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A novel hybrid of 3-benzyl coumarin seco-B-ring derivative and phenylsulfonylfuroxan induces apoptosis and autophagy in non-small-cell lung cancer
Mengxue Donga,1, Tao Yea,1, Yongyan Bia, Qian Wanga, Kudelaidi Kuerbana, Jiyang Lia, Meiqing Fenga, Ke Wangb, Ying Chenb, , Li Yea,
a Minghang Hospital & Department of Microbiological and Biochemical Pharmacy at School of Pharmacy, Fudan University, Shanghai 201199, China
b Department of Medicinal Chemistry at School of Pharmacy, Fudan University, Shanghai 201203, China
Non-small-cell lung cancer
Background: Compound 6, as a novel hybrid of 3-benzyl coumarin seco-B-ring derivative and nitric oxide (NO) donor phenylsulfonylfuroxan, has the potential to develop into an anticancer drug because it displays significant antiproliferation activitity for various solid cancer cell lines including non-small-cell lung cancer (NSCLC) cells. Purpose: We attempt to uncover the capacities of compound 6 to induce apoptosis and autophagy in NSCLC cells, as well as the underlying mechanism involved in this process.
Methods: The eﬀect of compound 6 on cell viability was evaluated in A549 cells by MTT assay. Apoptosis was mainly detected by flow cytometry. The induction of autophagy was observed by transmission electron mi-croscopy (TEM), confocal microscopy as well as western-blotting technique. The expression of all related-pro-teins including PI3K/Akt/mTOR signaling pathway were also examined by western-blotting technique.
Results: Above all, distinct growth inhibition and caspase-dependent apoptosis were detected in A549 cells administered with compound 6. Then, we confirmed the induction of autophagy triggered by compound 6 in A549 cells. Noticeably, blocking autophagy using a series of inhibitors and ATG5 siRNA had little eﬀect on the cytotoxicity of compound 6, elucidating nonprotective autophagy triggered in NSCLC cells. Further research illustrated that PI3K/Akt/mTOR signaling pathway was involved in compound 6-induced apoptosis, and 3-MA as well as LY294002 had synergistic inhibiting eﬀect on proliferation of A549 cells through the pathway mentioned above.
Conclusion: These findings raise a rationale that this 3-benzyl coumarin seco-B-ring derivative and phe-nylsulfonylfuroxan hybrid could be a promising candidate for developing as a therapeutic agent toward NSCLC, and the combination therapy through PI3K/Akt/mTOR signaling pathway may result in optimized treatment outcomes.
Non-small-cell lung carcinoma (NSCLC), accounting for approxi-mately 85% of all lung cancers, is one of the leading factors of cancer mortality worldwide (Ettinger et al., 2015). Based on the stage of lung cancer, certain treatment options ranging from surgical resection to radiotherapy, chemotherapy as well as immunotherapy are accepted (Zappa and Mousa, 2016). However, five-year overall survival rate for
NSCLC patients is still low due to the poor prognosis and multidrug resistance (Neal et al., 2014). Recently, some nanocarrier systems such as D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS)-functio-nalized mesoporous silica nanoparticles were used for chemother-apeutic drug delivery, exhibiting enhanced anti-tumor activity and re-duced multidrug resistance for a more eﬃcient and safer NSCLC therapy (Cheng et al., 2017; Liang et al., 2018). Nevertheless, it is still a great challenge to further investigate the novel therapeutics.