TY - JOUR
T1 - Dithiiranylmethyloxy azaxanthone shows potent anti-tumor activity via suppression of HER2 expression and HER2-mediated signals in HER2-overexpressing breast cancer cells
AU - Nam, Jung Min
AU - Jeon, Kyung Hwa
AU - Kwon, Hanbyeol
AU - Lee, Eunyoung
AU - Jun, Kyu Yeon
AU - Jin, Yeung Bae
AU - Lee, Yun Sil
AU - Na, Younghwa
AU - Kwon, Youngjoo
N1 - Funding Information:
This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009-0071926, 2009-0066925, 2010-0002646).
PY - 2013
Y1 - 2013
N2 - Dithiiranylmethyloxy azaxanthone (CHO10), which was discovered by screening compounds in a reporter gene assay, inhibited the ESX-Sur2 interaction in a dose-dependent manner with potency similar to canertinib. The intervention of CHO10 during the ESX-Sur2 interaction caused down-regulation of both HER2 gene amplification and HER2 protein expression, which led to the attenuation of HER2-mediated downstream signal cascades and autocrine cell growth in SK-BR-3 cells, which are HER2 overexpressing breast cancer cells. The cell growth inhibitory activity of CHO10 was more potent in HER2-overexpressing breast cancer cells (AU-565, BT474 and SK-BR-3) than in HER2-negative cells (HEK293) and breast cancer cells (MCF-7) that express a basal level of HER2. Treatment with CHO10 in combination with tamoxifen sensitized BT474 cells, tamoxifen-resistant ER-positive breast cancer cell line, toward chemotherapeutic. The anti-tumor activity of CHO10 was validated by the significant reduction in tumor size of NCI-H460 or DLD-1 subcutaneously implanted xenograft tumors through treatment with 1 mg/kg five times every other 2 days.
AB - Dithiiranylmethyloxy azaxanthone (CHO10), which was discovered by screening compounds in a reporter gene assay, inhibited the ESX-Sur2 interaction in a dose-dependent manner with potency similar to canertinib. The intervention of CHO10 during the ESX-Sur2 interaction caused down-regulation of both HER2 gene amplification and HER2 protein expression, which led to the attenuation of HER2-mediated downstream signal cascades and autocrine cell growth in SK-BR-3 cells, which are HER2 overexpressing breast cancer cells. The cell growth inhibitory activity of CHO10 was more potent in HER2-overexpressing breast cancer cells (AU-565, BT474 and SK-BR-3) than in HER2-negative cells (HEK293) and breast cancer cells (MCF-7) that express a basal level of HER2. Treatment with CHO10 in combination with tamoxifen sensitized BT474 cells, tamoxifen-resistant ER-positive breast cancer cell line, toward chemotherapeutic. The anti-tumor activity of CHO10 was validated by the significant reduction in tumor size of NCI-H460 or DLD-1 subcutaneously implanted xenograft tumors through treatment with 1 mg/kg five times every other 2 days.
KW - Azaxanthone derivatives
KW - ESX-Sur2 interaction inhibitor
KW - Epidermal growth factor receptor
KW - Human epidermal growth factor receptor 2
KW - Tamoxifen resistant breast cancer
UR - http://www.scopus.com/inward/record.url?scp=84881127838&partnerID=8YFLogxK
U2 - 10.1016/j.ejps.2013.06.014
DO - 10.1016/j.ejps.2013.06.014
M3 - Article
C2 - 23835029
AN - SCOPUS:84881127838
SN - 0928-0987
VL - 50
SP - 181
EP - 190
JO - European Journal of Pharmaceutical Sciences
JF - European Journal of Pharmaceutical Sciences
IS - 2
ER -