Motomasa Kobayashi

Altohyrtin A, a potent anti-tumor macrolide from the Okinawan marine sponge Hyrtios altum

Abstract Altohyrtin A ( 1 ) has been isolated from the Okinawan marine sponge Hyrtios altum and the plane structure and parts of its relative configurations elucidated. Altohyrtin A ( 1 ) exhibited extremely potent cytotoxicity against KB cells at IC 50 0.01 ng/ml.

Inhibition of in vitro Tumor Cell Invasion by Ginsenoside Rg3

The effect of plant glycosides on tumor cell invasion was examined. Among the glycosides tested, ginsenoside Rgs was found to be a potent inhibitor of invasion by rat ascites hepatoma cells (MM1), B16FE7 melanoma cells, human small cell lung carcinoma (OC10), and human pancreatic adenocarcinoma (PSN‐1) cells, when examined in a cell monolayer invasion model. Structurally analogous ginsenosides, Rb2, 20(R)‐ginsenoside Rg2 and 20(S)‐ginsenoside Rg3 (a stereoisomer of Rg3), showed little inhibitory activity. Neither Rh1, Rh2, 20(R)‐ginsenosides Rh1 Rb1, Rc nor Re had any effect. The effective ginsenoside, Rg3, tended to inhibit experimental pulmonary metastasis by highly metastatic mouse melanoma B16FE7 cells as well. Taking account of our previous finding that 1‐oleoyl‐lysophosphatidic acid (LPA) induced invasion by MM1 cells in the monolayer invasion model, the effect of Rg3 on molecular events associated with the invasion induced by LPA was analyzed in order to understand the mechanism of the inhibition. Rg3, which suppressed the invasion induced by LPA, dose‐dependently inhibited the LPA‐triggered rise of intracellular Ca2+. Protein tyrosine phosphorylation triggered by LPA was not inhibited by Rg3.

ARENASTATIN A, A POTENT CYTOTOXIC DEPSIPEPTIDE FROM THE OKINAWAN MARINE SPONGE DYSIDEA ARENARIA

Arenastatin A (1) has been isolated from the Okinawan marine sponge Dysidea arenaria and the chemical structure including parts of the absolute configurations elucidated. Arenastatin A (1) is a cyclic didepsipeptide and exhibited extremely potent cytotoxicity against KB cells at IC50 5 pg/ml.

Trichoderins, novel aminolipopeptides from a marine sponge-derived Trichoderma sp., are active against dormant mycobacteria

Three new aminolipopeptides, designated trichoderins A (1), A1 (2), and B (3), were isolated from a culture of marine sponge-derived fungus of Trichoderma sp. as anti-mycobacterial substances with activity against active and dormant bacilli. The chemical structures of trichoderins were determined on the basis of spectroscopic study. Trichoderins showed potent anti-mycobacterial activity against Mycobacterium smegmatis, Mycobacterium bovis BCG, and Mycobacterium tuberculosis H37Rv under standard aerobic growth conditions as well as dormancy-inducing hypoxic conditions, with MIC values in the range of 0.02-2.0 microg/mL.

Absolute stereostructures of altohyrtin A and its congeners, potent cytotoxic macrolides from the Okinawan marine sponge hyrtios altum

Abstract The absolute stereostructures of altohyrtins A ( 1 ), B ( 2 ), C ( 3 ), and 5-desacetylaltohyrtin A ( 4 ), which were isolated from the Okinawan marine sponge Hyrtios altum , have been elucidated.

CALLYSTATIN A, A POTENT CYTOTOXIC POLYKETIDE FROM THE MARINE SPONGE, CALLYSPONGIA TRUNCATA

Abstract Callystatin A (1) has been isolated from the marine sponge, Callyspongia truncata, and the plane structure, including parts of the absolute configurations, is elucidated. Callystatin A (1) is a novel polyketide with a terminal α,β-unsaturated δ-lactone and exhibited potent cytotoxicity against KB cells at IC50 0.01 ng/ml.

Reversal of the resistance to STI571 in human chronic myelogenous leukemia K562 cells.

