Curcumin has anticancer functions in various tumors. It has been shown to induce apoptosis through p53-dependent pathways. p73 gene is a member of the p53 family which encodes both a tumor suppressor (transactivation-competent p73 (TAp73)) and a putative oncogene (dominant-negative p73 (DNp73)); the former shares similarity with the tumor suppressor p53, and the latter behaves as dominant-negative proteins that interfere with the activity of TAp73. To understand the p73-dependent mechanisms that are engaged during curcumin-induced apoptosis, we established a p73 overexpression cell models using p53-deficient Hep3B cells (Hep3B(TAp73/DNp73)). Our results demonstrated that curcumin at concentrations of 40 and 80 μM induced DNA damage, increased TAp73/DNp73 ratio, and also led to apoptosis in the Hep3B(TAp73/DNp73) cells. The apoptotic cell death was concurrent with the loss of mitochondrial membrane potential; release of cytochrome c from mitochondria; and the cleavage of caspase 9, caspase 3, and poly(ADP-ribose) polymerase (PARP). These results demonstrated a p73-dependent mechanism for curcumin-induced apoptosis that involves the mitochondria-mediated pathway.

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Aminopeptidase N (APN) is important in tumour processes. The present study detected the anti‑tumour activity of the novel APN inhibitor DH‑12a, which is an indoline‑2,3‑dione derivative. In the present study, Bestatin, a clinical APN inhibitor was used as a positive control. The expression of APN in the ES-2 and 3AO cell lines were assessed using flow cytometry and the drug inhibition constants of DH‑12a (Ki=13.15 µM) and Bestatin (Ki=16.57 µM) were assessed using a double reciprocal method of competitive inhibition. The in vitro effects of DH‑12a on cell proliferation were assessed using a 3‑(4,5‑dimethyl‑thiazol‑2‑yl)‑2,5‑diphenyl tetrazolium bromide assay on human cell lines of ES‑2 (IC50=43.8 µM), A549 (inhibition rate=41.5% at 160 µM DH‑12a), HL60 (inhibition rate=47.83% at 160 µM DH‑12a) and 3AO (IC50=70.2 µM). The inhibition rates were consistently higher than those of Bestatin. The effects of DH‑12a on cell migration (inhibition rates in ES‑2 cells and 3AO cells were 56.4 and 76.5%, respectively at 15 µM) and invasion (inhibition rates in ES‑2 cells and 3AO cells were 75.6 and 66.5%, respectively at 15 µM) were assessed using transwell plates. The in vivo effects of DH‑12a on tumour proliferation and lung tumour metastasis were determined using an H22 xenograft mice model, where DH‑12a was administered in combination with genotoxic 5‑fluorouracil. The anti‑tumour activities of DH‑12a in vivo were also greater than those of Bestatin. In conclusion, the in vitro effects of DH‑12a on tumour proliferation, migration and invasion were consistent with the in vivo effects. In addition, DH‑12a exhibited greater anti‑tumour properties compared with Bestatin.

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