Versatile inhibitory effects of the flavonoid-derived PI3K/Akt inhibitor, LY294002, on ATP-binding cassette transporters that characterize stem cells

Stem cells are undifferentiated cells capable of proliferation, self-renewal, production of a large number of differentiated progeny, and regeneration of tissues [1]. In addition to embryonic stem (ES) cells, stem cells also exist in various adult tissues such as skin, bone marrow, liver, striated muscle, and brain [1]. After tissue damage, they not only replenish the tissue they originally resided but also may contribute to repair another tissue. Cells with stem-cell qualities have also been identified in malignancies of hematopoietic origin and in some solid tumors [2]. The cells, called cancer stem cells or cancer stem-like cells, share many properties of normal stem cell, such as relative quiescence, resistance to drugs and toxins, an active DNA-repair capacity, and a resistance to apoptosis, thus providing for a long lifespan.For decades, the unregulated growth of cancers was attributed to the serial acquisition of genetic events that resulted in the activation of oncogenes and silencing of tumor suppressor genes involved in apoptosis. Now, it is recognized that another key event in tumor progression is the alterations of genes involved in regulation of stem cell renewal. When cancer cells of different origins were analyzed for their proliferative potential in various assays, only a small minority of cells were able to proliferate extensively. Those cells, i.e., cancer stem cells, are derived either from transformed normal stem cells or more differentiated progenitor cells that have acquired the ability of self-renewal as a result of oncogenic mutation [3]. Thus, cancer stem cells may represent the origin of cancer and furthermore would play a pivotal role in maintaining cancer cell population. In this point of view, characterization of cancer stem cells would be significant and important for clinical cancer treatment.Stem cells can be purified based on the efflux of fluorescent dyes such as rhodamine 123 (rho123) and Hoechst 33342 (Hoechst). A widely used flow