7 抗腫瘍性プロスタグランジンの細胞挙動と活性発現分子機構(口頭発表の部)

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Prostaglandins (PGs) such as Δ^<12>-PGJ_2 and Δ^7-PGA_1 methyl ester that possess a cross-conjugated dienone unit exhibit unique anti-tumor and anti-viral activities independent of intracellular cAMP levels. These compounds are transported reversibly into cultured cells and accumulate in nuclei via covalent interaction, eliciting growth inhibition. PGA_1 methyl ester, a simple cyclopentenone analog, is less potent. The unique cellular behavior of the dienone PGs correlates well with their chemical properties. The PGs react specifically with thiol nucleophiles such as glutathione. Michael addition of thiols to Δ^7-PGA_1 methyl ester, an alkylidenecyclopentenone derivative, occurs facilely at the endocyclic C(11) position rather than at the C(7) position. This process is reversible and, in solution phase, the adducts are in equilibrium with the considerable amounts of free PG and thiols. However, the reaction of this PG with Sepharose-bound thiols, regarded to be plausible mimics of protein thiols, is irreversible and the resulting adducts are dissociated only by alkali treatment. On the other hand, PGA_1 methyl ester reacts with soluble or polymer-anchored thiols at lower rates thanΔ^7-PGA_1 methyl ester but the resulting thiol adducts are substantially more stable than those of the dienone PGs. This tendency of the PGA_1 methyl ester causes its equilibrium to shift to the adduct formation. The reversibility of the Michael reaction of PGs with thiols is consistent with their intracellular behavior and biological activities. Since glutathione adducts of PGs have no anti-proliferative activities for cancer cells, the intracellular free PGs are presumed to interact with target molecules to cause cell growth inhibition. The involvement of the ATP-dependent glutathione S-conjugate export pump (GS-X pump) in the efflux of PGs is clarified. Actually, the PG undergoes ATP-dependent uptake by inside-out vesicles of plasma membrane prepared from GS-X pump overexpressed HL-60/R-CP cells, proving the existence of the active extrusive transport mechanism of PGs from the cells. The newly designed GS-X pump inhibitor effects the increase of antiproliferative activity of Δ^7-PGA_1 methyl ester against the same tumor cells by blocking the GS-X pump, indicating a possibility of new cancer chemotherapy. In nuclei, Δ^7-PGA_1 methyl ester induces p21, a CDK inhibitor, independent of p53, arresting the cell cycle at G1 phase.
天然有機化合物討論会の論文
1997-07-20

7 抗腫瘍性プロスタグランジンの細胞挙動と活性発現分子機構(口頭発表の部)

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