Abstract
Chronic myeloid leukemia (CML) is a hematologic malignancy derived from the myeloid lineage molecularly characterized by t(9;22)(q34;q11) resulting in BCR-ABL1 gene fusion, which is known as Philadelphia (Ph) chromosome. Although tyrosine kinase inhibitors (TKIs) have restored and maintained the quality of life of patients with CML, an important minority of patients become resistant to first-and-second-generation TKIs and require an alternative treatment. The K562 cell (Ph+, p53-/-) line was treated with Vit E TPGS 1000 (20–80 μM) only or with other products of interest (e.g., antioxidant N-acetylcysteine (NAC), specific JNK and caspase-3 inhibitor SP600125, and NSCSI, respectively) for 24 h at 37°C. Cells were analyzed by fluorescence microscopy (FM), flow cytometry (FC), and Western blotting (WB) techniques. We show that TPGS induces apoptosis in K562 cells through H2O2 signaling mechanism comprising the activation of a minimal molecular cascade: the kinase JNK>the transcription factor c-JUN>the activation of BCL-only BH3 proapoptotic protein PUMA>loss of mitochondrial membrane potential (ΔΨm)>activation of caspase-3>chromatin condensation>fragmentation of DNA. Additionally, TPGS oxidizes the stress sensor protein DJ-1-Cys106-SH into DJ-1-Cys106-SO3 and arrested the cell cycle in the S phase. Remarkably, NAC, SP600125, and NSCSI blocked TPGS-induced OS and apoptosis in K562. Since TPGS is safe in mice and humans, it is especially promising for preclinical and clinical CML leukemia research. Our findings support the view that oxidation therapy offers an important opportunity to eliminate CML.
Highlights
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm of the bone marrow [1] characterized by a genetic alteration known as chromosome Philadelphia (Ph), which consists of the fusion of the Abelson murine leukemia (ABL1) gene on chromosome 9 with the breakpoint cluster region (BCR) gene on chromosome 22 [2]
To study the effect of tocopheryl polyethylene glycol succinate (TPGS) on CML cells, we first treated human K562 cells with increasing concentrations of TPGS (10–80 μM) for 24 h and stained the untreated or treated cells with mitochondrial lipophilic dye DiOC6(3) and nuclei with Propidium iodide (PI) to assess the viability of the cell in terms of the plasma membrane, ΔΨm, and nucleus integrity
Flow cytometry analysis (Figure 1) shows that the viability of K562 cells was concentration-dependently reduced by TPGS (Figure 1(a), quadrant Q3), reflected as a loss of ΔΨm and increased DNA fragmentation (Figure 1(a), Q1+Q4) and typical of apoptosis (Figures 1(b) and 1(c))
Summary
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm of the bone marrow [1] characterized by a genetic alteration known as chromosome Philadelphia (Ph), which consists of the fusion of the Abelson murine leukemia (ABL1) gene on chromosome 9 with the breakpoint cluster region (BCR) gene on chromosome 22 [2]. This gene fusion results in the expression of an oncoprotein termed BCRABL1 [3, 4]. It is urgent to investigate alternative therapeutic approaches such as natural product compounds and organic/synthetic new chemical entities [8,9,10,11] for CML treatment
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