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Fig. 3 | Molecular Cancer

Fig. 3

From: A novel HSP90 inhibitor targeting the C-terminal domain attenuates trastuzumab resistance in HER2-positive breast cancer

Fig. 3

NCT-547 administration inhibits tumor growth in trastuzumab-resistant JIMT-1 xenografts in vivo. a JIMT-1 cells (3 × 106) were injected into the animals and tumor volumes were measured with a caliper every other day for up to 40 days. Data were analyzed by two-way ANOVA followed by Bonferroni’s post hoc test (**p < 0.01). b-c Tumor weights and images from the control and NCT-547 treated groups (***p < 0.001). d-e Histological changes were examined in multiple organs (H&E staining: lung, liver and kidney), and hepatic and renal function were assessed via ALT/AST activity and BUN concentrations in the animal serum (NS; not significant). AST: aspartate aminotransferase; ALT: alanine aminotransferase; BUN: blood urea nitrogen. f Effect of NCT-547 on proliferating tumor cells was examined by Ki-67 staining. Tissue sections were stained for Ki-67 (red) and DAPI (blue), and Ki-67-positive cells were counted (***p < 0.001). Apoptosis induction following treatment with NCT-547 was determined by TUNEL assay (***p < 0.001). g-h NCT-547 treatment resulted in marked reductions of HER2 (g) and ICD-HER2 (h) in vivo, as determined by immunostaining of full-length HER2 and ICD-HER (***p < 0.001). i NCT-547-treated mice showed reduced expression of ALDH1 (***p < 0.001). All images were taken with a confocal microscope (original magnification: × 500). The fluorescence intensities were analyzed using a histogram tool in the Carl Zeiss software package. Data was analyzed by unpaired Student’s t-test. j Hypothetical models of i) Mode of action of NCT-547 is targeting of the C-terminal domain of HSP90 without induction of HSR. N-terminal HSP90 inhibitor activates HSF-1 to induce translocation into the nucleus and binding to HSEs, resulting in increased transcription of HSPs, such as HSP27, HSP40, and HSP70 which contribute to the attenuation of apoptosis. ii) NCT-547 degrades truncated p95HER2 and HER family members, and disturbs hetero-dimerization. iii) NCT-547 eradicates both proliferating tumor cells and cancer stem cells. [Heat shock response, HSR; Heat shock factor-1, HSF-1, Heat shock element, HSE]

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