Targeted MYCN expression affects cytotoxic potential of chemotherapeutic drugs in neuroblastoma cells.
Neuroblastoma (NB) is a solid childhood tumour that exhibits heterogeneous biological and clinical phenotypes. Multiple drug resistance marks a major complication especially in high-risk patients with advanced tumour stages and specific genetic aberrations, such as MYCN amplification and lp deletion. As an approach to further address the mechanisms of chemotherapeutic responsiveness of NB, we used a MYCN-inducible in vitro system and tested the susceptibility of NB cells to anti-tumour drugs currently included in NB treatment protocols dependent on MYCN expression. We observed cytotoxic effects using drug concentrations corresponding to blood plasma levels achieved in NB patients. The most potent drugs were microtubule inhibitors vindesin, paclitaxel and vincristin. Less effective were doxorubicine, arsenic trioxide, cisplatin, etoposide and carboplatin. Exposed to anti-tumour agents, NB cells with induced MYCN expression exhibited higher specific apoptosis than NB cells lacking MYCN expression. Anti-tumour drugs in MYCN-on cells accelerated G1-S phase transition, led to enhanced accumulation of cell populations in G2/M phase, and increased levels of apoptosis. In contrast, MYCN-off cell populations arrested in G1 and, to a smaller extent, in G2/M and exhibited delayed onset of apoptosis. In summary, apoptosis profiles and anti-proliferative potential of chemotherapeutic drugs, used at in vivo tolerable doses, are affected by MYCN overexpression and deregulated cell cycle in SH-EP(MYCN) cells.
Paffhausen
Tobias
T
Division of Tumour Genetics, German Cancer Research Center, DKFZ, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Schwab
Manfred
M
Westermann
Frank
F
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002453:Cell Cycle; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D018432:Drug Resistance, Multiple; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D017239:Paclitaxel / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology; D014751:Vindesine / Q000494:pharmacology
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D014750:Vincristine; D017239:Paclitaxel; D014751:Vindesine