PURPOSE: Of more than one million global cases of breast cancer diagnosed each year, a high percentage are characterized as triple-negative, lacking the oestrogen, progesterone and Her2/neu receptors. The incidence exceeds the incidence of malignancies like CML by far. Lack of effective therapies, younger age at onset and early metastatic spread have contributed to the poor prognosis and outcomes associated with these malignancies. METHODS: Here, we investigate the ability of the PI3K/AKT inhibitor AEZS 126 to selectively target the triple-negative breast cancer (TNBC) cell proliferation and survival in vitro by MTT-assays and FACS-based analysis. Furthermore, the mechanism of cytotoxicity is analysed by FACS-based assays and Western blots. RESULTS: AEZS 126 showed good anti-tumour activity in in vitro models of TNBC as well as in MCF-7 cells. Main mechanism of cytotoxicity seems to be programmed cell death after an incubation time of 72 h, which could be abrogated by co-incubation with z-VAD-fmk in MCF-7 and MDA-MB468 cells. In HCC1806 cells, addition of necrostatin-1 has only slightly protective effects, but in HCC1937 cells, the addition of necrostatin-1 has the same protective effect as co-incubation with z-VAD-fmk, and this observation argues for cell death caused by apoptosis and necroptosis in this cell line. CONCLUSION: We demonstrated the highly efficient anti-tumour activity of AEZS 126 in in vitro models of TNBC. Due to the good anti-tumour activity and the expected favourable toxicity profile, AEZS 126 in combination with chemotherapy seems to be a promising candidate for clinical testing in TNBC especially in the basal-like subgroup of TNBC.
PURPOSE: Of more than one million global cases of breast cancer diagnosed each year, a high percentage are characterized as triple-negative, lacking the oestrogen, progesterone and Her2/neu receptors. The incidence exceeds the incidence of malignancies like CML by far. Lack of effective therapies, younger age at onset and early metastatic spread have contributed to the poor prognosis and outcomes associated with these malignancies. METHODS: Here, we investigate the ability of the PI3K/AKT inhibitor AEZS 126 to selectively target the triple-negative breast cancer (TNBC) cell proliferation and survival in vitro by MTT-assays and FACS-based analysis. Furthermore, the mechanism of cytotoxicity is analysed by FACS-based assays and Western blots. RESULTS:AEZS 126 showed good anti-tumour activity in in vitro models of TNBC as well as in MCF-7 cells. Main mechanism of cytotoxicity seems to be programmed cell death after an incubation time of 72 h, which could be abrogated by co-incubation with z-VAD-fmk in MCF-7 and MDA-MB468 cells. In HCC1806 cells, addition of necrostatin-1 has only slightly protective effects, but in HCC1937 cells, the addition of necrostatin-1 has the same protective effect as co-incubation with z-VAD-fmk, and this observation argues for cell death caused by apoptosis and necroptosis in this cell line. CONCLUSION: We demonstrated the highly efficient anti-tumour activity of AEZS 126 in in vitro models of TNBC. Due to the good anti-tumour activity and the expected favourable toxicity profile, AEZS 126 in combination with chemotherapy seems to be a promising candidate for clinical testing in TNBC especially in the basal-like subgroup of TNBC.
Authors: Brian D Lehmann; Joshua A Bauer; Xi Chen; Melinda E Sanders; A Bapsi Chakravarthy; Yu Shyr; Jennifer A Pietenpol Journal: J Clin Invest Date: 2011-07 Impact factor: 14.808
Authors: G Frasci; P Comella; M Rinaldo; G Iodice; M Di Bonito; M D'Aiuto; A Petrillo; S Lastoria; C Siani; G Comella; G D'Aiuto Journal: Ann Oncol Date: 2009-02-13 Impact factor: 32.976
Authors: Richard D Kennedy; Jennifer E Quinn; Paul B Mullan; Patrick G Johnston; D Paul Harkin Journal: J Natl Cancer Inst Date: 2004-11-17 Impact factor: 13.506