Benzoxazole Derivative K313 Induces Cell Cycle Arrest, Apoptosis and Autophagy Blockage and Suppresses mTOR/p70S6K Pathway in Nalm-6 and Daudi Cells

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.

Biological activity of 3-(2-benzoxazol-5-yl)alanine derivatives

“…It was observed that some compounds based on benzoxazole have antituberculotic (Ertan-Bolelli et al 2016;Pytela and Klimešová 2011;Rana et al 2014a, b;Šlachtová and Brulíková 2018;Zhang et al 2018), or antimalarial (Ongarora et al 2015;Zhang et al 2018), or antiviral activity (Bernard et al 2014;Demmer and Bunch 2015;Jonckers et al 2012;Sattar et al 2020;Zhang et al 2018). Moreover, it was demonstrated that a large group of benzoxazole derivatives exert cytotoxic effect on some cancer cells such as breast cancer cells (MCF-7, MDA-MB-213, MDA-MB-231), lung cancer cells (A549, H1975, HCC827), liver cancer cells (HepG2), prostate cancer cells (PC3), colorectal cancer cells (HCT-116, HT-29), oral cancer cells (KB), melanoma cells (A375), and others (Bernard et al 2014;Chung et al 2015;Desai et al 2020;Giordano et al 2019;Han et al 2012;Kakkar et al 2018;Kakkar and Narasimhan 2019;Kumar et al 2002;Li et al 2015;Omar et al 2020;Reddy et al 2016;Reynolds et al 1999;Rida et al 2005;Sachweh et al 2015;Sato et al 2001;Sattar et al 2020;Sever et al 2021;Slotkin et al 2016;Ueki et al 1993Zhang et al 2018;Zhong et al 2020;Zi et al 2019).…”