Inhibitors of PARP-1 exert inhibitory effects on the biological characteristics of hepatocellular carcinoma cells in vitro

Abstract

It has been confirmed that the inhibitors of poly ADP-ribose polymerF(^9ase-1 (PARP-1) can inhibit the proliferation, apoptosis and invasion of tumor cells. However, the effects of inhibitors of PARP-1 on hepatocellular carcinoma remain to be elucidated. The aim of the present study was to investigate the effect of three types of PARP-1 inhibitor on the proliferation, apoptosis and migration of hepatocellular carcinoma in vitro. An MTT assay was performed to detect the proliferation of HepG2 cells following treatment with the PARP-1 inhibitors, AG014699, BSI-201 and AZD-2281. Flow cytometry was used to detect the apoptosis of HepG2 cells, Western blot analysis was used to detect the protein expression of Casepase-3, Casepase-8, B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Bcl-2, phosphatase and tensin homolog (PTEN), tissue inhibitor of metalloproteinase (TIMP) 3 and matrix metalloprotease (MMP) 3. A Transwell assay was performed to detect the migration of HepG2 cells. The results showed that AG014699, BSI-201 and AZD-2281 had an inhibitory effect on the proliferation of HepG2 cells in a time- and concentration-dependent manner. AG014699 at concentrations of 10, 30 and 50 µmol/l, and BSI-201 at concentrations of 20, 40 and 60 µmol/l induced the apoptosis of HepG2 cells, and the apoptotic rates were particularly high at 48 h (31, vs. 0.01%; P<0.01 and 24.12, vs. 0.03%, respectively; P<0.01). The protein expression levels of Caspase 3, Caspase 8, Bax, PTEN and TIMP 3 increased with increasing drug concentrations, whereas the protein levels of Bcl-2 and MMP3 decreased with increasing drug concentrations, and were significantly different compared with those in the control group (P<0.01). In conclusion, AG014699, BSI-201 and AZD-2281 inhibitors of PARP-1 significantly inhibited the proliferation of HepG2 cells, however, AG014699 and BSI-201 demonstrated more sensitivity, induced apoptosis and inhibited migration of the hepatocellular carcinoma cells, which may be associated with alterations of the apoptosis signaling pathway and the expression of proteins associated with migration.

Therapeutic Potential of PARP Inhibitors in the Treatment of Gastrointestinal Cancers

“…This is supported by a number of in vitro and in vivo studies, which have demonstrated pro-tumourigenic effects of PARP1 in HCC including increased proliferation, growth, angiogenesis, invasion and metastatic gene mRNA upregulation [64,68]. Supporting this, a number of in vitro studies in HCC have demonstrated that PARP inhibition results in an increase in apoptosis via the mitochondrial pathway [68,69]. However, Radnai et al, demonstrated an opposing effect with PARPi treatment inhibiting HCC apoptosis, an effect similarly observed in premalignant alcoholic liver disease [70,71].…”

BRCA in Gastrointestinal Cancers: Current Treatments and Future Perspectives

“…Indeed, Fehling et al highlighted a synergistic action of BET inhibitors (JQ1) with PARPi in CCA cell lines [102]. Another pre-clinical study suggested a potential role of olaparib in sensitizing CCA cells to radiation [103], as reported above for CRC. Moving from the benchside to the bedside, clinical trials are currently ongoing.…”

Identification of hub genes associated with prognosis, diagnosis, immune infiltration and therapeutic drug in liver cancer by integrated analysis

“…In our results, the dinaciclib and alvocidib interacted with the CDK1 . The rucaparib (AG014699), which was the inhibitor of the poly (ADP-ribose) polymerase-1 (PARP-1), might induce the apoptosis of HepG2 cells through the mitochondrial pathway and induced the migration of HepG2 cells by upregulating the PTEN and increasing the TIMP-3/MMP-3 ratio [ 90 ]. The traditional chemotherapeutic drugs (epirubicin, cyclophosphmide, and fluorouracil) played the important roles in treatment of liver cancer [ 91 ].…”