Lomustine and nimustine exert efficient antitumor effects against glioblastoma models with acquired temozolomide resistance

Sep 18, 2021Cancer science

Lomustine and nimustine effectively fight brain tumor models resistant to temozolomide

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Abstract

CCNU and ACNU demonstrated efficient antitumor effects on -resistant cells.

TMZ-resistant glioblastoma cells exhibited a significant reduction in antitumor effects when treated with temozolomide compared to parental cells.
Both CCNU and ACNU triggered growth arrest and in TMZ-resistant glioblastoma cells.
The TMZ resistance in these cells was linked to the initiation of DNA damage response mechanisms.
Systemic treatment with CCNU or ACNU significantly prolonged survival in mice with TMZ-resistant glioblastoma.

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(GBM) often acquire resistance against (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 GBM before TMZ, have occasionally been used for the salvage therapy of TMZ-R-GBM; however, their efficacy has not yet been thoroughly examined. Therefore, we investigated the antitumor effects of CCNU and ACNU against TMZ-R-GBM. As a model of TMZ-R-GBM, 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 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 compared to those of parental cells, whereas CCNU and ACNU demonstrated efficient antitumor effects on TMZ-R-cells as well as parental cells. It was also demonstrated that TMZ resistance of TMZ-R-cells was regulated at the initiation of DNA damage response. 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-GBM.

Key numbers

44 μM

IC50 for CCNU in U251 cells

Lowest IC50 value among tested drugs in resistant U251 cells.

not specified

Survival Prolongation by CCNU

Survival times significantly increased in mice treated with CCNU compared to control.

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Lomustine and nimustine exert efficient antitumor effects against glioblastoma models with acquired temozolomide resistance

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