Abstract
Benzoxazole derivative K313 has previously been reported to possess anti-inflammatory effects in lipopolysaccharide-induced RAW264.7 macrophages. To date, there have been no related reports on the anticancer effects of K313. In this study, we found that K313 reduced the viability of human B-cell leukemia (Nalm-6) and lymphoma (Daudi) cells in a dose-dependent manner without affecting healthy peripheral blood mononuclear cells (PBMCs) and induced moderate cell cycle arrest at the G0/G1 phase. Meanwhile, K313 mediated cell apoptosis, which was accompanied by the activation of caspase-9, caspase-3, and poly ADP-ribose polymerase (PARP). Furthermore, cells treated with K313 showed a significant decrease in mitochondrial membrane potential (MMP), which may have been caused by the caspase-8-mediated cleavage of Bid, as detected by Western blot analysis. We also found that K313 led to the downregulation of p-p70S6K protein, which plays an important role in cell survival and cell cycle progression. In addition, treatment of these cells with K313 blocked autophagic flux, as reflected in the accumulation of LC3-II and p62 protein levels in a dose- and time-dependent manner. In conclusion, K313 decreases cell viability without affecting normal healthy PBMCs, induces cell cycle arrest and apoptosis, reduces p-p70S6K protein levels, and mediates strong autophagy inhibition. Therefore, K313 and its derivatives could be developed as potential anticancer drugs or autophagy blockers in the future.
Highlights
Human B-cell acute lymphoblastic leukemia (B-ALL), which is the most common childhood cancer, is an aggressive hematological disease accounting for ~70% of acute lymphoblastic leukemia [1,2]. childhood B-ALL has a good treatment outcome, with a five-year survival rate of ~90%, adults usually have worse outcomes, with five-year overall survival rates of 30% to 40% [3,4,5].Compared with a relapse rate of 20% in children, adults have a higher relapse rate of Molecules 2020, 25, 971; doi:10.3390/molecules25040971 www.mdpi.com/journal/molecules~50% [6,7]
Nalm-6 and cells were treated witha different concentrations of K313 for
K313-only group, the percentage the percentage of apoptotic cells greatly decreased in Nalm-6 and Daudi cells in the combination apoptotic cells greatly decreased in Nalm-6 and Daudi cells in the combination group of K313 and group of K313 and Z-VAD-FMK. These results demonstrated that K313 induced apoptosis in NalmZ-VAD-FMK
Summary
Human B-cell acute lymphoblastic leukemia (B-ALL), which is the most common childhood cancer, is an aggressive hematological disease accounting for ~70% of acute lymphoblastic leukemia [1,2]. childhood B-ALL has a good treatment outcome, with a five-year survival rate of ~90%, adults usually have worse outcomes, with five-year overall survival rates of 30% to 40% [3,4,5].Compared with a relapse rate of 20% in children, adults have a higher relapse rate of Molecules 2020, 25, 971; doi:10.3390/molecules25040971 www.mdpi.com/journal/molecules~50% [6,7]. Childhood B-ALL has a good treatment outcome, with a five-year survival rate of ~90%, adults usually have worse outcomes, with five-year overall survival rates of 30% to 40% [3,4,5]. Compared with a relapse rate of 20% in children, adults have a higher relapse rate of Molecules 2020, 25, 971; doi:10.3390/molecules25040971 www.mdpi.com/journal/molecules. An increasing number of antibody-based drugs exist, e.g., anti-CD20 antibody (rituximab, ofatumumab), anti-CD22 antibody (epratuzumab), and anti-CD25 antibody (ADCT-301) [2,9]. Combination therapies including chemotherapy–radiotherapy and chemotherapy–biotherapy are usually used to increase survival rates for patients with relapsed or refractory acute lymphoblastic leukemia [8,10]. Chemoresistance and adverse effects still present major limitations in the clinical treatment of B-ALL patients [1,11]
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