Increased Hypoxia following Vessel Targeting in a Murine Model of Retinoblastoma

Boutrid, Hinda; Piña, Yolanda; Cebulla, Colleen M.; Feuer, William J.; Lampidis, Théodore J.; Jockovich, Maria-Elena; Murray, Timothy G.

doi:10.1167/iovs.09-3702

Cited by 20 publications

(15 citation statements)

References 42 publications

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“…Taken together, our data suggest that 2-DG-mediated inhibition of the KSHV lytic cycle with concomitant inhibition of host angiogenic genes and endothelial cell proliferation could have significant anti-KS effects in vivo. In concurrence with our previous findings that 2-DG inhibition of N-linked glycosylation leading to the UPR could be exploited as an anticancer approach (33), we and others are investigating the use of this glucose analog both as a single agent and in combination in in vitro and in vivo models of human cancer, such as cultured prostate (3), melanoma (36), non-small cell lung cancer (24,38), osteosarcoma (38), and retinoblastoma (4,49). The following are among the promising combinations with 2-DG: MBT to inhibit the antiapoptotic activity of Bcl-2, which blocks UPR-induced apoptosis (62), inhibitors of autophagy (61), and rapamycin, which blocks hypoxia-inducible factors (37,60).…”

Section: Fig 4 2-dg Inhibits Angiogenic Gene Expression Meck36 (A) Asupporting

confidence: 86%

Activation of the Unfolded Protein Response by 2-Deoxy- d -Glucose Inhibits Kaposi's Sarcoma-Associated Herpesvirus Replication and Gene Expression

Leung

Duran

Kurtoğlu

et al. 2012

Antimicrob Agents Chemother

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Lytic replication of the Kaposi's sarcoma-associated herpesvirus (KSHV) is essential for the maintenance of both the infected state and characteristic angiogenic phenotype of Kaposi's sarcoma and thus represents a desirable therapeutic target. During the peak of herpesvirus lytic replication, viral glycoproteins are mass produced in the endoplasmic reticulum (ER). Normally, this leads to ER stress which, through an unfolded protein response (UPR), triggers phosphorylation of the ␣ subunit of eukaryotic initiation factor 2 (eIF2␣), resulting in inhibition of protein synthesis to maintain ER and cellular homeostasis. However, in order to replicate, herpesviruses have acquired the ability to prevent eIF2␣ phosphorylation. Here we show that clinically achievable nontoxic doses of the glucose analog 2-deoxy-D-glucose (2-DG) stimulate ER stress, thereby shutting down eIF2␣ and inhibiting KSHV and murine herpesvirus 68 replication and KSHV reactivation from latency. Viral cascade genes that are involved in reactivation, including the master transactivator (RTA) gene, glycoprotein B, K8.1, and angiogenesis-regulating genes are markedly decreased with 2-DG treatment. Overall, our data suggest that activation of UPR by 2-DG elicits an early antiviral response via eIF2␣ inactivation, which impairs protein synthesis required to drive viral replication and oncogenesis. Thus, induction of ER stress by 2-DG provides a new antiherpesviral strategy that may be applicable to other viruses.

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Section: Fig 4 2-dg Inhibits Angiogenic Gene Expression Meck36 (A) Asupporting

confidence: 86%

Activation of the Unfolded Protein Response by 2-Deoxy- d -Glucose Inhibits Kaposi's Sarcoma-Associated Herpesvirus Replication and Gene Expression

Leung

Duran

Kurtoğlu

et al. 2012

Antimicrob Agents Chemother

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“…One limitation of the current model is the lack of vitreous tumor seeding. Vascular targeting agents, such as anecortave acetate, have proven efficacious in the LH ⁡ BETA T AG mouse model for retinoblastoma, demonstrating a decrease in the vascularity of tumors and enhancing tumor control when combined with chemotherapy or other agents [42]. Glycolytic inhibitors, such as 2-deoxy-D-glucose, have also been investigated in the LH ⁡ BETA T AG model and shown to target hypoxic regions of tumors [43].…”

