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Inhibition of non-small cell lung cancer (NSCLC) growth by a novel small molecular inhibitor of EGFR.

Li J, Deng H, Hu M, Fang Y, Vaughn A, Cai X, Xu L, Wan W, Li Z, Chen S, Yang X, Wu S, Xiao J - Oncotarget (2015)

Bottom Line: WB-308 decreased NSCLC cell proliferation and colony formation, by causing G2/M arrest and apoptosis.Furthermore, WB-308 inhibited the engraft tumor growths in two animal models in vivo (lung orthotopic transplantation model and patient-derived engraft mouse model).WB-308 was less cytotoxic than Gefitinib.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.

ABSTRACT
The epidermal growth factor receptor (EGFR) is a therapeutic target (oncotarget) in NSCLC. Using in vitro EGFR kinase activity system, we identified a novel small molecule, WB-308, as an inhibitor of EGFR. WB-308 decreased NSCLC cell proliferation and colony formation, by causing G2/M arrest and apoptosis. Furthermore, WB-308 inhibited the engraft tumor growths in two animal models in vivo (lung orthotopic transplantation model and patient-derived engraft mouse model). WB-308 impaired the phosphorylation of EGFR, AKT, and ERK1/2 protein. WB-308 was less cytotoxic than Gefitinib. Our study suggests that WB-308 is a novel EGFR-TKI and may be considered to substitute for Gefitinib in clinical therapy for NSCLC.

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Related in: MedlinePlus

WB-308 exhibits evidences to be a better EGFR inhibitor than Gefitinib11 NSCLC cell lines (HCC-827, PC-9, NCI-H1650, SPC-A1, A549, NCI-H1975, HCC-827GR, MRC-5, HFL1, IMR-90 and BEAS-2B) were subjected to the cell viability assay stained by SRB as described in Materials and Methods. Columns, mean; bars, SE (n = 3; t-test, P < 0.05).
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Figure 3: WB-308 exhibits evidences to be a better EGFR inhibitor than Gefitinib11 NSCLC cell lines (HCC-827, PC-9, NCI-H1650, SPC-A1, A549, NCI-H1975, HCC-827GR, MRC-5, HFL1, IMR-90 and BEAS-2B) were subjected to the cell viability assay stained by SRB as described in Materials and Methods. Columns, mean; bars, SE (n = 3; t-test, P < 0.05).

Mentions: The aforementioned results suggest that WB-308 inhibits the proliferation of NSCLC cells. Furthermore, we questioned if WB-308 had ideal selective effects between NSCLC cells and healthy human lung tissue cells, such as the human lung fibroblast cell MRC-5, and the normal human lung epithelial cells including HFL1, IMR-90 and BEAS-2B, compared to Gefitinib. Eleven NSCLC cell lines, including HCC-827, PC-9, NCI-H1650, SPC-A1, A549, NCI-H1975 and HCC-827GR, together with the human normal lung tissue cells MRC-5, HFL1, IMR-90 and BEAS-2B, were utilized to conduct the cell viability assay. A549 and SPC-A1 represent the wild type EGFR while in PC-9 the 19 del (Del E746–A750) mutation of EGFR occurs, and NCI-H1975, NCI-H1650, and HCC-827 all three possess the T790M mutation of EGFR. HCC-827GR cells contain Met amplification after the T790M mutation occurred. SRB assay results clearly showed that the half maximal inhibitory concentration for WB-308 inhibition of NSCLC cellular proliferation was approximately 5 μM, while that of 4 human normal lung tissue cells were much more than 100 μM (Figure 3). In short, WB-308 was more toxic to NSCLC cells than to normal lung tissue cells. Meanwhile, WB-308 at all concentrations caused less cytotoxicity to 4 human normal lung tissue cells than did Gefitinib (Figure 3 for MRC-5, HFL1, IMR-90 and BEAS-2B), which suggested that WB-308 had higher levels of bio-safety than Gefitinib. Although in these 6 EGFR-WT or EGFR-mutated cells, WB-308 showed comparable effects to Gefitinib, regardless of cell type. In each of EGFR-WT cells (SPC-A1 and A549), EGFR T790M mutant cells (NCI-H1975), or in Met-amplification cells (HCC-827GR), WB-308 caused severe inhibition effects when compared with Gefitinib (Figure 3), indicating that WB-308 should have less toxicity. Therefore, it can be considered that WB-308 has unique properties compared to the existing EGFR inhibitor Gefitinib and may serve as a better EGFR inhibitor than Gefitinib.


