Abstract
Aim: To identify a drug that can effectively eliminate these cancer stem cells (CSCs) and determine its mode of action.Methods: CSCs were obtained from mouse induced pluripotent stem cells (miPSCs) using cancer cell-conditioned media. Drug screening was performed on these cells or after transplantation into mice. Apoptosis was analyzed by flow cytometry and western blotting.Results: Drug screening studies showed that daunorubicin, a topoisomerase II inhibitor, is specifically cytotoxic to miPS-CSCs. Daunorubicin-induced apoptosis was found to be associated with p53 accumulation, activation of the caspase cascade, and oligonucleosomal DNA fragmentation. Treatment with the caspase inhibitor abolished daunorubicin-induced DNA fragmentation and was therefore considered to act downstream of caspase activation. This was also suppressed by treatment with a Ca2+-specific chelator, which suggested that CAD endonuclease does not contribute. Moreover, no obvious ICAD reduction/degradation was detected.Conclusion: Daunorubicin effectively eliminated CSCs, which are dependent on the p53/caspase signaling cascade. The current findings provided the basis for further studies on CSC-targeted drugs for the development of cancer treatment strategies.
Highlights
Cancer stem cells (CSCs) are considered to be responsible for various pathological phenomena in cancer, such as tumor initiation, growth, tumor vascularization, recurrence, and metastasis[1,2]
We reported that culturing miPS-LLCcm cells without the differentiated population influenced the endothelial differentiation capacity of CSCs, thereby suggesting that the signal(s) from the endothelial cells contribute to endothelial differentiation of CSCs[11,12]
The miPS-LLCcm cells are cancer stem-like cells that are spontaneously generated from mouse induced pluripotent stem cells (miPSCs) cultured in the presence of CM of mouse Lewis lung cancer cells[8]
Summary
Cancer stem cells (CSCs) are considered to be responsible for various pathological phenomena in cancer, such as tumor initiation, growth, tumor vascularization, recurrence, and metastasis[1,2]. Multiple studies have consistently reported that the higher resistance capacity of CSCs against chemo- and/or radio-therapies compared to those of non-stem cancer cells significantly contributes to CSC survival after treatment. We have established mouse induced pluripotent stem cells (miPSCs) that possess self-renewal and differentiation capacities, as well as malignant tumorigenicity, which is in strong agreement with the definition of CSC[8,9,10]. These miPSCs-derived CSCs (miPS-CSCs) could be maintained in vitro under conditions that allow spontaneous differentiation. We concluded that the generated miPS-CSCs established their niche in vitro by autonomously sustaining self-renewal and differentiation, consistent with the endothelial/ perivascular niche of CSCs[13,14,15,16,17]. miPS-CSCs could serve as an advanced model for the development of antiCSC drugs
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