Section: Discussionmentioning

confidence: 99%

Intravitreal and Subconjunctival Melphalan for Retinoblastoma in Transgenic Mice

Shah

Pham

Murray³

et al. 2014

Journal of Ophthalmology

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Purpose. To measure the chemotherapeutic effects of focal melphalan (intravitreal and subconjunctival) on tumor burden, hypoxia, and vasculature in LHBETATAG murine retinoblastoma model. Methods. LHBETATAG transgenic mice were treated with a single 1 mcg intravitreal injection of melphalan, 100 mcg subconjunctival injection, or semiweekly 10 mcg subconjunctival injections for 3 weeks. At 1 or 3 weeks, eyes were enucleated, serially sectioned, and processed with haematoxylin and eosin (H&E) for tumor burden measurements and probed with immunofluorescence to analyze tumor hypoxia and vasculature. Results. Focal melphalan significantly reduced retinal tumor size (P < 0.02) when given intravitreally or subconjunctivally. Eyes treated with a one-time intravitreal injection of 1 mcg melphalan had significantly smaller tumors at both 1 week (P = 0.017) and at 3 weeks after injection (P = 0.005). Intratumoral hypoxia showed a significant decline in hypoxia at 1 week following intravitreal injection and after maximum dosage of subconjunctival melphalan. Total vasculature was not significantly affected following intravitreal administration. Conclusion. Focal delivery of melphalan via intravitreal or subconjunctival injection has a significant effect on reducing tumor burden, hypoxia, and vasculature, in the treatment of murine retinoblastoma tumors.

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“…Further, with the current study, timing of 2-DG following AA treatment led to significant differences in advanced tumor control. AA has been shown to significantly reduce total vessel density in tumors, primarily immature neovessels, as well as increase hypoxia in tumors by 28% and 17% 1 day and 1 week post-treatment, respectively 44. With reduction in blood vessels, there is a decrease in blood flow resulting in less delivery of oxygen and nutrients to highly metabolic neoplastic cells.…”

Section: Discussionmentioning

confidence: 99%

Novel retinoblastoma treatment avoids chemotherapy: the effect of optimally timed combination therapy with angiogenic and glycolytic inhibitors on LHBETATAG retinoblastoma tumors

Houston¹,

Piña²,

Murray³

et al. 2011

OPTH

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PurposeThe purpose of this study was to evaluate the effect of optimally timed combination treatment with angiogenic and glycolytic inhibitors on tumor burden, hypoxia, and angiogenesis in advanced retinoblastoma tumors.MethodsLHBETATAG mice (n =30) were evaluated. Mice were divided into 5 groups (n =6) and received injections at 16 weeks of age (advanced tumors) with a) saline, b) anecortave acetate (AA), c) 2-deoxyglucose (2-DG), d) AA +2-DG (1 day post-AA treatment), or e) AA +2-DG (1 week post-AA treatment). Eyes were enucleated at 21 weeks and tumor sections were analyzed for hypoxia, angiogenesis, and tumor burden.ResultsEyes treated with 2-DG 1 day post-AA injection showed a 23% (P =0.03) reduction in tumor burden compared with 2-DG alone and a 61% (P < 0.001) reduction compared with saline-treated eyes. Eyes treated with 2-DG 1 week post-AA injection showed no significant decrease in tumor burden compared with 2-DG alone (P = 0.21) and a 56% (P < 0.001) decrease in comparison with saline-treated eyes. 2-DG significantly reduced the total density of new blood vessels in tumors by 44% compared to saline controls (P < 0.001), but did not affect the density of mature vasculature.ConclusionsCombination therapy with angiogenic and glycolytic inhibitors significantly enhanced tumor control. Synergistic effects were shown to be dependent on the temporal course of treatment, emphasizing optimal timing. 2-DG was shown to reduce the density of neovessels, demonstrating an antiangiogenic effect in vivo. As a result, angiogenic and glycolytic inhibitors may have significant potential as alternative therapies for treating children with retinoblastoma.

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Increased Hypoxia following Vessel Targeting in a Murine Model of Retinoblastoma

Cited by 20 publications

References 42 publications

Activation of the Unfolded Protein Response by 2-Deoxy- d -Glucose Inhibits Kaposi's Sarcoma-Associated Herpesvirus Replication and Gene Expression

Activation of the Unfolded Protein Response by 2-Deoxy- d -Glucose Inhibits Kaposi's Sarcoma-Associated Herpesvirus Replication and Gene Expression

Intravitreal and Subconjunctival Melphalan for Retinoblastoma in Transgenic Mice

Novel retinoblastoma treatment avoids chemotherapy: the effect of optimally timed combination therapy with angiogenic and glycolytic inhibitors on LHBETATAG retinoblastoma tumors

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