CCNU and ACNU exert efficient antitumor effects against glioblastoma models with acquired temozolomide resistance

Glioblastomas (GBMs) often acquire resistance against temozolomide (TMZ) after continuous treatment and recur as TMZ-resistant GBM (TMZ-R-GBM). Lomustine (CCNU) and nimustine (ACNU), which were previously used as standard therapeutic agents against GBMs before TMZ, have occasionally been employed for the salvage therapy of TMZ-R-GBMs; however, their efficacy has not yet been thoroughly examined. We therefore investigated the antitumor effects of CCNU and ACNU against TMZ-R-GBMs. As a model of TMZ-R-GBMs, TMZ resistant clones of human GBM cell lines (U87, U251MG, and U343MG) were established (TMZ-R-cells) by the culture of each GBM cells under continuous TMZ treatment, and the antitumor effects of TMZ, CCNU or ACNU against these cells were analyzed in vitro and in vivo. As a result, although growth arrest and apoptosis were triggered in all TMZ-R-cells after the administration of each drug, the antitumor effects of TMZ against TMZ-R-cells were significantly reduced as compared to those of parental cells, whereas CCNU and ACNU demonstrated efficient antitumor effects on TMZ-R-cells as well as parental cells. In addition, it was also demonstrated that TMZ resistance of TMZ-R-cells was regulated at the level of DNA damage response initiation. Furthermore, survival in mice was significantly prolonged by systemic treatment with CCNU or ACNU but not TMZ after implantation of TMZ-R-cells. These findings suggest that CCNU or ACNU may serve as a therapeutic agent in salvage treatment against TMZ-R-GBMs.