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Anti-tumor activity of WK88-1, a novel geldanamycin derivative, in gefitinib-resistant non-small cell lung cancers with Met amplification.

Jang WJ, Jung SK, Kang JS, Jeong JW, Bae MK, Joo SH, Park GH, Kundu JK, Hong YS, Jeong CH - Cancer Sci. (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Keimyung University, Daegu, South Korea.

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WK88-1 suppresses the proliferation of gefitinib-resistant non-small cell lung cancers (NSCLCs) via the downregulation of oncogenic RTKs. Gefitinib-sensitive HCC827 cells (a) and resistant HCC827GR cells (b) were treated with the indicated concentration of GA derivatives for 3 days, and cell proliferation was estimated using the MTS assay. Cell viability relative to controls was determined after 3 days. Data shown are the representative of 5 independent experiments. Error bars represent the mean ± SD. Statistical significance was determined by the Student's t-test (***P < 0.001). Effect of GA derivatives on the expression or activity of EGFR, Met, ErbB3, and downstream proteins (c). Cells were treated with 1 μM GA derivatives for 24 h and whole cell lysates were assayed by Western blot. β-Actin was used as a loading control. GA, Geldanamycin; G, Gefitinib; W1, WK88-1; W2, WK88-2, W3, WK88-3.
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fig02: WK88-1 suppresses the proliferation of gefitinib-resistant non-small cell lung cancers (NSCLCs) via the downregulation of oncogenic RTKs. Gefitinib-sensitive HCC827 cells (a) and resistant HCC827GR cells (b) were treated with the indicated concentration of GA derivatives for 3 days, and cell proliferation was estimated using the MTS assay. Cell viability relative to controls was determined after 3 days. Data shown are the representative of 5 independent experiments. Error bars represent the mean ± SD. Statistical significance was determined by the Student's t-test (***P < 0.001). Effect of GA derivatives on the expression or activity of EGFR, Met, ErbB3, and downstream proteins (c). Cells were treated with 1 μM GA derivatives for 24 h and whole cell lysates were assayed by Western blot. β-Actin was used as a loading control. GA, Geldanamycin; G, Gefitinib; W1, WK88-1; W2, WK88-2, W3, WK88-3.

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.


Anti-tumor activity of WK88-1, a novel geldanamycin derivative, in gefitinib-resistant non-small cell lung cancers with Met amplification.

Jang WJ, Jung SK, Kang JS, Jeong JW, Bae MK, Joo SH, Park GH, Kundu JK, Hong YS, Jeong CH - Cancer Sci. (2014)

WK88-1 suppresses the proliferation of gefitinib-resistant non-small cell lung cancers (NSCLCs) via the downregulation of oncogenic RTKs. Gefitinib-sensitive HCC827 cells (a) and resistant HCC827GR cells (b) were treated with the indicated concentration of GA derivatives for 3 days, and cell proliferation was estimated using the MTS assay. Cell viability relative to controls was determined after 3 days. Data shown are the representative of 5 independent experiments. Error bars represent the mean ± SD. Statistical significance was determined by the Student's t-test (***P < 0.001). Effect of GA derivatives on the expression or activity of EGFR, Met, ErbB3, and downstream proteins (c). Cells were treated with 1 μM GA derivatives for 24 h and whole cell lysates were assayed by Western blot. β-Actin was used as a loading control. GA, Geldanamycin; G, Gefitinib; W1, WK88-1; W2, WK88-2, W3, WK88-3.
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fig02: WK88-1 suppresses the proliferation of gefitinib-resistant non-small cell lung cancers (NSCLCs) via the downregulation of oncogenic RTKs. Gefitinib-sensitive HCC827 cells (a) and resistant HCC827GR cells (b) were treated with the indicated concentration of GA derivatives for 3 days, and cell proliferation was estimated using the MTS assay. Cell viability relative to controls was determined after 3 days. Data shown are the representative of 5 independent experiments. Error bars represent the mean ± SD. Statistical significance was determined by the Student's t-test (***P < 0.001). Effect of GA derivatives on the expression or activity of EGFR, Met, ErbB3, and downstream proteins (c). Cells were treated with 1 μM GA derivatives for 24 h and whole cell lysates were assayed by Western blot. β-Actin was used as a loading control. GA, Geldanamycin; G, Gefitinib; W1, WK88-1; W2, WK88-2, W3, WK88-3.
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.

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.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Keimyung University, Daegu, South Korea.

Show MeSH
Related in: MedlinePlus