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Antitumor effects of tyropeptin-boronic acid derivatives: New proteasome inhibitors.

Momose I, Abe H, Watanabe T, Ohba S, Yamazaki K, Dan S, Yamori T, Masuda T, Nomoto A - Cancer Sci. (2014)

Bottom Line: Here we report the antitumor effects of two new tyropeptin-boronic acid derivatives, AS-06 and AS-29.We show that these derivatives also suppress the degradation of the NF-κB inhibitor IκB-α and the nuclear translocation of NF-κB p65 in multiple myeloma cells, resulting in the inhibition of NF-κB activation.Our results indicate that tyropeptin-boronic acid derivatives could be lead therapeutic agents against human multiple myeloma.

View Article: PubMed Central - PubMed

Affiliation: Institute of Microbial Chemistry, Numazu, Japan.

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Related in: MedlinePlus

Antitumor effect of tyropeptin-boronic acid derivatives. (a) In vivo imaging of proteasome inhibition. Inhibitors were administrated i.v. to mice bearing HEK293PS tumors. After 24 h, the tumors were monitored using the in vivo imaging system. (b) Inhibition of proteasome activity. Inhibitors were administered i.v. to mice bearing RPMI8226 tumors. Proteasome activity in tumor lysates was determined at 24 h after administration. (c) Antitumor activity on RPMI8226 xenografts. RPMI8226 cells were subcutaneously inoculated into SCID mice on day 0. Inhibitors were administrated i.v. twice weekly for 4 weeks from day 11 or 13.
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fig04: Antitumor effect of tyropeptin-boronic acid derivatives. (a) In vivo imaging of proteasome inhibition. Inhibitors were administrated i.v. to mice bearing HEK293PS tumors. After 24 h, the tumors were monitored using the in vivo imaging system. (b) Inhibition of proteasome activity. Inhibitors were administered i.v. to mice bearing RPMI8226 tumors. Proteasome activity in tumor lysates was determined at 24 h after administration. (c) Antitumor activity on RPMI8226 xenografts. RPMI8226 cells were subcutaneously inoculated into SCID mice on day 0. Inhibitors were administrated i.v. twice weekly for 4 weeks from day 11 or 13.

Mentions: To examine whether tyropeptin-boronic acid derivatives inhibit the proteasome in tumors, we used HEK293PS cells that are continuously expressing a proteasome-sensitive fluorescent protein. AS-06 and AS-29 were administrated at doses that were fourfold higher than bortezomib, because AS-06 and AS-29 had fourfold lower acute toxicity on mice than bortezomib. Intravenous administration of AS-29 to mice bearing HEK293PS tumors significantly induced strong fluorescence in tumors at 24 h after administration (Fig. 4a). Compared with AS-06, AS-29 inhibited more potently the proteasome activity in tumors (Fig. 4b). Furthermore, we assessed the in vivo antitumor activity of tyropeptin-boronic acid derivatives using xenograft models of human multiple myeloma RPMI8226 cells ( Fig.4c). When administered i.v. twice weekly for 4 weeks, AS-06 moderately suppresses the growth of subcutaneous tumor of RPMI8226 xenograft, while AS-29 potently suppresses tumor growth. These results clearly show that tyropeptin-boronic acid derivatives inhibit the proteasome activity in tumors, and, in particular, AS-29 has potent antitumor activity.


Antitumor effects of tyropeptin-boronic acid derivatives: New proteasome inhibitors.

Momose I, Abe H, Watanabe T, Ohba S, Yamazaki K, Dan S, Yamori T, Masuda T, Nomoto A - Cancer Sci. (2014)

Antitumor effect of tyropeptin-boronic acid derivatives. (a) In vivo imaging of proteasome inhibition. Inhibitors were administrated i.v. to mice bearing HEK293PS tumors. After 24 h, the tumors were monitored using the in vivo imaging system. (b) Inhibition of proteasome activity. Inhibitors were administered i.v. to mice bearing RPMI8226 tumors. Proteasome activity in tumor lysates was determined at 24 h after administration. (c) Antitumor activity on RPMI8226 xenografts. RPMI8226 cells were subcutaneously inoculated into SCID mice on day 0. Inhibitors were administrated i.v. twice weekly for 4 weeks from day 11 or 13.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317970&req=5

fig04: Antitumor effect of tyropeptin-boronic acid derivatives. (a) In vivo imaging of proteasome inhibition. Inhibitors were administrated i.v. to mice bearing HEK293PS tumors. After 24 h, the tumors were monitored using the in vivo imaging system. (b) Inhibition of proteasome activity. Inhibitors were administered i.v. to mice bearing RPMI8226 tumors. Proteasome activity in tumor lysates was determined at 24 h after administration. (c) Antitumor activity on RPMI8226 xenografts. RPMI8226 cells were subcutaneously inoculated into SCID mice on day 0. Inhibitors were administrated i.v. twice weekly for 4 weeks from day 11 or 13.
Mentions: To examine whether tyropeptin-boronic acid derivatives inhibit the proteasome in tumors, we used HEK293PS cells that are continuously expressing a proteasome-sensitive fluorescent protein. AS-06 and AS-29 were administrated at doses that were fourfold higher than bortezomib, because AS-06 and AS-29 had fourfold lower acute toxicity on mice than bortezomib. Intravenous administration of AS-29 to mice bearing HEK293PS tumors significantly induced strong fluorescence in tumors at 24 h after administration (Fig. 4a). Compared with AS-06, AS-29 inhibited more potently the proteasome activity in tumors (Fig. 4b). Furthermore, we assessed the in vivo antitumor activity of tyropeptin-boronic acid derivatives using xenograft models of human multiple myeloma RPMI8226 cells ( Fig.4c). When administered i.v. twice weekly for 4 weeks, AS-06 moderately suppresses the growth of subcutaneous tumor of RPMI8226 xenograft, while AS-29 potently suppresses tumor growth. These results clearly show that tyropeptin-boronic acid derivatives inhibit the proteasome activity in tumors, and, in particular, AS-29 has potent antitumor activity.

Bottom Line: Here we report the antitumor effects of two new tyropeptin-boronic acid derivatives, AS-06 and AS-29.We show that these derivatives also suppress the degradation of the NF-κB inhibitor IκB-α and the nuclear translocation of NF-κB p65 in multiple myeloma cells, resulting in the inhibition of NF-κB activation.Our results indicate that tyropeptin-boronic acid derivatives could be lead therapeutic agents against human multiple myeloma.

View Article: PubMed Central - PubMed

Affiliation: Institute of Microbial Chemistry, Numazu, Japan.

Show MeSH
Related in: MedlinePlus