Importance of cell death (Pallis, 2000). Cell death can be broadly divided into two categories. Necrosis is the process in which cells die because of external stimuli. Apoptosis is a carefully controlled cellular mechanism which is induced by the cell. In the simplest terms, it can be seen as cellular suicide. Recent studies have implicated Pgp in modulation of apoptosis. Apoptotic pathways represent one way of controlling tumor formation, and so an agent which inhibits the cellular signals which lead to apoptosis could potentially augment the survival rate of tumor cells. Pgp is thought to modulate apoptosis through a variety of cellular mechanisms including the sphingomyelin-ceramide, fas ligand, and UV-induced caspase pathways.

Pgp and apoptosis (Pallis, 2000). Cultured acute myeloblastic leukemia (AML) cells were used to study apoptosis and Pgp by comparing cells which were or were not exposed to Pgp inhibitors. Cell death was induced by withholding serum and growth factors from cell cultures, and flow cytometry (a technique using fluorescene to analyze cell populations) was used to analyze the results. Approximately 50% of the cells which were simply deprived of nutrients were nonviable after 48 hours (Figure 27). In Figure 27, the % in each box indicates the number of non-viable cells. The cell populations in boxes A and B were not exposed to a Pgp inhibitor while the cell populations analyzed in boxes C and D were exposed to Pgp inhibitors. Flow cytometry revealed that the majority of the cells which were nonviable seemed to be necrotic rather than apoptotic. These cells still possessed functional Pgp and so the observed cell death was not mediated by apoptotic mechanisms. In contrast, the cells which were exposed to Pgp inhibitors(Figure 27C/D) exhibited a much higher rate of cell death, approximately 80%. Even more interesting, the majority of the dying cells were undergoing apoptosis, not necrosis. When Pgp was inhibited, the cells were able to undergo apoptosis in response to starvation conditions. These results implicate Pgp in the regulation of apoptotic mechanisms in addition to its role as a drug efflux pump.

Figure 27 (figure taken from Pallis, 2000)