The translocator protein (TSPO) ligand PK11195 induces apoptosis and cell cycle arrest and sensitizes to chemotherapy treatment in pre- and post-relapse neuroblastoma cell lines

Abstract

High-risk neuroblastoma (NB) has a poor prognosis. Even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal, and new treatments are needed. Translocator protein 18kDa (TSPO) ligands have been studied as potential new therapeutic agents in many cancers, but not in NB.

We studied the effects of TSPO ligands on cell proliferation, cell cycle progression and apoptosis using paired cell lines derived from the same patient at the time of initial surgery and again after development of progressive disease or relapse post-chemotherapy. We found that TSPO expression was significantly increased 2- to 10-fold in post-relapse cell lines compared with pre-treatment lines derived from the same individual. Subsequently, these cell lines were treated with the specific TSPO ligand 1-(2-chlorophenyl-N-methylpropyl)-3-isoquinolinecarboxamide (PK11195) (0–160µM) as a single agent, with cytotoxic chemotherapy agents alone (carboplatin, etoposide or melphalan), or with combinations of PK11195 and chemotherapy drugs. We found that PK11195 inhibited proliferation in a dose-dependent manner, induced apoptosis and caused G₁/S cell cycle arrest in all tested NB cell lines at micromolar concentrations. In addition, PK11195 significantly decreased mRNA expression of the chemotherapy resistance efflux pumps ABCA3, ABCB1 and ABCC1 in two post-relapse NB cell lines. We also found that pre-treatment with PK11195 sensitized these cell lines to treatment with cytotoxic chemotherapy agents. These results suggest that PK11195 alone or in combination with standard chemotherapeutic drugs warrants further study for the treatment of neuroblastoma.

Keywords::

• apoptosis
• neuroblastoma
• RT-PCR
• PK11195
• TSPO
• cell cycle analysis