Combination of autophagy inducer rapamycin and oncolytic adenovirus improves antitumor effect in cancer cells

Cheng, Pei-Hsin; Lian, Serena; Zhao, Robin; Rao, Xiao‐Mei; McMasters, Kelly M.; Zhou, Huiyun

doi:10.1186/1743-422x-10-293

Cited by 36 publications

(48 citation statements)

References 76 publications

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“…Interestingly, RIDa was shown to rescue the cholesterol storage phenotype of Niemann-Pick disease type C mutant fibroblasts, and is involved in lipid droplet formation (Cianciola and Carlin, 2009;Cianciola et al, 2013). One can envisage that a combination of autophagy-inducing compounds together with HAdV may enhance oncolytic efficacy of viral therapies (Rodriguez-Rocha et al, 2011;Cheng et al, 2013).…”

Section: Autophagy: Proviral or Antiviral?mentioning

confidence: 99%

Innate Immunity to Adenovirus

et al. 2014

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Human adenoviruses are the most widely used vectors in gene medicine, with applications ranging from oncolytic therapies to vaccinations, but adenovirus vectors are not without side effects. In addition, natural adenoviruses pose severe risks for immunocompromised people, yet infections are usually mild and selflimiting in immunocompetent individuals. Here we describe how adenoviruses are recognized by the host innate defense system during entry and replication in immune and nonimmune cells. Innate defense protects the host and represents a major barrier to using adenoviruses as therapeutic interventions in humans. Innate response against adenoviruses involves intrinsic factors present at constant levels, and innate factors mounted by the host cell upon viral challenge. These factors exert antiviral effects by directly binding to viruses or viral components, or shield the virus, for example, soluble factors, such as blood clotting components, the complement system, preexisting immunoglobulins, or defensins. In addition, Toll-like receptors and lectins in the plasma membrane and endosomes are intrinsic factors against adenoviruses. Important innate factors restricting adenovirus in the cytosol are tripartite motif-containing proteins, nucleotide-binding oligomerization domain-like inflammatory receptors, and DNA sensors triggering interferon, such as DEAD (Asp-Glu-Ala-Asp) box polypeptide 41 and cyclic guanosine monophosphate-adenosine monophosphate synthase. Adenovirus tunes the function of antiviral autophagy, and counters innate defense by virtue of its early proteins E1A, E1B, E3, and E4 and two virusassociated noncoding RNAs VA-I and VA-II. We conclude by discussing strategies to engineer adenovirus vectors with attenuated innate responses and enhanced delivery features.

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Section: Autophagy: Proviral or Antiviral?mentioning

confidence: 99%

Innate Immunity to Adenovirus

et al. 2014

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“…In addition, the combination of an adenovirus with an autophagy inducer correlates positively with virus replication, improving the efficacy of Ad-mediated oncolysis. Therefore, we explored whether the oncolytic adenovirus loaded to L-carnosine, a mimic of rapamycin, improves antitumor effects in cancer cells (16). LC3II conversion performed in HCT-116 and in A549 cells demonstrates that the complex increases autophagy promoting virus replication only in colon cancer cells (HCT-116).…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that virus-induced autophagy correlates positively with virus replication and that the combination of an adenovirus with an autophagy inducer improves antitumor effects in cancer cells (16). L-carnosine has been defined as a mimic of rapamycin, an inhibitor of the mTOR, and so may be able to induce autophagy (17).…”

Section: Oncolytic Adenovirus Loaded With L-carnosine Induces Autophamentioning

confidence: 99%

Oncolytic Adenovirus Loaded with L-carnosine as Novel Strategy to Enhance the Antitumor Activity

Garofalo

Iovine²,

Kuryk

et al. 2016

Molecular Cancer Therapeutics

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Oncolytic viruses are able to specifically replicate, infect, and kill only cancer cells. Their combination with chemotherapeutic drugs has shown promising results due to the synergistic action of virus and drugs; the combinatorial therapy is considered a potential clinically relevant approach for cancer. In this study, we optimized a strategy to absorb peptides on the viral capsid, based on electrostatic interaction, and used this strategy to deliver an active antitumor drug. We used L-carnosine, a naturally occurring histidine dipeptide with a significant antiproliferative activity. An ad hoc modified, positively charged L-carnosine was combined with the capsid of an oncolytic adenovirus to generate an electrostatic virus-carnosine complex. This complex showed enhanced antitumor efficacy in vitro and in vivo in different tumor models. In HCT-116 colorectal and A549 lung cancer cell lines, the complex showed higher transduction ratio and infectious titer compared with an uncoated oncolytic adenovirus. The in vivo efficacy of the complex was tested in lung and colon cancer xenograft models, showing a significant reduction in tumor growth. Importantly, we investigated the molecular mechanisms underlying the effects of complex on tumor growth reduction. We found that complex induces apoptosis in both cell lines, by using two different mechanisms, enhancing viral replication and affecting the expression of Hsp27. Our system could be used in future studies also for delivery of other bioactive drugs. Mol Cancer Ther; 15(4); 651-60. Ó2016 AACR.

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“…Adhz60 is an E1b-deleted vector similar to dl1520 and H101 and was used as a cancer selective control in these studies [43]. AdGFP is E1 (E1a and E1b) deleted, with green fluorescent protein (GFP) expression driven by the cytomegalovirus (CMV) promoter [35]. AdGFP, as a negative control, does not replicate nor induce cytopathic effects (CPE) [9,23].…”

Section: Adenoviral Vectorsmentioning

confidence: 99%

Adenovirus with DNA Packaging Gene Mutations Increased Virus Release

Wechman

Rao

McMasters

et al. 2016

Preprint

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Adenoviruses (Ads) have been extensively manipulated for the development of cancer selective replication, leading to cancer cell death or oncolysis. Clinical studies using E1-modified oncolytic Ads have shown that this therapeutic platform was safe, but with limited efficacy, indicating the necessity of targeting other viral genes for manipulation. To improve the therapeutic efficacy of oncolytic Ads, we treated the entire Ad genome repeatedly with UV-light and have isolated AdUV which efficiently lyses cancer cells as reported previously (Wechman, S. L. et al. Development of an Oncolytic Adenovirus with Enhanced Spread Ability through Repeated UV Irradiation and Cancer Selection. Viruses 2016, 8, 6). In this report, we show that no mutations were observed in the early genes (E1 or E4) of AdUV while several mutations were observed within the Ad late genes which have structural or viral DNA packaging functions. This study also reported the increased release of AdUV from cancer cells. In this study, we found that AdUV inhibits tumor growth following intratumoral injection. These results indicate the potentially significant role of the viral late genes, in particular the DNA packaging genes, to enhance Ad oncolysis.

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Combination of autophagy inducer rapamycin and oncolytic adenovirus improves antitumor effect in cancer cells

Cited by 36 publications

References 76 publications

Innate Immunity to Adenovirus

Innate Immunity to Adenovirus

Oncolytic Adenovirus Loaded with L-carnosine as Novel Strategy to Enhance the Antitumor Activity

Adenovirus with DNA Packaging Gene Mutations Increased Virus Release

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