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Regulation of cellular growth, apoptosis, and Akt activity in human U251 glioma cells by a combination of cisplatin with CRM197

Wang, Lifeia,b; Wang, Pinga,b; Liu, Yunhuic; Xue, Yixuea,b

doi: 10.1097/CAD.0b013e32834b9b72

The aberrantly activated antiapoptotic phospatidyl-3-inositol-kinase (PI3K)/Akt signaling induced by cisplatin limits the effectiveness of chemotherapy; inhibition of this pathway may augment the sensitivity of tumor cells to cisplatin-induced toxicity and promote apoptosis. Cross-reacting material 197 (CRM197), the nontoxic mutant of diphtheria toxin, could act as an heparin-binding epidermal growth factor inhibitor and has been shown to have some anticancer effects, but the effect of CRM197 on glioma cells remains unclear. The aim of this study was to investigate the effects of a combination of cisplatin with CRM197 on the growth and apoptosis of human U251 glioma cells and the possible mechanism. In this study, we demonstrated that cisplatin or CRM197 induced a dose-dependent growth inhibition in U251 cells, but cisplatin at 5 µg/ml and CRM197 at 1 µg/ml did not affect the viability of human astrocytes. Cisplatin induced a time-dependent growth inhibition in U251 cells, whereas the growth-inhibitory effects induced by CRM197 alone or combined with cisplatin reached a peak at 24 h after treatment. Compared with the administration of cisplatin or CRM197 alone, CRM197 combined with cisplatin significantly enhanced U251 cell growth inhibition and apoptosis. Cisplatin induced sustained activation of Akt, whereas CRM197 markedly suppressed the Akt phosphorylation induced by cisplatin. The effects of growth inhibition and apoptosis were markedly enhanced after a combination of cisplatin with CRM197 plus the PI3K inhibitor LY294002 or wortmannin. Therefore, CRM197 combined with cisplatin could enhance growth inhibition and apoptosis of glioma cells by inhibiting the cisplatin-induced PI3K/Akt pathway.

aDepartment of Neurobiology, College of Basic Medicine

bInstitute of Pathology and Pathophysiology

cDepartment of Neurosurgery, Shengjing Hospital, China Medical University, Shenyang, People’s Republic of China

Lifei Wang and Ping Wang contributed equally to this study.

Correspondence to Yixue Xue, PhD, Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001, Liaoning province, People’s Republic of China Tel: +86 24 2325666 5506; fax: +86 24 2295 8989; e-mail:

Received June 16, 2011

Accepted August 4, 2011

© 2012 Lippincott Williams & Wilkins, Inc.