Isolation of a Novel Tyrosine Kinase Inhibitor, Lavendustin A, from Streptomyces griseolavendus

Onoda, Takeru; Iinuma, Hironobu; Sasaki, Yumi; Hamada, Masa; Isshiki, Kunio; Naganawa, Hiroshi; Takeuchi, Tomio; Tatsuta, Kuniaki; Umezawa, Kazuo

doi:10.1021/np50066a009

Cited by 255 publications

(184 citation statements)

References 3 publications

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“…Here we show for the first time that the angiogenic activity of VEGF in vivo can be prevented by lavendustin A. Lavendustin A is a potent and selective PTK inhibitor in vitro, with an IC50 of 11 nM. In contrast, the IC50 of its negative control, lavendustin B, is 1.3 jiM (Onoda et al, 1989). Thus, the ability of lavendustin A and B to suppress VEGF-induced angiogenesis is entirely consistent with their relative potency as PTK blockers.…”

Section: Discussionsupporting

confidence: 71%

“…Since the mitogenic and angiogenic activities of VEGF are thought to be mediated by distinct membranespanning tyrosine kinase receptors, we predicted that specific inhibitors of protein tyrosine kinase (PTK) should block the biological functions of VEGF in vivo. To test this hypothesis, we used a highly potent and specific PTK inhibitor lavendustin A (Onoda et al, 1989;Odell et al, 1991) and showed that it is an effective inhibitor of the angiogenic activity of VEGF. Suramin is an effective analogue of heparin/heparan sulphate which inhibits the activities of several heparin-binding growth factors such as fibroblast growth factors (FGFs) and platelet-derived growth factor . Although suramin blocks the growth-stimulating activity of VEGF in vitro (Olander et al, 1991), its action against VEGF in vivo is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Suppression of VEGF‐induced angiogenesis by the protein tyrosine kinase inhibitor, lavendustin A

Fan

1995

British J Pharmacology

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3 Daily local administration of 250 ng VEGF165 accelerated the rate of "33Xe clearance from the sponges and induced an intense neovascularisation. This VEGF165-induced angiogenesis was inhibited by daily co-administration of the selective PTK inhibitor, lavendustin A (10 jig), but not its negative control, lavendustin B (10 jig). Blood flow measurements and morphometric analysis of 8-day-old sponges showed that lavendustin A reduced the "33Xe clearance of VEGF165-treated sponges from 32.9 ± 1.5% to 20.9 ± 1.6% and the total fibrovascular growth area from 62.4 ± 6.1% to 21.6 ± 6.8% (n = 1 2, P < 0.05). 4 Co-injection of suramin (3 mg), an inhibitor of heparin-binding growth factors, also suppressed the VEGF165-elicited neovascular response. In contrast, neither lavendustin A nor suramin produced any effect on the basal sponge-induced angiogenesis. 5 When given alone, low doses of VEGF 165 (25 ng) or basic fibroblast growth factor (bFGF; 10 ng) did not modify the basal sponge-induced neovascularisation. However, co-administration of these two peptides to a single sponge together caused a significant increase in the rate of '33Xe clearance and angiogenesis similar to that seen with the high dose of VEGF165 (250 ng) acting alone. This VEGF/ bFGF neovascular response was also blocked by daily co-administration of lavendustin A (10 jig), suramin (3 mg) or a monoclonal anti-bFGF antibody (DG2, I jig), but not lavendustin B (10 g). 6 These results suggest that selective inhibition of PTK could have therapeutic potential in angiogenic diseases where VEGF plays a dominant role. Furthermore, blockade of the angiogenic activity of VEGF and VEGF,/bFGF by suramin reveals an alternative strategy in angiosuppression.

