p53 inactivation is a hallmark in non-small-cell lung cancer (NSCLC). It is therefore highly desirable to develop tumor-specific treatment for NSCLC therapy by restoring p53 function. Herein, a novel naphthalimide compound, NA-17, was identified as a promising drug candidate in view of both its anticancer activity and mechanism of action. NA-17 exhibited strong anticancer activity on a broad range of cancer cell lines but showed low toxicity to normal cell lines, such as HL-7702 and WI-38. Moreover, NA-17 showed p53-dependent inhibition selectivity in different NSCLC cell lines due to the activation state of endogenous p53 in the background level. Further studies revealed that NA-17 caused cell cycle arrest at the G 1 phase, changed cell size, and induced apoptosis and cell death by increasing the proportion of sub-G 1 cells. Molecular mechanism studies suggested that targeted accumulation of phospho-p53 in mitochondria and nuclei induced by NA-17 resulted in activation of Bak and direct binding of phospho-p53 to the target DNA sequences, thereby evoking cell apoptosis and cell cycle arrest and eventually leading to irreversible cancer cell inhibition. This work provided new insights into the molecular interactions and anticancer mechanisms of phosphop53-dependent naphthalimide compounds.

Chemotherapy resistance, the molecular mechanism of which is complex and has not been fully understood, poses a major challenge in the treatment of patients with non‑small cell lung cancer (NSCLC). The dysregulation of microRNAs (miRs) has been reported to serve a pivotal role in the development of cancer and drug resistance. In the present study, reverse transcription‑quantitative polymerase chain reaction analysis revealed a significant increase in miR‑328 and a significant decrease in phosphatase and tensin homolog (PTEN) mRNA expression levels within tumor tissues from patients with cisplatin‑resistant NSCLC compared with those of cisplatin‑sensitive NSCLC patients. In addition, there was a negative correlation between PTEN mRNA and the miR‑328 expression levels. In addition, higher miR‑328 expression levels, and lower PTEN mRNA and protein expression levels, were detected in cisplatin‑resistant A549 (A549rCDDP) cells when compared with in their parental cells. A549rCDDP cells demonstrated significantly higher cell viability compared with A549 cells following treatment with all concentrations of cisplatin tested (2, 4, 6 and 8 µM). Additionally, transfection of miR‑328 inhibitor significantly increased PTEN mRNA and protein expression levels. Furthermore, the present study predicted and confirmed PTEN, a well‑known tumor suppressor, as a direct target of miR‑328 in NSCLC cells via the online tool MiRanda and a dual luciferase assay, respectively. Cell viability assay and flow cytometry analysis demonstrated that inhibition of miR‑328 also induced cellular apoptosis and decreased cell proliferation in A549rCDDP cells treated with cisplatin. In conclusion, these results suggested that abnormal expression of miR‑328 may contribute to cisplatin resistance in NSCLC, and may be considered to be a novel therapeutic target and indicator for the treatment and prognosis of patients with NSCLC treated with cisplatin‑based chemotherapy.

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A novel nickel(ii) complex of 6-methoxy-1-pyridine-β-carboline () was synthesized and characterized. The cytotoxicities of the complex towards six cancer cell lines, including MGC-803, Hep G2, T24, OS-RC-2, NCI-H460, and SK-OV-3, and human normal liver cell line HL-7702 were investigated. The IC values for MGC-803, Hep G2, T24, OS-RC-2, NCI-H460 and SK-OV-3 were generally in the micromolar range (3.77-15.10 μM), lower than those of ligand and cisplatin. Furthermore, (6 μM) significantly induced cell cycle arrest at the S phase, and caused the down-regulation of p-AKT, cyclin E, cyclin A and CDK2 and the up-regulation of p27. Various experiments showed that induced apoptosis, activated caspase-3, increased the levels of reactive oxygen species (ROS) and enhanced the intracellular [Ca] levels in MGC-803. In addition, the expression of intrinsic apoptotic proteins, including cytochrome c and apaf-1, increased. Further intrinsic apoptosis was triggered executive molecular caspase-9 and caspase-3. In short, exerted its cytotoxic activity primarily through inducing cell cycle arrest at the S phase and intrinsic apoptosis.