Peripheral benzodiazepine receptor ligands induce apoptosis and cell cycle arrest in human hepatocellular carcinoma cells and enhance chemosensitivity to paclitaxel, docetaxel, doxorubicin and the Bcl–2 inhibitor HA14–1
Background/Aims: Hepatocellular carcinoma (HCC) is one of the most common causes of cancer deaths worldwide. Thus, novel therapies are urgently needed. A promising approach is the use of peripheral benzodiazepine receptor (PBR) ligands which have been shown to inhibit the proliferation of various tumors. There exist no functional studies of PBR in HCC
Methods: PBR expression both in human HCC cell lines and in tumor specimens of HCC patients was analyzed by RT-PCR and immunostaining. To evaluate PBR as a target for the treatment of HCC, we tested the effects of PBR ligands on human HCC cells.
Results: PBR was localized to the mitochondria both of the two human HCC cell lines Huh–7 and HepG2 and of tumor tissues of HCC patients. In contrast, normal liver did not express PBR. PBR ligands inhibited the proliferation of HCC cell lines by inducing apoptosis and cell cycle arrest. PBR ligands caused a breakdown of the mitochondrial membrane potential, caspase–3 activation and nuclear degradation. Pro-apoptotic Bax was overexpressed while anti-apoptotic Bcl–2 and Bcl-XL were suppressed in response to PBR ligands. Cell cycle was arrested both at the G1/S- and G2/M-checkpoints. Synergistic antineoplastic effects were obtained by a combination of PBR ligands with cytostatic drugs (paclitaxel, docetaxel, doxorubicin), or with an experimental Bcl–2 inhibitor.
Conclusion: This is the first report on the specific induction of apoptosis and cell cycle arrest by PBR ligands in HCC cells. Moreover, PBR ligands sensitized HCC cells to taxans and doxorubicin.
Bax; Bcl-2; chemoresistance; chemotherapy; peripheral benzodiazepine receptor; apoptosis; cell cycle