Potentiation of the growth inhibition activity of 2-({4-4-(acridin-9-ylamino)phenylthiophenyl}(2-hydroxyethyl)amino)ethan-1-ol (CK0402) by Herceptin in SKBR-3 human breast cancer cells

摘要

The 9-aminoacridine derivative, 2-({4-[4-(acridin-9-ylamino)phenylthio]phenyl}(2-hydroxyethyl) amino)ethan-1-ol (CK0402) was selected as a potential anticancer agent among a series of sulfur-containing 9-aminoacridine analogues. CK0402 is a topoisomerase II inhibitor and has been shown to exert impressive anticancer activities in both in vitro and in vivo assays. In the present study, we tested the effects of CK0402 in a panel of established human breast cancer cells with varying ER and HER2eu status. The ER(−) and HER2-overexpressing SKBR-3 cells were the most sensitive cells tested in growth inhibition to CK0402 treatment, and the growth inhibition was in a time-and concentration-dependent manner. In addition, CK0402 also induced stronger G2/M arrest, apoptosis and autophagy in SKBR-3 cells than in ER(+) and HER2(−) MCF-7 cells. To the best of our knowledge, CK0402 is the first 9-aminoacridine analogue to induce autophagy. These findings suggest that CK0402 may be effective against the more aggressive and malignant ER(−) and HER2-overexpressing breast cancer. Towards this end, we further demonstrated that the combination of CK0402 and Herceptin exhibited synergistic/additive cytotoxic effects in SKBR-3 cells using the median-effect/combination-index isobologram methodology (CI value). Our results indicate that the combination of CK0402 and Herceptin may be a potential therapeutic option against the more aggressive ER(−) and HER2-overexpressing breast cancer.