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Effect of temozolomide on cell viability in gonadotroph adenoma cell lines
Sihai Ma1, Xiaohai Liu, Yong Yao
1Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, PR China.
Abstract:
Invasive pituitary adenomas are usually refractory to routine neurosurgery, radiosurgery or medications, and alternative therapies are needed. The effects of temozolomide (TMZ) on the inhibition of gonadotroph adenoma cell viability and hormone secretion were evaluated. Cell viability and IC50 values were evaluated after αT3-1 cells were treated with TMZ (31.25-1000 µM) or vehicle for 0-72 h. Cell cycle changes and the extent of apoptosis were detected using flow cytometry, TUNEL and TEM. The molecular mechanism of TMZ action was investigated by the Caspase-Glo® assay and immunoblotting. Gonadotropin secretion was assessed using an immunoassay system. TMZ dose- and time-dependently suppressed cell proliferation (P<0.01 vs. control, 250 µM, 24 h) and induced S-phase accumulation and G2/M-phase arrest (P<0.05 vs. control, 250 µM, 24 h). Early apoptotic cells increased following a 24-h TMZ incubation (P<0.001 vs. control, 250 µM), consistent with TEM and TUNEL detection that exhibited morphological features of apoptosis. TMZ (250 µM) increased the level of caspase-3/7 by 6-fold, caspase-9 by 7-fold and caspase-8 by 3-fold after a 24-h incubation, while it attenuated Bcl-2 expression (P<0.001 vs. control) and raised the proteolysis of PARP. Both FSH and LH levels were significantly decreased by TMZ (P<0.01 vs. control, 250 µM, 24 h). TMZ inhibited cell proliferation and hormone secretion, and induced cell cycle arrest and apoptotic cell death in gonadotroph adenoma cells via both death receptor and mitochondrial pathways, suggesting that it may represent a useful medical management strategy of invasive gonadotroph adenomas.
Insights
Temozolomide (TMZ) effectively inhibits invasive gonadotroph adenoma cell growth and hormone secretion. This chemotherapy agent induces cell cycle arrest and apoptosis, offering a potential new treatment for these difficult-to-treat tumors.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Invasive pituitary adenomas, particularly gonadotroph adenomas, are often resistant to conventional treatments like surgery, radiation, and medication.
- There is a critical need for alternative therapeutic strategies to manage these challenging tumors.
Purpose of the Study:
- To evaluate the efficacy of temozolomide (TMZ) in inhibiting the viability and hormone secretion of gonadotroph adenoma cells.
- To elucidate the molecular mechanisms underlying TMZ's action on these cells.
Main Methods:
- αT3-1 gonadotroph adenoma cells were treated with varying concentrations of TMZ (31.25-1000 µM) for 0-72 hours.
- Cell viability, proliferation, cell cycle progression, and apoptosis were assessed using assays including flow cytometry, TUNEL, and transmission electron microscopy (TEM).
- Molecular pathways involving caspases and Bcl-2 were investigated, and follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion was measured.
Main Results:
- TMZ significantly suppressed cell proliferation and hormone secretion in a dose- and time-dependent manner.
- TMZ induced cell cycle arrest at the S and G2/M phases and significantly increased early apoptotic cell death.
- TMZ activated caspase-3/7, caspase-9, and caspase-8, downregulated Bcl-2 expression, and increased PARP cleavage, indicating activation of both death receptor and mitochondrial apoptotic pathways.
Conclusions:
- Temozolomide demonstrates potent anti-proliferative and hormone-suppressive effects on gonadotroph adenoma cells.
- TMZ effectively induces cell cycle arrest and apoptosis through intrinsic and extrinsic pathways.
- TMZ represents a promising therapeutic option for the medical management of invasive gonadotroph adenomas.