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Section: Discussionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Suppression of VEGF‐induced angiogenesis by the protein tyrosine kinase inhibitor, lavendustin A

Fan

1995

British J Pharmacology

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“…Chronic application of lavendustin A has been shown to inhibit the EGF-receptor-associated tyrosine kinase at very low concentration under in vitro condition (IC 50 of ca. 12 nM; Onoda et al, 1989). However, it has been also found that lavendustin A does not inhibit the tyrosine kinase in situ (Onoda et al, 1990).…”

Section: Discussionmentioning

confidence: 98%

Inhibitory effects of genistein on ATP‐sensitive K⁺ channels in rabbit portal vein smooth muscle

Ogata

Kitamura

Ito

et al. 1997

British J Pharmacology

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1 E ects on the pinacidil-induced outward current of inhibitors of tyrosine kinases and phosphatases were investigated by use of a patch-clamp method in smooth muscle cells of the rabbit portal vein. 2 A speci®c tyrosine kinase inhibitor, genistein, inhibited the pinacidil-induced current in a concentration-dependent manner with an IC 50 of 5.5 mM. Superfusion of Ca 2+ -free solution did not a ect this inhibitory e ect of genistein. At higher concentrations, genistein inhibited the voltagedependent Ba 2+ and K + currents with IC 50 values of 4100 mM and 75 mM respectively. Tyrphostin B46 (30 mM), a tyrosine kinase inhibitor, also inhibited the pinacidil-induced current by 70 % of the control. 3 Sodium orthovanadate (100 mM), an inhibitor of tyrosine phosphatase, slightly but signi®cantly enhanced both the pinacidil-induced and delayed recti®er K + currents. Daidzein (100 mM), an inactive analogue of genistein, did not inhibit these currents. 4 Neither herbimycin A (1 mM), lavendustin A (30 mM), tyrphostin 23 (10 mM), which are also tyrosine kinase inhibitors, nor wortmannin (10 mM), a phosphatidylinositol 3-kinase inhibitor, had an e ect on either the pinacidil-induced or delayed recti®er K + currents. Epidermal growth factor (EGF; 1 mg ml 71 ) did not induce an outward current or enhance the pinacidil-induced current. 5 Pinacidil alone, in the cell-attached con®guration, or pinacidil with GDP, in the inside-out con®guration, activated a 42 pS channel in the smooth muscle cells of the rabbit portal vein. Genistein (30 mM) reduced the channel's open probability without inducing a change in unitary conductance at any holding potential (730 to +20 mV). 6 In the inside-out con®guration, genistein at 30 mM did not change the mean channel open time, but reduced the burst duration. At 100 mM genistein abolished channel opening. The inhibitory potencies with which 30 and 100 mM genistein acted on the unitary current of the ATP-sensitive K + channel were similar to those seen in the whole-cell voltage-clamp con®guration. 7 Although direct inhibitory actions of genistein on the ATP-sensitive K + channels are not ruled out, our results suggest that a protein tyrosine kinase may play a role in the regulation of ATP-sensitive K + channel activity in the rabbit portal vein.

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“…Also half of all proto-oncogenes discovered so far code for proteins with PTK activity; [19] thus, there is an intensive search underway for selective inhibitors of PTKs. [20] [21] lavendustin A 2, [22] and the tyrphostines 3, [20a,b,e] (Fig. 1).…”

Section: Inhibition Of Protein Tyrosine Kinases (Ptks)mentioning

confidence: 99%

Organic Synthesis and Biological Signal Transduction

Schmittberger¹,

Waldmann²

1998

Synlett

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Isolation of a Novel Tyrosine Kinase Inhibitor, Lavendustin A, from Streptomyces griseolavendus

Cited by 255 publications

References 3 publications

Suppression of VEGF‐induced angiogenesis by the protein tyrosine kinase inhibitor, lavendustin A

Suppression of VEGF‐induced angiogenesis by the protein tyrosine kinase inhibitor, lavendustin A

Inhibitory effects of genistein on ATP‐sensitive K⁺ channels in rabbit portal vein smooth muscle

Organic Synthesis and Biological Signal Transduction

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Isolation of a Novel Tyrosine Kinase Inhibitor, Lavendustin A, from Streptomyces griseolavendus

Cited by 255 publications

References 3 publications

Suppression of VEGF‐induced angiogenesis by the protein tyrosine kinase inhibitor, lavendustin A

Suppression of VEGF‐induced angiogenesis by the protein tyrosine kinase inhibitor, lavendustin A

Inhibitory effects of genistein on ATP‐sensitive K+ channels in rabbit portal vein smooth muscle

Organic Synthesis and Biological Signal Transduction

Contact Info

Product

Resources

About

Inhibitory effects of genistein on ATP‐sensitive K⁺ channels in rabbit portal vein smooth muscle