Modulation of growth and radiochemosensitivity of human malignant glioma cells by acidosis

Abstract

BACKGROUNDGlioblastoma commonly is characterized by hypoxia and acidosis and the histologic features of tissue necrosis and neovascularization. Current approaches of adjuvant radiochemotherapy for patients with glioblastoma have only a modest impact on the natural course of this disease.METHODSThe authors examined the effects of acidosis on growth and response to irradiation and chemotherapy in cultured human malignant glioma cells.RESULTSThe authors found that mild acidosis (pH 7.0) inhibited the growth of cell lines that retained wild type p53 activity but did not inhibit the growth of cell lines that were devoid of p53 function. Transfer of a dominant‐negative p53 gene into p53 wild type cells failed to override the acidosis‐conferred growth arrest, suggesting that loss of p53 activity per se does not mediate escape from acidosis‐induced growth inhibition. Moderate acidosis (pH 6.6) inhibited the growth of all cell lines. Acidosis‐mediated growth arrest was not associated with a specific type of cell cycle arrest, e.g., in G0/G1 or G2/M phase. Acidosis did not result in consistent changes in radiosensitivity; however, it enhanced the cytotoxic effects of lomustine but conferred protection from topotecan, vincristine, teniposide, and cisplatin cytotoxicity. Lomustine exhibited enhanced stability at low pH, providing a putative mechanism for the enhanced cytotoxic effects of lomustine in acidotic conditions. Decreased sensitivity to the other drugs did not result from altered multidrug resistance drug transport activity.CONCLUSIONSTaken together, the current results suggest that tissue acidosis may be an important determinant of glioma cell responses to adjuvant radiochemotherapy. The superior activity of nitrosoureas, such as lomustine, compared with other agents in patients with glioblastoma may result in part from prolonged drug stability in an acidotic microenvironment. Cancer 2002;95:1113–9. © 2002 American Cancer Society.DOI 10.1002/cncr.10767

Promotion of glioma cell survival by acyl-CoA synthetase 5 under extracellular acidosis conditions

“…Under tumor microenvironmental stresses, the defect in the p53 tumor suppressor protein is a critical factor for apoptosis resistance and cancer cell survival (Soengas et al, 1999). However, low pH stress inhibits cell growth in a p53-independent manner, suggesting the involvement of other mechanisms (Reichert et al, 2002). Our results suggest that enhanced cell survival by ACSL5 under low pH conditions could have a function in the progression of cancer.…”

Autophagy Is a Protective Mechanism for Human Melanoma Cells under Acidic Stress

“…Acidic pH-An acidic pH environment is known to delay cell growth and increase spontaneous apoptosis in cell lines derived from colon cancer and malignant glioma (45,46). However, human melanoma cells are known to survive during acidic stress (41,47).…”

Low-pH-induced apoptosis: role of endoplasmic reticulum stress-induced calcium permeability and mitochondria-dependent signaling

“…Acidic pH-mediated induction of apoptosis was suggested to be a consequence of caspase activity (Park et al 1999). Acidic environment could modulate growth as well as radiochemosensitivity of glioma cells (Reichert et al 2002) and was demonstrated to have immunomodulatory activity by promoting the expression of IL-8 in cervical cancer cells (Xu and Fidler 2000). Hypoxia and acidity represent two factors that might be exploited therapeutically to destroy such cells.…”