br Abbreviations NSCLC non small cell
Abbreviations: NSCLC, non-small cell lung cancer; TEM, transmission electron microscopy; MTT, 3-(4, 5-dimetrylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; 3-MA, 3-methyladenine; CQ, chloroquine; NH4Cl, ammonium chloride; Baf A1, bafilomycin A1; PFOA, perfluorooctanoic acid
Correspondence author. Correspondence author.
E-mail addresses: [email protected] (Y. Chen), [email protected] (L. Ye). 1 These authors contributed equally to this work.
Coumarin is a natural compound with benzo alpha-pyrone nucleus, and its derivatives are widely reported to have antibacterial, antic-oagulant, anti-inflammatory, antiviral and anti-parasite activities (Ren et al., 2018), especially anti-tumor activity on many tumor Acarbose including colon cancer, gastric cancer, breast cancer and NSCLC cells (Guo et al., 2018; Kumar et al., 2018; Lin et al., 2014; Wang et al., 2017a). Besides, coumarin derivatives can be used for labeling lipid droplets in cancer and non-cancer cells to reveal the biochemical dif-ferences between them (Chowdhury et al., 2015, 2014). We previously synthesized and reported a hybrid of coumarin and phenylsulfonylfur-oxan (compound 1) which showed enhanced anti-NSCLC activity (Liu et al., 2014). As a coumarin derivative with phenylsulfonylfuroxan, a nitric oxide (NO) donor, compound 1 can induce notable cytotoxicity and caspase-dependent apoptosis in NSCLC cells (Wang et al., 2018).
It has been reported that the combined treatment of MEK inhibitors and NO donors could have synergistic inhibitory eﬀect on proliferation and invasion of tumor cells (Furuhashi et al., 2012), and 4-fluorobenzyl fragment at 3-position of coumarin skeleton enhanced MEK inhibitory activity of coumarin (Han et al., 2005). Therefore, we introduced 4-fluorobenzyl fragment to the same position of lead compound 1 and obtained a novel seco-B-ring derivative of coumarin (compound 6). Compared to compound 1, compound 6 displayed more pronounced antiproliferation activity on various solid cancer cell lines including NSCLC A549 cells and lower toxicity on nontumorigenesis cell lines in vitro (Guo et al., 2018).
In our research, both apoptosis and autophagy were found after administration of compound 6 in A549 cells, and this two types of programmed cell death are deemed as a promising therapeutic target to fight against cancer (Yoshida, 2017). Autophagy, in particular, con-tributes significantly to the maintenance of intracellular homeostasis under conditions of oxidative stress, nutrient deprivation, and chemi-cals treatment (Fougeray and Pallet, 2015). The ample evidences sug-gest that autophagy functions as a ``double-edged sword'' in carcino-genesis, whereas it plays more of a cytoprotective role in cancer therapy (Liu et al., 2017c; White, 2015). In terms of lung cancer, autophagy serves as a modulator by regulating the initiation, progression, and treatment of the tumor as well as sensitization to some specific thera-pies (Chen et al., 2017; Zhan et al., 2014).
So far, the relationship between apoptosis and autophagy remains controversial, depending on the therapeutic milieu, therapeutic ap-proaches and many other factors (Liu et al., 2017a). Nevertheless, it is clear that when apoptosis and autophagy simultaneously occur in the same cells, they could make a close connection through some signaling pathways (Liu et al., 2017b; Xie et al., 2016). Among them, the PI3K/ Akt/mTOR signaling pathway appeals much attention, given its im-plication in many cellular activities including regulation of cell growth, survival, and proliferation (Fu et al., 2017; Kumar et al., 2015). The frequently aberrance of PI3K/Akt/mTOR signaling pathway in diﬀerent kinds of neoplasm makes it more research value.
In this study, we aim to reveal the correlation between apoptosis and autophagy as well as further characterize the molecular mechanism of compound 6 acting on the human NSCLC cells.
Materials and methods