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

Ulasov, Ilya V.; Sonabend, Adam M.; Nandi, Sumon; Khramtsov, Andrey; Han, Yu; Lesniak, Maciej S.

doi:10.1038/sj.bjc.6604969

Cited by 59 publications

(51 citation statements)

References 43 publications

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“…34 Activation of TRAIL receptor 2 by a human Cancer targeting Gene-Viro-Therapy of hepatoma X Cao et al single-chain fragment variable antibody HW1 can induce autophagic cell death in both TRAIL-sensitive and -resistant cancer cells. 35 Although the concurrence of autophagic and apoptotic cell death was reported from a combination of adenoviral virotherapy and temozolomide chemotherapy in malignant glioma, 36 the results presented here are the first to show that these two distinct programmed cell death pathways can be simultaneously induced by a single geneviral agent in hepatoma.…”

Section: Discussionmentioning

confidence: 87%

Cancer targeting Gene-Viro-Therapy of liver carcinoma by dual-regulated oncolytic adenovirus armed with TRAIL gene

et al. 2011

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Liver cancer is a common and aggressive malignancy, but available treatment approaches remain suboptimal. Cancer targeting Gene-Viro-Therapy (CTGVT) has shown excellent anti-tumor effects in a preclinical study. CTGVT takes advantage of both gene therapy and virotherapy by incorporating an anti-tumor gene into an oncolytic virus vector. Potent anti-tumor activity is achieved by virus replication and exogenous expression of the anti-tumor gene. A dual-regulated oncolytic adenoviral vector designated AdÁAFPÁE1AÁE1B (D55) (AdÁAFPÁD55 for short thereafter) was constructed by replacing the native viral E1A promoter with the simian virus 40 enhancer/a-fetoprotein (AFP) composite promoter (AFPep) based on an E1B-55K-deleted construct, ZD55. AdÁAFPÁD55 showed specific replication and cytotoxicity in AFP-positive hepatoma cells. It also showed enhanced safety in normal cells when compared with the mono-regulated vector ZD55. To improve the anti-hepatoma activities of the virus, the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene was introduced into AdÁAFPÁD55. AdÁAFPÁD55-TRAIL exhibited remarkable anti-tumor activities in vitro and in vivo. Treatment with AdÁAFPÁD55-TRAIL can induce both autophagy owing to the AdÁAFPÁD55 vector and caspase-dependent apoptosis owing to the TRAIL protein. Therefore, AdÁAFPÁD55-TRAIL could be a potential anti-hepatoma agent with anti-tumor activities due to AFP-specific replication and TRAIL-induced apoptosis.

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Section: Discussionmentioning

confidence: 87%

Cancer targeting Gene-Viro-Therapy of liver carcinoma by dual-regulated oncolytic adenovirus armed with TRAIL gene

et al. 2011

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“…One of the potential avenues to increasing adenovirus potency that remains understudied is the mechanism by which adenoviruses induce cell lysis. In this regard, we along with other groups have shown that adenovirus infection results in macroautophagy (here referred to as autophagy) (12,15,41). Although it has been suggested that this cellular process might be linked to adenovirus-induced cell lysis (17), the underlying mechanism is still largely unknown.…”

mentioning

confidence: 98%

Human Adenovirus Type 5 Induces Cell Lysis through Autophagy and Autophagy-Triggered Caspase Activity

