Anti-tumor activity of WK88-1, a novel geldanamycin derivative, in gefitinib-resistant non-small cell lung cancers with Met amplification.
Bottom Line: Despite preclinical efficacy of geldanamycin-anasamycin (GA)-derivatives containing benzoquinone moiety as Hsp90 inhibitors, the hepatotoxicity of these GA-derivatives restricts their therapeutic benefit.Moreover, WK88-1 attenuated phosphorylation of these Hsp90 client proteins and reduced the anchorage-independent growth of HCC827GR cells.Administration of WK88-1 did not cause hepatotoxicity in animals and significantly reduced the growth of HCC827GR cells xenograft tumors in nude mice.
Affiliation: College of Pharmacy, Keimyung University, Daegu, South Korea.Show MeSH
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Mentions: We have previously designed and synthesized non-benzoquinone GA derivatives by following mutasynthetic and directed biosynthetic approaches.37,38 As shown in Figure1, DHQ3, a 15-hydroxyl-17-demethoxyreblastin, was prepared from a genetically engineered strain (AC15) of S. hygroscopicus38 and WK88-1, WK88-2, and WK88-3 were purified from a culture of S. hygroscopicus AC2, in which the AHBA synthase gene was disrupted by the kanamycin-resistance gene, supplemented with 3-aminobenzoic acid(Fig.1).37 In this study, we examined the possible effects of DHQ3 and the WK88 series of non-benzoquinone GA derivatives in alleviating gefitinib resistance in NSCLC. For this purpose, we used a gefitinib-sensitive HCC827 cells and gefitinib-resistant HCC827GR cell line harboring Met gene amplification. As reported, our data also showed that HCC827 cells were highly sensitive to exposure to gefitinib, whereas HCC827GR cells were relatively resistant to gefitinib treatment (Fig.2a,b). Given that Hsp90 inhibition seems promising to overcome gefitinib resistance, we first assessed the anti-proliferative effects of these compounds in these NSCLC cell lines. Our data revealed that a potent growth-inhibitory effect was observed in NSCLCs, which was treated with WK88 compounds or GA, whereas DHQ3 didn't show any desirable effects (Fig.2a,b). Notably, this anti-proliferative effect of WK88 compounds was evidently observed in HCC827GR cells as well as HCC827 cells, suggesting that WK88 compounds might be a potential alternative of GA to overcome acquired resistance to gefitinib in NSCLCs.
Affiliation: College of Pharmacy, Keimyung University, Daegu, South Korea.