and clearly indicates that JNKs are required for phosphorylation of c-Jun, activation of p53, and subsequent apoptosis induced by polycarpines.
Purpose 3-Demethylubiquinone Q2 (1) was isolated from the ascidian Aplidium glabrum. The cancer-p... more Purpose 3-Demethylubiquinone Q2 (1) was isolated from the ascidian Aplidium glabrum. The cancer-preventive properties and the structure–activity relationship for 3-demethylubiquinone Q2 (1) and 12 of its synthetic analogs (3–14) are reported. Methods Compounds 3–14, having one or several di- or triprenyl substitutions and quinone moieties with methoxyls in different positions, were synthesized. The cancer-preventive properties of compounds 1 and 3–14 were tested in JB6 Cl41 mouse skin cells, using a variety of assessments, including the methanethiosulfonate (MTS) assay, flow cytometry, and soft agar assay. Statistical nonparametric methods were used to confirm statistical significance. Results All quinones tested were shown to inhibit JB6 Cl41 cell transformation, to induce apoptosis, AP-1, and NF-κB activity, and to inhibit p53 activity. The most promising effects were indicated for compounds containing two isoprene units in a side chain and a methoxyl group at the para-position to a polyprenyl substitution. Conclusions Quinones 1 and 3–14 demonstrated cancer-preventive activity in JB6 Cl41 cells, which may be attributed to the induction of p53-independent apoptosis. These activities depended on the length of side chains and on the positions of the methoxyl groups in the quinone part of the molecule.
a b s t r a c t 3-and 10-Bromofascaplysins was previously found to possess cytotoxic activity. In... more a b s t r a c t 3-and 10-Bromofascaplysins was previously found to possess cytotoxic activity. In this study, we investigated their cancer preventive and proapoptotic properties. These effects were tested on mouse skin epidermal JB6 P + Cl41 cell line, its stable transfectants, and human tumor HL-60, THP-1, SNU-C4, SK-MEL-28, DLD-1, MDA-MB-231, and HeLa cells using a variety of assessments, including a cell viability (MTS) assay, flow cytometry, anchorage-independent soft agar assay, luciferase assay, mitochondrial permeability assay, and Western blotting. 3-and 10-Bromofascaplysins were effective at submicromolar concentrations as the anticancer agents, which exerted their action, at least in part, through the induction of caspase-8, -9, -3-dependent apoptosis.
Frondoside A is a pentaoside having an acetyl moiety at the aglycon ring and xylose as a third mo... more Frondoside A is a pentaoside having an acetyl moiety at the aglycon ring and xylose as a third monosaccharide residue. Cucumarioside A 2 -2 is a pentaoside having glucose as a third monosaccahride unit. We compared the effects of frondoside A and A 2 -2 for cell death-inducing capability with close attention paid to structure-activity relationships. Both frondoside A and A 2 -2 strongly induced apoptosis of leukemic cells. Frondoside A-induced apoptosis was more potent and rapid than A 2 -2-induced apoptosis. A 2 -2-induced but not frondoside A-induced apoptosis was caspase-dependent. This suggests that holothurians may induce apoptosis of leukemic cells caspase-dependently or -independently, depending on the holothurian structure.
Other natural products U 0800 Desmethylubiquinone Q 2 from the Far-Eastern Ascidian Aplidium glab... more Other natural products U 0800 Desmethylubiquinone Q 2 from the Far-Eastern Ascidian Aplidium glabrum: Structure and Synthesis. -(SHUBINA, L. K.; FEDOROV, S. N.; RADCHENKO, O. S.; BALANEVA, N. N.; KOLESNIKOVA, S. A.; DMITRENOK, P. S.; BODE, A.; DONG, Z.; STONIK*, V. A.; Tetrahedron Lett. 46 (2005) 4, 559-562; Pac. Inst.
New asterosaponins archasterosides A (1), B (2), and the known regularoside A (3) were isolated f... more New asterosaponins archasterosides A (1), B (2), and the known regularoside A (3) were isolated from the Vietnamese starfish Archaster typicus and structurally elucidated by extensive NMR techniques and chemical transformations. Compounds 1-3 showed moderate cytotoxic activities against HeLa and mouse JB6 P + Cl41 cell lines. The most active, 2, induced basal AP-1-and p53-, but not NF-jB-transcriptional activations in JB6 Cl41 cells.