Inhibition of non-small cell lung cancer (NSCLC) growth by a novel small molecular inhibitor of EGFR.

Li J, Deng H, Hu M, Fang Y, Vaughn A, Cai X, Xu L, Wan W, Li Z, Chen S, Yang X, Wu S, Xiao J - Oncotarget (2015)

WB-308 exhibits evidences to be a better EGFR inhibitor than Gefitinib11 NSCLC cell lines (HCC-827, PC-9, NCI-H1650, SPC-A1, A549, NCI-H1975, HCC-827GR, MRC-5, HFL1, IMR-90 and BEAS-2B) were subjected to the cell viability assay stained by SRB as described in Materials and Methods. Columns, mean; bars, SE (n = 3; t-test, P < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466647&req=5

Figure 3: WB-308 exhibits evidences to be a better EGFR inhibitor than Gefitinib11 NSCLC cell lines (HCC-827, PC-9, NCI-H1650, SPC-A1, A549, NCI-H1975, HCC-827GR, MRC-5, HFL1, IMR-90 and BEAS-2B) were subjected to the cell viability assay stained by SRB as described in Materials and Methods. Columns, mean; bars, SE (n = 3; t-test, P < 0.05).
Mentions: The aforementioned results suggest that WB-308 inhibits the proliferation of NSCLC cells. Furthermore, we questioned if WB-308 had ideal selective effects between NSCLC cells and healthy human lung tissue cells, such as the human lung fibroblast cell MRC-5, and the normal human lung epithelial cells including HFL1, IMR-90 and BEAS-2B, compared to Gefitinib. Eleven NSCLC cell lines, including HCC-827, PC-9, NCI-H1650, SPC-A1, A549, NCI-H1975 and HCC-827GR, together with the human normal lung tissue cells MRC-5, HFL1, IMR-90 and BEAS-2B, were utilized to conduct the cell viability assay. A549 and SPC-A1 represent the wild type EGFR while in PC-9 the 19 del (Del E746–A750) mutation of EGFR occurs, and NCI-H1975, NCI-H1650, and HCC-827 all three possess the T790M mutation of EGFR. HCC-827GR cells contain Met amplification after the T790M mutation occurred. SRB assay results clearly showed that the half maximal inhibitory concentration for WB-308 inhibition of NSCLC cellular proliferation was approximately 5 μM, while that of 4 human normal lung tissue cells were much more than 100 μM (Figure 3). In short, WB-308 was more toxic to NSCLC cells than to normal lung tissue cells. Meanwhile, WB-308 at all concentrations caused less cytotoxicity to 4 human normal lung tissue cells than did Gefitinib (Figure 3 for MRC-5, HFL1, IMR-90 and BEAS-2B), which suggested that WB-308 had higher levels of bio-safety than Gefitinib. Although in these 6 EGFR-WT or EGFR-mutated cells, WB-308 showed comparable effects to Gefitinib, regardless of cell type. In each of EGFR-WT cells (SPC-A1 and A549), EGFR T790M mutant cells (NCI-H1975), or in Met-amplification cells (HCC-827GR), WB-308 caused severe inhibition effects when compared with Gefitinib (Figure 3), indicating that WB-308 should have less toxicity. Therefore, it can be considered that WB-308 has unique properties compared to the existing EGFR inhibitor Gefitinib and may serve as a better EGFR inhibitor than Gefitinib.

Bottom Line: WB-308 decreased NSCLC cell proliferation and colony formation, by causing G2/M arrest and apoptosis.Furthermore, WB-308 inhibited the engraft tumor growths in two animal models in vivo (lung orthotopic transplantation model and patient-derived engraft mouse model).WB-308 was less cytotoxic than Gefitinib.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.

ABSTRACT
The epidermal growth factor receptor (EGFR) is a therapeutic target (oncotarget) in NSCLC. Using in vitro EGFR kinase activity system, we identified a novel small molecule, WB-308, as an inhibitor of EGFR. WB-308 decreased NSCLC cell proliferation and colony formation, by causing G2/M arrest and apoptosis. Furthermore, WB-308 inhibited the engraft tumor growths in two animal models in vivo (lung orthotopic transplantation model and patient-derived engraft mouse model). WB-308 impaired the phosphorylation of EGFR, AKT, and ERK1/2 protein. WB-308 was less cytotoxic than Gefitinib. Our study suggests that WB-308 is a novel EGFR-TKI and may be considered to substitute for Gefitinib in clinical therapy for NSCLC.

Show MeSH
Related in: MedlinePlus