STI571, an Abl‐specific tyrosine kinase inhibitor, selectively kills Bcr‐Abl‐containing cells in vitro and in vivo. However, some chronic myelogenous leukemia (CML) cell lines are resistant to STI571. We evaluated whether STI571 interacts with P‐glycopro‐tein (P‐gp) and multidrug resistance protein 1 (MRP1), and examined the effect of agents that reverse multidrug resistance (MDR) on the resistance to SI571 in MDR cells. STI571 inhibited the [125l]azidoagosterol A‐photolabeling of P‐gp, but not that of MRP1. K562/MDR cells that overexpress P‐gp were 3.67 times more resistant to STI571 than the parental Philadelphia‐chromosome‐positive (Ph+) CML K562 cells, and this resistance was most effectively reversed by cepharanthine among the tested reversing agents. The concentration of STI571 required to completely inhibit tyrosine phosphorylation in K562/MDR cells was about 3 times higher than that in K562 cells, and cepharanthine abolished the difference. In KB‐G2 cells that overexpress P‐gp, but not Bcr‐Abl, 2.5 μM STI571 partly reversed the resistance to vincristine (VCR), paclitaxel, etoposide (VP‐16) and actinomycin D (ACD) but not to Adriamycin (ADM) or colchicine. STI571 increased the accumulation of VCR, but not that of ADM in KB‐G2 cells. STI571 did not reverse resistance to any agent in KB/MRP cells that overexpress MRP1. These findings suggest that STI571 is a substrate for P‐gp, but is less efficiently transported by P‐gp than VCR, and STI571 is not a substrate for MRP1. Among the tested reversing agents that interact with P‐gp, cepharanthine was the most effective agent for the reversal of the resistance to STI571 in K562/ MDR cells. Furthermore, STI571 itself was a potent reversing agent for MDR in P‐gp‐expressing KB‐G2 cells.

Structure of swinholide A, a potent cytotoxic macrolide from the okinawan marine sponge Theonella swinhoei

Abstract A potent cytotoxic macrolide, isolated from the Okinawan marine sponge Theonella swinhoei , was found identical with swinholide A, which was previously isolated from the Red Sea marine sponge of the same species. The structure of swinholide A has been elucidated to be 1 having a 44-membered dilactone ring.

Pyridoacridine alkaloids inducing neuronal differentiation in a neuroblastoma cell line, from marine sponge Biemna fortis.

A new and three known pyridoacridine alkaloids were isolated from the Indonesian marine sponge Biemna fortis as neuronal differentiation inducers against a murine neuroblastoma cell line, Neuro 2A. The chemical structure of the new compound, labuanine A (1), was determined by spectroscopic study and chemical conversion. These pyridoacridine alkaloids induced multipolar neuritogenesis in more than 50% of cells at 0.03-3 micro M concentration. Compound 3, which showed the strongest neuritogenic activity among them, also induced increase of acetylcholinesterase, a neuronal marker in Neuro 2A and arrested cell cycle at the G2/M phase.

Reversal of drug resistance mediated by multidrug resistance protein (MRP) 1 by dual effects of agosterol a on MRP1 function

We previously isolated agosterol A (AG‐A) from a marine Spongia sp. and found that it completely reversed colchicine resistance in P‐glycoprotein (Pgp)‐over‐expressing KB‐C2 cells and vincristine resistance in multidrug‐resistance protein (MRP)1‐over‐expressing CV60 cells. However, a tri‐deacetylated derivative of AG‐A (IAG‐A) showed almost no activity in reversing Pgp‐ or MRP1‐mediated drug resistance. In this study, we examined the mechanisms by which AG‐A reverses MRP1‐mediated drug resistance by investigating the interaction between agosterols and MRP1 in MRP1‐over‐expressing human KB carcinoma (KB/MRP) cells. [3H]‐Leukotriene C4 (LTC4), [3H]‐2,4‐dinitrophenyl‐S‐glutathione uptake into membrane vesicles prepared from KB/MRP cells and intracellular [3H]‐vincristine accumulation and efflux in KB/MRP cells were measured with or without AG‐A and/or inactive IAG‐A. AG‐A reduced MRP1‐mediated [3H]‐LTC4 transport in a dose‐dependent manner, but IAG‐A did not. Inhibition by AG‐A was competitive, with a Ki value of 31 μM. AG‐A at 10 μM enhanced the accumulation of [3H]‐vincristine in KB/MRP cells to the level of that in control cells in the absence of the agent. Likewise, ATP‐dependent efflux of [3H]‐vincristine from KB/MRP cells was enhanced compared with KB‐3‐1 cells and inhibited by AG‐A. In addition, AG‐A reduced intracellular levels of glutathione, a compound required for MRP1‐mediated transport of some anti‐cancer drugs. These findings suggest that AG‐A reverses MRP1‐mediated drug resistance by directly inhibiting the capacity of MRP1 to transport drugs. In addition, the capacity of AG‐A to reduce cellular glutathione levels may contribute to the modulating activity of MRP1.