Abstract
Cancer stem cells (CSCs) are considered a serious sub-population in cancer tissues because of their strong resistance to conventional chemotherapy and radiotherapy. Thus, the current advancements in the use of liver cancer stem cells (LCSC) to develop efficient and organized means to an antitumor agent is quickly gaining recognition as a novel goal. Previously, we characterized CSCs in primary hepatocellular carcinoma (HCC) and identified CD133 as a CSC cell-surface marker. In this study, we proposed to use non-target based high throughput screening (HTS) approach to specifically target AFP+/CD133+ HCC present in mixed populations of HCC cells with hepatocytes. Through screening, we identified oxytetracycline, which showed significant inhibition activity of LCSC population without damage on hepatocytes. To determine whether oxytetracycline targets LCSC, we examined whether oxytetracycline treatment could change the CD133 expression, spheroid forming ability as well as the levels of stem cell-related markers. Treatment of spheroid-forming LCSC with oxytetracycline effectively decreased the spheroid formation and the CD133+ cell population. oxytetracycline could suppress expression of CD133 without changing of expression of other stem cell-related markers. Importantly, these series of phenomena by oxytetracycline occurs because of alteration of CD133 protein stability by oxytetracycline. Alterations in the malignant properties of AFP+/CD133+ HCC by oxytetracycline were also investigated by xenograft assay in nude mice. Treatment of oxytetracycline significantly attenuated tumor formation and CD133+ cell population in xenograft mice. These results indicate that the oxytetracycline suppresses stemness and malignancies in HCC cells through destabilization of CD133 in LCSC population, providing novel therapeutic strategies targeting specifically cancer stem-like cells.
Highlights
Liver cancer stem cells (LCSCs) is quickly gaining recognition as a novel goal to develop efficient antitumor agents[5,6]
Compounds were screened at an initial concentration of 10 uM with a readout looking at a decreased liver cancer stem cells (LCSC) population but not hepatocellular carcinoma (HCC) (AFP+/CD133−), hepatocyte (AFP−/CD133−) population [Fig. 1B]
Here, we have developed the mixed HCC cell population using HCC cells and hepatocytes that are state of the art, comparable with the mixed culture system published in the literature
Summary
Liver cancer stem cells (LCSCs) is quickly gaining recognition as a novel goal to develop efficient antitumor agents[5,6]. Resistance to radio- and chemotherapy remains elusive, and research in these areas will directly translate into acquisition of novel technologies and improved knowledge of fundamental biological knowledge For this reason, we focused on elucidation of chemotherapy resistance mechanisms in LCSC to define novel target for liver cancer therapy. We aimed to develop LCSC-specific drugs that could induce cell death in LCSC, while minimizing the damage to normal hepatocytes, in a mixed cell culture system containing hepatocytes, LCSC and HCC cells To this end, we developed image-based approaches to quantify complex HCC cell populations, in terms of cellular phenotype and global cell population evaluations that could be used for drug discovery for liver cancer therapy. We performed screening to identify compounds that alter the properties of the LCSC in HCC-mixed population
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