The patellazoles inhibit protein synthesis at nanomolar concentrations in human colon tumor cells.
The patellazoles are a family of compounds consisting of a 24-member macrolide ring with a thiazole-epoxide tail. The opening of this epoxide does not greatly affect the bioactivity of these compounds, although the cellular toxicity is generally decreased. The patellazoles are extremely cytotoxic towards HCT 116 human colon tumor cells. Treatment with nanomolar amounts of these compounds results in immediate inhibition of protein synthesis and cell cycle arrest at the G1 and S phase. HCT 116 wild-type cells underwent apoptosis after extended patellazole treatment. Although treatment with the patellazoles resulted in an increased amount of p53, the p53 null cells were still strongly affected by treatment. The inhibition of translation by patellazole treatment is linked to the inhibition of the mTOR/p70 pathway. Like the mTOR inhibitor rapamycin, the patellazoles inhibit translation through the 4EBP1 and S6 kinase pathways. However, the cytotoxicity of rapamycin and the patellazoles differs greatly in HCT 116 cells. The cellular target of the patellazoles is still unknown; the patellazole-induced inhibition of this pathway occurs either downstream or parallel to AKT.
Richardson
Adam D
AD
Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
Aalbersberg
William
W
Ireland
Chris M
CM
D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D036103:Nanotechnology; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D020411:Oligonucleotide Array Sequence Analysis; D014176:Protein Biosynthesis / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology*; D014561:Urochordata / Q000737:chemistry*
D000970:Antineoplastic Agents; D018942:Macrolides; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D013844:Thiazoles