Anti-competence Effects of Synthetic Phthalide Derivatives on Platelet-Derived Growth Factor-Induced DNA Synthesis in Primary Cultures of Rat Aorta Smooth Muscle Cells.

Q4 · MEDICINE

Article

Author: Mimura, Yasuhiko ; Kimura, Masayasu ; Kobayashi, Shinjiro ; Kimura, Ikuko ; Horikoshi, Isamu ; Okabe, Motonori

The inhibitory effect of 3-butylidene-4,5-dihydroxyphthalide (BP-42) on platelet derived growth factor (PDGF)-BB-induced DNA synthesis was investigated in synchronized smooth muscle cells (SMC) in primary culture of rat aorta. BP-42 (0.3-3 micrograms/ml) inhibited the PDGF-BB (30 ng/ml)-stimulated [3H]thymidine incorporation of the SMC in a concentration-dependent manner. BP-42 inhibited both the competence and progression phases of [3H]thymidine incorporation induced by PDGF-BB. Using the competence assay, BP-42 (0.3-10 micrograms/ml) delayed PDGF-BB (30 ng/ml)-accelerated starting time of [3H]thymidine incorporation in a concentration-dependent manner, confirming that BP-42 inhibited PDGF-BB-induced competence phase of DNA synthesis of SMC. BP-42 (1-10 micrograms/ml) also delayed basic fibroblast growth factor (bFGF: 30 ng/ml)-accelerated starting time of [3H]thymidine incorporation. The inhibitory potency of BP-42 for the competence action of PDGF-BB was similar to that for the action of bFGF. BP-421 (3-heptylidene-4,5-dihydroxyphthalide) and BP-422 (3-benzylidene-4,5-dihydroxyphthalide) had 3-fold greater inhibitory potencies than BP-42 for the PDGF-BB-induced competence activity. These results demonstrated that BP-42 inhibited PDGF-BB-induced competence activity of DNA synthesis in primary cultured SMC of rat aorta via a common signal transduction mechanism with bFGF. BP-421 and BP-422 were more potent inhibitors for the competence activity, suggesting that they may become a prototype of new anti-atherosclerotic drugs.

01 Jan 1995·Biological and Pharmaceutical BulletinQ4 · MEDICINE

Competence Effect of PDGF on Ki-67 Antigen and DNA Contents, and Its Inhibition by Trichostatin-A and a Butylydene Phthalide BP-421 in Primary Smooth Muscle Cells of Rat Aorta by Flow Cytometry.

Q4 · MEDICINE

Article

Author: Kimura, Masayasu ; Okabe, Motonori ; Kimura, Ikuko

We investigated with flow cytometry the platelet-derived growth factor (PDGF)-induced competence in primary cultured smooth muscle cells (SMC) of rat thoracic aorta. A cytogram was obtained by a double staining technique with fluorescein isothiocyanate-conjugated mouse monoclonal antibody against the proliferation-associated nucleus antigen Ki-67, and propidium iodide for total DNA content. (1) The nearly confluent SMC after 6 d-culture with 5% fetal bovine serum (FBS) were further cultured under serum starvation for 2d. (2) SMC was cultured with 5% FBS for 4 d, and then with 5% FBS+trichostatin-A (TS-A) (1 microgram/ml) for 2d. The cytogram showed the broadening of Ki-67 antigen signal for G0/G1 phase by TS-A compared with that of SMC under serum starvation, suggesting the existence of early and late phases of G1. (3) After serum starvation, the preculture with PDGF (100 ng/ml) for 3 h which was followed by a further 15 h-culture with 3% FBS caused significant more entry into S phase than control culture. The extent was greater than that with 15 h-culture with 10% FBS. (4) 15 h-culture with 1% FBS after PDGF (30 ng/ml) pretreatment stimulated entry into S phase cells, which was inhibited by TS-A (1 microgram/ml) and by a butylydene phthalide derivative BP-421 (3 micrograms/ml). Flow cytometric analysis demonstrate that PDGF pretreatment stimulates the entry into S phase by 20% of total SMC having early and late phases of G1, and that the PDGF-competence is inhibited by TS-A and BP-421.

01 Jan 1995·Biological and Pharmaceutical BulletinQ4 · MEDICINE

The Structure-Activity Relationship between Synthetic Butylidenephthalide Derivatives Regarding the Competence and Progression of Inhibition in Primary Cultures Proliferation of Mouse Aorta Smooth Muscle Cells.

Q4 · MEDICINE

Article

Author: Naitoh, Takeshi ; Mimura, Yasuhiko ; Kimura, Masayasu ; Kobayashi, Shinjiro ; Kimura, Ikuko

The inhibitory effects of synthetic butylidenephthalide (BP) derivatives on 10% fetal bovine serum-stimulated proliferation were assayed by measuring the proliferative cell number at an interval of 12 h in primary cultures of mouse aorta smooth muscle cells (SMC). Their potencies for the anti-proliferation effect were in the order BP-42 (4,5-dihydroxy BP) > BP-92 (4,5-dihydroxy butylphthalide) > BP-97 (6,7-dihydroxy-3-(3-bromo-1-octenyl)-phthalide) > BP-82 (6,7-dihydroxy BP) > BP-86 (5,6-dihydroxy BP) > BP-87 (4,5,6-trihydroxy BP) > BP-85 (4,7-dihydroxy BP) > BP-84 (5,7-dihydroxy BP) > BP-4C3 (4-methoxy propylphthalide) > BP-7 (4-hydroxy BP) > BP-40 (4,5-dimethoxy butylphthalide) > BP-5C3 (4-hydroxy propylphthalide). We divided these anti-proliferative effects into anti-competence and anti-progression effects by using a convenient assay. BP-42 had the greatest potency in used phthalides for competence inhibition of the SMC proliferation. BP-92 had small potency for competence inhibition. BP-97 had greater potency for competence inhibition than BP-82. These results demonstrated that the anti-proliferative effect of BP-42 was greatest in used phthalides in primary cultures of vascular SMC. The 4,5-dihydroxy group and 3-butylidene or 3-(3-bromo-1-octenyl) group in these synthetic BP derivatives contributed to the anti-competence effect on SMC. BP-42 may become a prototype of an anti-atherosclerotic drug.

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Indication	Highest Phase	Country/Location	Organization	Date
Atherosclerosis	Phase 3	JP	Toyama Medical and Pharmaceutical University Graduate School of Pharmacy	-

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