The marine natural chamigrane-type sesquiterpenoid, dactylone, is closely related to secondary me... more The marine natural chamigrane-type sesquiterpenoid, dactylone, is closely related to secondary metabolites of some edible species of red algae. In the present study, the effect of dactylone was tested on the mouse skin epidermal JB6 P + Cl41 cell line and its stable transfectants as well as on several human tumor cell lines, including lung (H460), colon (HCT-116), and skin melanomas (SK-MEL-5 and SK-MEL-28). This natural product was effective at nontoxic doses as a cancerpreventive agent, which exerted its actions, at least in part, through the inhibition of cyclin D3 and Cdk4 expression and retinoblastoma tumor suppressor protein (Rb) phosphorylation. The inhibition of these cell cycle components was followed by cell cycle arrest at the G 1 -S transition with subsequent p53-independent apoptosis. Therefore, these data showed that application of dactylone and related compounds may lead to decreased malignant cell transformation and/or decreased tumor cell proliferation. [Cancer Res 2007;67(12):5914-20]
Three new triterpene oligoglycosides, okhotosides B 1 (1), B 2 (2), and B 3 (3), have been isolat... more Three new triterpene oligoglycosides, okhotosides B 1 (1), B 2 (2), and B 3 (3), have been isolated from the sea cucumber Cucumaria okhotensis along with the known compounds frondoside A (4), frondoside A 1 , cucumarioside A 2 -5, and koreoside A. The structures of 1-3 were elucidated on the basis of their spectroscopic data (2D NMR and MS). Compounds 1-3 were moderately toxic against HeLa tumor cells. Frondoside A (4) showed more potent cytotoxicity against THP-1 and HeLa tumor cell lines (with IC 50 values of 4.5 and 2.1 µg/mL, respectively) and decreased both the AP-1-dependent trascriptional activities induced by UVB, EGF, or TPA in JB6-LucAP-1 cells and the EGF-induced NF-κB-dependent transcriptional activity in JB6-LucNF-kB cells at doses of about 1 µg/mL. At the same doses, it increased the p53dependent transcriptional activity in nonactivated JB6-Lucp53 cells and inhibited the colony formation of JB6 P + Cl 41 cells activated with EGF (INCC 50 ) 0.8 µg/mL).
Frondoside A is a pentaoside having an acetyl moiety at the aglycon ring and xylose as a third mo... more Frondoside A is a pentaoside having an acetyl moiety at the aglycon ring and xylose as a third monosaccharide residue. Cucumarioside A 2 -2 is a pentaoside having glucose as a third monosaccahride unit. We compared the effects of frondoside A and A 2 -2 for cell death-inducing capability with close attention paid to structure-activity relationships. Both frondoside A and A 2 -2 strongly induced apoptosis of leukemic cells. Frondoside A-induced apoptosis was more potent and rapid than A 2 -2-induced apoptosis. A 2 -2-induced but not frondoside A-induced apoptosis was caspase-dependent. This suggests that holothurians may induce apoptosis of leukemic cells caspase-dependently or -independently, depending on the holothurian structure.
Four isoforms of actinoporins were isolated in 2002-2004 from the tropical sea anemone Heteractis... more Four isoforms of actinoporins were isolated in 2002-2004 from the tropical sea anemone Heteractis crispa (=Radianthus macrodactylus). Their potent hemolytic activities and effects on Ehrlich ascites carcinoma bearing mice were also studied. In this study, the individual actinoporin (RTX-A) demonstrated potential cancer-preventive activity at extremely low and non-cytotoxic concentrations. The substance suppressed the malignant transformation of mouse JB6 P + Cl41 cells stimulated by epidermal growth factor (EGF) in soft agar with the inhibition of number of the colonies C 50 (INCC 50 ) = 0.034 nM. Actinoporin RTX-A also was shown to inhibit the phenotype expression of HeLa human cancer cells with an INCC 50 = 0.03 nM. The cytotoxic effect of RTX-A against JB6 P + Cl41 cells and HeLa, THP-1, MDA-MB-231, and SNU-C4 human tumor cell lines was high (IC 50 = 0.57, 2.26, 1.11, 30.0 and 4.66 nM), but significantly less than their capacity to suppress tumor cell colony formation or phenotype expression. RTX-A also induced apoptosis and inhibited basal AP-1, NF-κB, and p53-dependent transcriptional activity in JB6 Cl41 cells. These results confirmed that actinoporin RTX-A from H. crispa, at least partially, might exhibit cancer-preventive and anticancer cytotoxic properties through the induction of p53-independent apoptosis and inhibition of the oncogenic AP-1 and NF-κB nuclear factors activity.
Recently, we have shown that two biologically active, disulfated polyhydroxysteroids from the Pac... more Recently, we have shown that two biologically active, disulfated polyhydroxysteroids from the Pacific brittle star Ophiopholis aculeata stimulate Ca 2+ influx into different cell types. In the present study, 45 Ca 2+ and two fluorescent calcium probes, quin-2/AM and fura-2/AM, were employed to investigate the course and amplitude of calcium signals induced in different mouse cells using an radio-isotope, spectrofluorimetry, and microcytofluorimetry techniques. The cytotoxic and hemolytic effects were not observed for both steroids at the wide range of concentrations. Steroids did not influence [ 3 H]-uridine incorporation in a variety of cells. The investigated steroids stimulated a rapid increase in cytosolic Ca 2+ content in Ehrlich mouse carcinoma cells, mouse spleen lymphocytes, and mouse peritoneal macrophages in the concentration range 1-100 g/ml on a dose-dependent basis. Blockers of L-type calcium channels, such as verapamil, diltiazem, nifedipine (1 × 10 −7 M), and 1 mM EGTA, inhibited this process and reduced the response of cells to steroid application. The stimulatory effect of steroids on human fibroblast proliferation and mouse macrophage lysosome activity was observed also. It is suggested that the investigated compounds may act as Ca 2+ -agonists and increase Ca 2+ -transport across cell membranes.
... and Valentin A. Stonik* . Pacific Institute of Bioorganic Chemistry and Institute of Chemist... more ... and Valentin A. Stonik* . Pacific Institute of Bioorganic Chemistry and Institute of Chemistry of the Far-Eastern Division of the Russian Academy of Sciences 690022, Prospect 100-letya Vladivostoka 159c and 159b, Vladivostok, Russia. ... Michaud, DP; Schmidt, PG J. Am. Chem. ...
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