Combination of adenoviral virotherapy and temozolomide chemotherapy eradicates malignant glioma through autophagic and apoptotic cell death in vivo

• Published in: British journal of cancer Vol. 100; no. 7; pp. 1154 - 1164
• Main Authors: Ulasov, I V, Sonabend, A M, Nandi, S, Khramtsov, A, Han, Y, Lesniak, M S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-04-2009; Nature Publishing Group
• Subjects: Adenoviridae - physiology; Adenoviruses; Animals; Antineoplastic Agents, Alkylating - therapeutic use; Apoptosis; Autophagy; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - mortality; Brain Neoplasms - pathology; Brain research; Cancer Research; Cancer therapies; Caspase 3 - metabolism; Cell death; Cell Line, Tumor; Chemotherapy; Combined Modality Therapy; Dacarbazine - analogs & derivatives; Dacarbazine - therapeutic use; Drug Resistance; Epidemiology; Female; Glioma - mortality; Glioma - pathology; Glioma - therapy; Humans; Immunotherapy; Medical research; Medical sciences; Mice; Mice, Inbred BALB C; Microtubule-Associated Proteins - analysis; Mitosis; Molecular Diagnostics; Molecular Medicine; Neurology; Oncology; Oncolytic Virotherapy; Radiation therapy; Temozolomide; Tumors; Tumors of the nervous system. Phacomatoses; Xenograft Model Antitumor Assays; United States > US; Japan; Chicago Illinois; temozolomide; glioma; apoptosis; oncolytic adenovirus; autophagy; brain tumour; Antineoplastic agent; Nervous system diseases; Adenoviridae; Virotherapy; Malignant tumor; Oncolytic virus; Autophagy; Intracranial tumor; Cerebral disorder; Virus; Malignant glioma; In vivo; Alkylating agent; Chemotherapy; Cancerology; Treatment; Cell death; Central nervous system disease; Temozolomide; Cancer; Apoptosis
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6604969

Conditionally replicative adenoviruses (CRAds) represent a novel treatment strategy for malignant glioma. Recent studies suggest that the cytopathic effect elicited by these vectors is mediated through autophagy, a form of programmed cell death. Likewise, temozolomide (TMZ), a chemotherapeutic agent used for the treatment of malignant gliomas, also triggers autophagic cell death. In this study, we examined the potential to combine the two treatments in the setting of experimental glioma.
In vitro
, pretreatment with TMZ followed by CRAd-Surivin-pk7 enhanced cytotoxicity against a panel of glioma cell lines. Western blot analysis showed increased expression of BAX and p53, decreased expression of BCL2 and elevated level of APG5. Treatment with TMZ followed by CRAd-Survivin-pk7 (CRAd-S-pk7) led to a significant over-expression of autophagy markers, acidic vesicular organelles and light-chain 3 (LC3). These results were further evaluated
in vivo
, in which 90% of the mice with intracranial tumours were long-term survivors (>100 days) after treatment with TMZ and CRAd-S-pk7 (
P
<0.01). Analysis of tumours
ex vivo
showed expression of both LC3 and cleaved Caspase-3, proving that both autophagy and apoptosis are responsible for cell death
in vivo
. These results suggest that combination of chemovirotherapy offers a powerful tool against malignant glioma and should be further explored in the clinical setting.