Abstract
Various derivatives that mimic ceramide structures by introducing a triazole to connect the aminodiol moiety and long alkyl chain have been synthesized and screened for their anti-leukemia activity. SPS8 stood out among the derivatives, showing cytotoxic selectivity between leukemic cell lines and human peripheral blood mononuclear cells (about ten times). DAPI nuclear staining and H&E staining revealed DNA fragmentation under the action of SPS8. SPS8 induced an increase in intracellular Ca2+ levels and mitochondrial stress in HL-60 cells identified by the loss of mitochondrial membrane potential, transmission electron microscopy (TEM) examination, and altered expressions of Bcl-2 family proteins. SPS8 also induced autophagy through the detection of Atg5, beclin-1, and LC3 II protein expression, as well as TEM examination. Chloroquine, an autophagy inhibitor, promoted SPS8-induced apoptosis, suggesting the cytoprotective role of autophagy in hindering SPS8 from apoptosis. Furthermore, SPS8 was shown to alter the expressions of a variety of genes using a microarray analysis and volcano plot filtering. A further cellular signaling pathways analysis suggested that SPS8 induced several cellular processes in HL-60, including the sterol biosynthesis process and cholesterol biosynthesis process, and inhibited some cellular pathways, in which STAT3 was the most critical nuclear factor. Further identification revealed that SPS8 inhibited the phosphorylation of STAT3, representing the loss of cytoprotective activity. In conclusion, the data suggest that SPS8 induces both apoptosis and autophagy in leukemic cells, in which autophagy plays a cytoprotective role in impeding apoptosis. Moreover, the inhibition of STAT3 phosphorylation may support SPS8-induced anti-leukemic activity.
Highlights
Leukemia involves various malignant conditions that influence blood and its forming tissues
Normal hematopoiesis is inhibited in leukemia by the uncontrolled production and accumulation of leukemic cells, which are classified according to the types of cells affected and the developmental stages of the initiating cells, and are categorized into acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphoblastic leukemia (CLL) [1,2]
An MTT assay, which relies on a mitochondrial reductase to convert tetrazolium compound to formazan, was applied in this study, to assess the SPS8-induced cytotoxicity in HL-60 and human peripheral blood mononuclear cells (PBMCs)
Summary
Leukemia involves various malignant conditions that influence blood and its forming tissues. Normal hematopoiesis is inhibited in leukemia by the uncontrolled production and accumulation of leukemic cells, which are classified according to the types of cells affected and the developmental stages of the initiating cells, and are categorized into acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphoblastic leukemia (CLL) [1,2]. Leukemia remains a key tumor for the rational design of chemotherapeutic approaches and drug discovery [3,4]. Significant progress has been made in some types of leukemia, such as CML and CLL, cytotoxic therapy for AML and acute promyelocytic leukemia (APL) has remained more-or-less unaltered in recent decades. AML is composed of cancer stem cells that are responsible for disease progression, drug resistance, and relapse after treatment. The detection of intracellular signaling has demonstrated the dysfunction of multiple pathways in AML, which has made researchers rethink current approaches and attracted attention to identifying novel therapeutic targets for AML treatment [5]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
