Selective Targeting of Cancer Stem Cells by 2-Aminodihydroquinoline Analogs

Abstract

Many aminodihydroquinoline compounds have been studied to determine their cytotoxicity to cancer cells. However, anti-cancer stem cells (CSCs) activity of aminodihydroquinoline has not been tested in spite that CSC is believed to do an important roles in chemotherapy resistance and recurrence. The CSC selective targeting activities of 10 recently synthesized 2-aminodihydroquinoline analogs were examined on CSCs and bulk culture of a glioblastoma cell line. A diethylaminopropyl substituted aminodihydroquinoline, 5h, showed a strong anti-CSC effect and general cytotoxicity. However, a benzyl substituted aminodihydroquinoline, 5i, displayed the most effective anti-CSC effect, with no or small significant cytotoxic effect in bulk culture conditions. While 5h temporarily enhanced CSC marker-positive cells and eventually suppressed the CSC population, which is similar to other cytotoxic anticancer reagents reported, 5i selectively eliminated CSC marker-positive cells based on fluorescence activated cell sorter (FACS) analysis. 5h also temporarily activated some genes associated with signaling required for CSC, while 5i selectively suppressed these genes supporting that the differential effects are resulted from different molecular responses. In addition, the selective CSC effect is also found against a colon cancer cell line. Collectively, we suggest that these two novel aminodihydroquinoline compounds possess novel anti-CSC effects in colon and brain tumor derived cell lines probably through independent pathways. Key words 2-aminodihydroquinoline; cancer stem cell; selective targeting More than 50 years ago, it was noted that heterogeneous cell populations may exist in a tumor, and that in vivo tumor intimating cells are only a small portion of the tumor.1,2) These tumor initiating cells have been isolated from most types of tumors. These cells are now referred to as cancer stem cells (CSC) because they share many characteristics with tissue stem cells and mediate stem-like roles in cancer.2) Due to the critical roles of CSCs in chemotherapy and radiotherapy resistance, many pre-clinical studies and clinical trials have been undertaken to develop new strategies to eliminate CSCs. 3)Several novel compounds have been developed and are under evaluation as CSC therapeutics (reviewed in Jung et al. 3)). The majority of currently used clinical anti-cancer reagents target the fast proliferation effect of cancer cells. Most of those chemo-therapeutic agents have been developed based on their cytotoxic effect since the first chemotherapeutic agent, aminopterin, was used for leukemia in 1947. 4,5) Since then, hundreds of thousands of chemicals have been developed as cancer therapies to target cancer cell cycle. However, acquired resistance is the most serious problem for virtually all currently used chemotherapeutic agents. Therefore, to overcome chemo-resistance, anti-CSC agents need to be urgently developed. Aminodihydroquinoline analogs have attracted attention in drug discovery due to their variable range of biological act...

DJ-1 Contributes to Self-renewal of Stem Cells in the U87-MG Glioblastoma Cell Line

“…By contrast, clonogenicity did not significantly differ between DJ-1-depleted and control U251 cells. We next quantified ALDH bright cells as an indicator of CSCs (18)(19)(20).…”