Vitamin E TPGS 1000 Induces Apoptosis in the K562 Cell Line: Implications for Chronic Myeloid Leukemia

Figure 9

Proposed model of minimal completeness of cell death signaling induced by TPGS as a mechanistic explanation of CML cell demise. The TPGS (step 1) triggers a cell death subroutine in K562, a well-established model of CML. Once TPGS enters the cell, it is metabolically processed by cytoplasmic esterases and converted into alpha-tocopherol acetate (α-TOS, s2). This compound targets mitochondrial complex I or II (s3), resulting in an over generation of ROS-H₂O₂ (s4). The signaling molecule H₂O₂ either oxidized the oxidative sensor protein DJ-1-Cys106-SH into DJ-1-SO₃ (s5) or indirectly activated prodeath kinases (ASK-1 (s6) and MKK4 (s7)) and JNK (s8), which in turn activate c-JUN (s9). This transcription factor transcribes proapoptotic PUMA (s10), contributing to the permeabilization of the outer mitochondrial membrane (s11). Mitochondrial damage allows the release of apoptogenic proteins such as cytochrome c and ATP, which are responsible for the formation of an apoptosome complex (s12) and activation of caspase-3 protease (s13). This protease in turn activates the endonucleases DFF40/CAD, by cutting the nuclease’s inhibitor DFF45/ICAD. Finally, DFF40/CAD causes nuclear chromatin fragmentation (s14), typical of apoptosis. Remarkably, the antioxidant N-acetylcysteine (NAC, red stop signs in s4), the specific JNK inhibitor SP600125 (red stop sign in s8), and the specific caspase-3 inhibitor NSCI (red stop sign in s13) block TPGS-induced apoptosis in K562 ratifying the involvement of OS signaling and caspase-3 as end-executor protein in the apoptotic pathway in this leukemia cell line. The TPGS-induced cell death mechanism provides the basis for an oxidative therapy strategy to combat leukemia.