Jiang¹,

White

Ríos-Vicil

et al. 2011

J Virol

122

107

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Oncolytic adenoviruses, such as Delta-24-RGD, are promising therapies for patients with brain tumor. Clinical trials have shown that the potency of these cancer-selective adenoviruses should be increased to optimize therapeutic efficacy. One potential strategy is to increase the efficiency of adenovirus-induced cell lysis, a mechanism that has not been clearly described. In this study, for the first time, we report that autophagy plays a role in adenovirus-induced cell lysis. At the late stage after adenovirus infection, numerous autophagic vacuoles accompany the disruption of cellular structure, leading to cell lysis. The virus induces a complete autophagic process from autophagosome initiation to its turnover through fusion with the lysosome although the formation of the autophagosome is sufficient for virally induced cell lysis. Importantly, downmodulation of autophagy genes (ATG5 or ATG10) rescues the infected cells from being lysed by the virus. Moreover, autophagy triggers caspase activity via the extrinsic FADD/caspase 8 pathway, which also contributes to adenovirus-mediated cell lysis. Therefore, our study implicates autophagy and caspase activation as part of the mechanism for cell lysis induced by adenovirus and suggests that manipulation of the process is a potential strategy to optimize clinical efficacy of oncolytic adenoviruses.We reported previously the antiglioma effect of the E1A mutant oncolytic adenovirus Delta-24, which is targeted to the aberrant Rb/E2F1 pathway in cancer cells (10). In subsequent reports, we described how Delta-24-RGD, a version of Delta-24 whose infectivity in cancer cells is enhanced through insertion of an RGD-4C motif in the HI loop of the adenoviral fiber protein (37), showed oncolytic potency in intracranial models of human glioma xenografts derived from both malignant glioma cell lines (9) and brain tumor stem cells (15). On the basis of these preliminary data and toxicity studies performed under the guidance of the National Cancer Institute, we have translated Delta-24-RGD to the clinical setting, and it is currently being tested for toxicity in patients with recurrent malignant glioma at The University of Texas M. D. Anderson Cancer Center. Although we anticipate that the studies will show negligible toxicity, we expect that further improvements in the oncolytic potency of Delta-24-RGD will be necessary to induce optimal therapeutic effect. One of the potential avenues to increasing adenovirus potency that remains understudied is the mechanism by which adenoviruses induce cell lysis. In this regard, we along with other groups have shown that adenovirus infection results in macroautophagy (here referred to as autophagy) (12,15,41). Although it has been suggested that this cellular process might be linked to adenovirus-induced cell lysis (17), the underlying mechanism is still largely unknown.

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“…Till now, multimodality treatments with surgery, radiation and chemotherapy have led to some improvement in prognosis for patients with GBM (2,3). However, the 5-year survival rate for patients with GBM remains less than 5% and the median survival time is approximately one year (4).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of Nrf2 enhances autophagy induced by temozolomide in U251 human glioma cell line

et al. 2012

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Abstract. Glioblastoma multiforme (GBM) and oxidative stress are closely linked. Oxidative stress affects many signaling pathways and may cause the induction of autophagy. The NF-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling pathway is the main pathway responsible for cell defense against oxidative stress and Nrf2 is a critical transcription factor related with cancer multidrug resistance. However, the relation between Nrf2 and regulation of autophagy is not well understood. In this study, we used temozolomide (TMZ), which inhibited the viability of GBM cells mainly by inducing autophagic cell death and explored the role of Nrf2 downregulation on autophagy induced by TMZ in GBM cells. In U251-Si-Nrf2 48 h after transfection the protein levels of Nrf2 were significantly downregulated, while the protein levels of LC3B-II increased by western blot analysis. Knockdown of Nrf2 also led to a significant increase of autophagic vacuoles and acidic vesicular organelles (AVOs), revealed by trans mission electron microscopy (TEM) and acridine orange (AO) staining using flow cytometry. Collectively, these findings demonstrate that knockdown of Nrf2 can enhance the basal level of autophagy in the U251 glioma cell line. Furthermore, after the treatment with TMZ (100 µM) for 3 days, the U251-Si-Nrf2 transfected cells showed less viability rate by cell counting kit-8 (CCK-8) assay and the levels of autophagy increased obviously through analysis of western blot and AO staining using flow cytometry. Taken together, our results suggest that knockdown of Nrf2 may enhance autophagy induced by TMZ in the U251 glioma cell line, which should be further evaluated for novel anticancer activity.

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

Cited by 59 publications

References 43 publications

Cancer targeting Gene-Viro-Therapy of liver carcinoma by dual-regulated oncolytic adenovirus armed with TRAIL gene

Cancer targeting Gene-Viro-Therapy of liver carcinoma by dual-regulated oncolytic adenovirus armed with TRAIL gene

Human Adenovirus Type 5 Induces Cell Lysis through Autophagy and Autophagy-Triggered Caspase Activity

Knockdown of Nrf2 enhances autophagy induced by temozolomide in U251 human glioma cell line

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