Abstract
Streptomyces-derived natural products have been become a major focus of anti-tumor drug discovery studies. Neoantimycin F (NAT-F), was isolated from Streptomyces conglobatus by our group. Here, we examined the anti-cancer activities and its underlying molecular mechanisms implicated in NAT-F–induced apoptosis of non–small cell lung cancer (NSCLC) cells. Our results showed that NAT-F exerted excellent growth-inhibitory activity against PC9 and H1299 cells in a concentration-dependent manner. NAT-F–induced cell cycle arrest at S and G0/G1 phase in PC9 and H1299 cells, respectively. Further investigation revealed that the key proteins (including cyclinD1, cyclinE1, cyclinB1, CDK2, and CDK4) were involved in the cell regulation by NAT-F. Additionally, NAT-F significantly increased the production of reactive oxygen species (ROS), induced DNA damage, nuclear condensation, and cell apoptosis in both cell lines. Moreover, loss of the mitochondrial membrane potential (MMP) was markedly induced by NAT-F. Additional results revealed that NAT-F could up-regulate pro-apoptotic protein Bax and down-regulate anti-apoptotic protein Bcl-2, Mcl-1, and Bcl-xL, resulting in cytochrome c release from mitochondria and sequential activation of caspase-9 and -3, as well as the cleavage of poly (ADP-ribose) polymerase. Meanwhile, c-Jun N-terminal kinase (JNK), p38 MAPK (p38), and extracellular signal-regulated kinase (ERK) signaling pathway were also involved in anti-cancer activity of NAT-F in NSCLC cells. Taken together, these findings indicated that NAT-F possessed anti-proliferative effect and induced apoptosis in NSCLC cells in vitro and may be conducive to promote the development of novel anti-NSCLC agents.
Highlights
Lung cancer is one of the leading causes of cancer death worldwide, and non-small cell lung cancer (NSCLC), the most common histologic type, accounts for approximately 75% to 85% of all lung cancers (Aisner and Marshall, 2012; Blandin Knight et al, 2017)
Our results showed that Neoantimycin F (NAT-F) inhibited the cell viability of HaCaT, NCM-460, and H9c2 cells with their IC50 values >50 μM (Figure 1C)
We investigated whether NAT-F suppressed cell proliferation in the two cell lines using trypan blue assay
Summary
Lung cancer is one of the leading causes of cancer death worldwide, and non-small cell lung cancer (NSCLC), the most common histologic type, accounts for approximately 75% to 85% of all lung cancers (Aisner and Marshall, 2012; Blandin Knight et al, 2017). Natural Streptomyces-derived products have received increasing attention owing to their wide variety of biological activities, especially their anti-tumor activities (Calcul et al, 2012; Valipour et al, 2018). Neoantimycin F (NAT-F) (Figure 1A), a new member of NATs, with its derivatives, including D and E, were previously isolated from Streptoverticillium orinoci in 2013, but they were demonstrated to have no significant antiproliferative activity in HT-29 colorectal cancer cells (Li et al, 2013). We studied the biosynthetic pathways of Streptomyces conglobatus and isolated a series of NATs, including the known NAT-A, F, H, and a new NAT-I, and revealed that these compounds displayed interesting anti-cancer properties against multiple cell lines (Zhou et al, 2018). We investigated NAT-F’s growth inhibitory and apoptotic effects on human NSCLC cells and preliminarily elucidated the underlying molecular mechanism
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