Abstract
Temozolomide (TMZ) is used for the treatment of high-grade gliomas. Acquired chemoresistance is a serious limitation to the therapy with more than 90% of recurrent gliomas showing little response to a second line of chemotherapy. Therefore, it is necessary to explore an alternative strategy to enhance the sensitivity of glioblastoma (GBM) to TMZ in neuro-oncology. Celecoxib is well known and widely used in anti-inflammatory and analgesic. Cyclooxygenase-2 (COX-2) expression has been linked to the prognosis, angiogenesis, and radiation sensitivity of many malignancies such as primitive neuroectodermal tumor and advanced melanoma. The objective of this study was to explore the chemotherapy-sensitizing effect of celecoxib on TMZ in GBM cells and its potential mechanisms. From the study, we found that the combination therapy (TMZ 250uM+celecoxib 30uM) showed excellent inhibitory effect to the GBM, the LN229 and LN18, which were the TMZ resistant GBM cell lines. Our data suggest that the combination therapy may inhibits cell proliferation, increases apoptosis, and increases the autophagy on LN229 and LN18. The potential molecular mechanisms were related to mitochondrial metabolism and respiratory chain inhibition.
Highlights
GBM is an aggressive and prevalent brain tumor of the astrocytic lineage characterized as a high-grade tumor of the central nervous system [1]
The LN229 cell line was inhibited at the same dose of celecoxib but was later than LN18, when the LN229 was treated with celecoxib dose up to 60uM and more at D3 (Supplementary Table 1 for specific data), these results were consistent with previous research [14, 15]
Both LN18 and LN229 cell lines were resistant to the TMZ, which were consistent with the results of previous studies [11, 12], the 60uM and more dose of celecoxib has obvious inhibitory effect on LN18 and LN229 proliferation at D2 or D3 (Figure 1A, 1B and Supplementary Table 1)
Summary
GBM is an aggressive and prevalent brain tumor of the astrocytic lineage characterized as a high-grade tumor of the central nervous system [1]. The standard treatment for GBM consists of tumor removal followed by radiotherapy with concurrent and adjuvant TMZ [2]. Chemotherapy becomes impaired by development of chemo-resistance, especially for the patients with GBM who are frequently exhibited an early deterioration of performance status [4], with the 5year survival rate of just 9% [5]. This phenomenon presents the most challenging barrier in the successful treatment of GBM and is the principal reason for chemotherapy failure [2, 6]
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