© The Author 2006. Published by Oxford University Press.
ARTICLE |
Autophagic Cell Death of Malignant Glioma Cells Induced by a Conditionally Replicating Adenovirus
Affiliations of authors: Departments of Neurosurgery (HI, HA, YK, EI, AI, KF, FFL, RS, S. Kondo) and Biostatistics and Applied Mathematics (KRH), University of Texas M. D. Anderson Cancer Center, Houston; Department of Gastroenterology, Hepatology, and Endocrinology, Medical School of Hannover, Hannover, Germany (FK, S. Kubicka, TW); University of Texas Graduate School of Biomedical Sciences at Houston, Houston (S. Kondo); Department of Neurosurgery, Baylor College of Medicine, Houston, TX (RS, S. Kondo)
Correspondence to: Seiji Kondo, MD, PhD, Department of Neurosurgery, BSRB Unit 1004, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail: seikondo{at}mdanderson.org).
Background: Conditionally replicating adenoviruses (CRAds) can be engineered to replicate selectively in cancer cells and cause cancer-specific cell lysis; thus they are considered a promising cancer therapy. Methods: To elucidate the mechanisms by which CRAds induce cancer-specific cell death, we infected normal human fibroblasts (MRC5, telomerase negative), human malignant glioma (U373-MG and U87-MG), human cervical cancer (HeLa), and human prostate cancer (PC3) cells (all telomerase positive) with CRAds regulated by the human telomerase reverse transcriptase promoter (hTERT-Ad) or control nonreplicating adenoviruses (Ad-GFP). Nonapoptotic autophagy was assessed in Ad-GFP- and hTERT-Ad–infected cells by examining cell morphology, the development of acidic vesicular organelles, and the conversion of microtubule-associated protein 1 light chain 3 from the cytoplasmic form to the autophagosome membrane form; signaling via mammalian target of rapamycin (mTOR), an autophagy-associated molecule, was monitored by western blot analysis. We also compared the growth of subcutaneous gliomas in nude mice that were treated by intratumoral injection with Ad-GFP or hTERT-Ad. Survival of athymic mice carrying intracranial gliomas treated by intratumoral injection with Ad-GFP or hTERT-Ad was compared by using the Kaplan–Meier method and the Cox–Mantel log-rank analysis. All statistical tests were two-sided. Results: hTERT-Ad induced tumor-specific autophagic cell death in tumor cells and in subcutaneous gliomas. hTERT-Ad–induced autophagy was associated with hTERT-Ad infection kinetics. The mTOR signaling pathway was suppressed in tumor cells and in subcutaneous gliomas treated with hTERT-Ad compared with GFP-Ad or no treatment as shown by reduced phosphorylation of mTOR's downstream target p70S6 kinase (p70S6K). hTERT-Ad treatment of mice (n = 7) slowed growth of subcutaneous gliomas (mean tumor volume = 39 mm3, 95% confidence interval [CI] = 23 to 54 mm3) compared with GFP-Ad treatment (n = 7) (mean tumor volume = 200 mm3, 95% CI = 149 to 251 mm3) at day 7 (volume difference = 161 mm3, 95% CI = 126 to 197 mm3; P<.001). Mice carrying intracranial tumors that were treated with three intratumoral injections of hTERT-Ad survived longer (53 days) than after treatment with GFP-Ad (29 days) (seven mice per group, difference = 24 days, 95% CI = 20 to 28 days; P<.001). Conclusions: hTERT-Ad may kill telomerase-positive cancer cells by inducing autophagic cell death.
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