High CD46 Receptor Density Determines Preferential Killing of Tumor Cells by Oncolytic Measles Virus

Anderson, Bambi D.; Nakamura, Takafumi; Russell, Stephen J.; Peng, Kah Whye

doi:10.1158/0008-5472.can-04-0884

Cited by 276 publications

(266 citation statements)

References 45 publications

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“…It has been shown that selectivity of measles virus Edmonston vaccine strain derivatives against tumor cells can be explained on the basis of CD46 overexpression in tumor cells, in contrast to low expression levels in normal cells. 37 The lack of CD46 receptor induction both in tumor as well as normal cells in response to GA treatment, as we have demonstrated here, could explain the selective sparing of normal cells from the cytopathic effect of MV/GA combination, despite the increased cytopathic effect in tumor cells.…”

Section: Combining Measles Virus With Heat Shock Protein Inhibitors Csupporting

confidence: 52%

“…Quantitation of the syncytial surface per plate (Syncytial Index) was analyzed using NIH software. 37 Determination of CD46 expression levels. One million tumor or NHDF cells were harvested before and at 24, 48 and 72 h after GA treatment, washed and then incubated with fluorescein isothiocyanate-labeled mouse anti-human CD46 (PharMingen, San Jose, CA, USA).…”

Section: Syncytial Index Mda-mb-231 Cells Were Infected Withmentioning

confidence: 99%

“…Quantification of the syncytial area (Syncytial Index) was performed using NIH software (ImageJ). 37 …”

Section: Detection Of Surface Mv-h Protein Expressionmentioning

confidence: 99%

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Heat shock protein inhibitors increase the efficacy of measles virotherapy

Liu

Erlichman

et al. 2008

Gene Ther

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Oncolytic measles virus strains have activity against multiple tumor types and are currently in phase I clinical testing. Induction of the heat shock protein 70 (HSP70) constitutes one of the earliest changes in cellular gene expression following infection with RNA viruses including measles virus, and HSP70 upregulation induced by heat shock has been shown to result in increased measles virus cytotoxicity. HSP90 inhibitors such as geldanamycin (GA) or 17-allylaminogeldanamycin result in pharmacologic upregulation of HSP70 and they are currently in clinical testing as cancer therapeutics. We therefore investigated the hypothesis that heat shock protein inhibitors could augment the measles virus-induced cytopathic effect. We tested the combination of a measles virus derivative expressing soluble human carcinoembryonic antigen (MV-CEA) and GA in MDA-MB-231 (breast), SKOV3.IP (ovarian) and TE671 (rhabdomyosarcoma) cancer cell lines. Optimal synergy was accomplished when GA treatment was initiated 6-24 h following MV infection. Western immunoblotting confirmed HSP70 upregulation in combination-treated cells. Combination treatment resulted in statistically significant increase in syncytia formation as compared to MV-CEA infection alone. Clonogenic assays demonstrated significant decrease in tumor colony formation in MV-CEA/GA combination-treated cells. In addition there was increase in apoptosis by 4,6-diamidino-2-phenylindole staining. Western immunoblotting for caspase-9, caspase-8, caspase-3 and poly(ADP-ribose) polymerase (PARP) demonstrated increase in cleaved caspase-8 and PARP. The pan-caspase inhibitor Z-VAD-FMK and caspase-8 inhibitor Z-IETD-FMK, but not the caspase-9 inhibitor Z-IEHD-FMK, protected tumor cells from MV-CEA/GA-induced PARP activation, indicating that apoptosis in combinationtreated cells occurs mainly via the extrinsic caspase pathway. Treatment of normal cells, such as normal human fibroblasts, however, with the MV-CEA/GA combination, did not result in cytopathic effect, indicating that GA did not alter the MV-CEA specificity for tumor cells. One-step viral growth curves, western immunoblotting for MV-N protein expression, QRT-PCR quantitation of MV-genome copy number and CEA levels showed comparable proliferation of MV-CEA in GAtreated vs -untreated tumor cells. Rho activation assays and western blot for total RhoA, a GTPase associated with the actin cytoskeleton, demonstrated decrease in RhoA activation in combination-treated cells, a change previously shown to be associated with increase in paramyxovirus-induced cell-cell fusion. The enhanced cytopathic effect resulting from measles virus/GA combination supports the translational potential of this approach in the treatment of cancer.

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Section: Combining Measles Virus With Heat Shock Protein Inhibitors Csupporting

confidence: 52%

Section: Syncytial Index Mda-mb-231 Cells Were Infected Withmentioning

confidence: 99%

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Heat shock protein inhibitors increase the efficacy of measles virotherapy

Liu

Erlichman

et al. 2008

Gene Ther

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“…Ad.5/3 uses group B receptors, CD46 and CD80/CD86, and displays enhanced transduction of malignant glioma cells having low CAR (U87MG and U373MG) compared with wild-type Ad.5. 38,39 CD46 has also been shown to be overexpressed in some human neoplasms, 40 thereby protecting tumor cells from identification and destruction by the complement system, indicating a tumor-selective transduction ability by Ad.5/3. This concept was supported by the observation that Ad.5/3-Luc showed superior tumor-specific luciferase transgene expression when compared with Ad.5-Luc in normal human astrocytes.…”

Section: Discussionmentioning

confidence: 99%

Enhanced delivery of mda-7/IL-24 using a serotype chimeric adenovirus (Ad.5/3) improves therapeutic efficacy in low CAR prostate cancer cells

Dash

Dmitriev

et al. 2010

Cancer Gene Ther

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“…28 In addition, a strong correlative effect has been illustrated between increased CD46 expression and increased potency of MV-Edm oncolytic infection. 29 Bone marrow samples collected from myeloma patients revealed a sevenfold increase in CD46 expression levels on myeloma cells compared to non-myeloma cells. In addition, the myeloma cells showed greatly increased susceptibility to MV infection, fusion and killing, which correlated to their increased expression of CD46.…”

Section: Measles Virusmentioning

confidence: 96%