Survivin promoter-regulated oncolytic adenovirus with Hsp70 gene exerts effective antitumor efficacy in gastric cancer immunotherapy

Wang, Weiguo; Ji, Weidan; Hu, Huanzhang; Ma, Juming; Li, Xiaoya; Mei, Weiqun; Xu, Yang; Hu, Hui-Zhen; Yan, Yan; Song, Qi; Li, Zhigang; Su, Changqing

doi:10.18632/oncotarget.1430

Cited by 36 publications

(33 citation statements)

References 32 publications

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“…Researchers are attempting to improve modern cancer treatment therapies by implementing Hsp70 inhibitors for the development of novel drugs in the near future [117–119]. Hsp70 demonstrates various functions, including acting as a cellular lifeguard and exerting anti-apoptotic effects.…”

Section: Discussionmentioning

confidence: 99%

Targeting Hsp70: A possible therapy for cancer

et al. 2016

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In all organisms, heat-shock proteins (HSPs) provide an ancient defense system. These proteins act as molecular chaperones by assisting proper folding and refolding of misfolded proteins and aid in the elimination of old and damaged cells. HSPs include Hsp100, Hsp90, Hsp70, Hsp40, and small HSPs. Through its substrate-binding domains, Hsp70 interacts with wide spectrum of molecules, ranging from unfolded to natively folded and aggregated proteins, and provides cytoprotective role against various cellular stresses. Under pathophysiological conditions, the high expression of Hsp70 allows cells to survive with lethal injuries. Increased Hsp70, by interacting at several points on apoptotic signaling pathways, leads to inhibition of apoptosis. Elevated expression of Hsp70 in cancer cells may be responsible for tumorigenesis and for tumor progression by providing resistance to chemotherapy. In contrast, inhibition or knockdown of Hsp70 reduces the size of tumors and can cause their complete regression. Moreover, extracellular Hsp70 acts as an immunogen that participates in cross presentation of MHC-I molecules. The goals of this review are to examine the roles of Hsp70 in cancer and to present strategies targeting Hsp70 in the development of cancer therapeutics.

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Section: Discussionmentioning

confidence: 99%

Targeting Hsp70: A possible therapy for cancer

et al. 2016

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“…The Survivin promoter-regulated cancer-selectively replicating adenovirus AdSurp (23)(24)(25), which we previously recombined and named oncolytic adenovirus because of its capability to lyse tumor cells, was used as the vector to express the artificially designed lncRNAi to allow a targeted transcription and expression of lncRNAi in high copy number in HCC cells. The complementary sequences of 12 OncomiR seed sequences (Supplementary Table S1) were connected in tandem and repeated six times as the encoding gene for lncRNAi.…”

Section: Construction Of the Viral Vectorsmentioning

confidence: 99%

An Artificially Designed Interfering lncRNA Expressed by Oncolytic Adenovirus Competitively Consumes OncomiRs to Exert Antitumor Efficacy in Hepatocellular Carcinoma

Sun

et al. 2016

Molecular Cancer Therapeutics

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Endogenous miRNAs, especially oncogenic miRNAs (OncomiR), have been molecular targets for cancer therapy. We generated an artificially designed interfering long noncoding RNA (lncRNAi), which contains the sequences that can complementarily bind to multiple OncomiRs and is expressed by cancer-selectively replicating adenovirus. The adenovirus-expressed lncRNAi with high levels in hepatocellular carcinoma (HCC) cells competes with OncomiR target genes to bind to and consume OncomiRs, thereby achieving the targeted anti-HCC efficacy. With the targeting replication of adenovirus in HCC cells, lncRNAi was highly expressed and resulted in decreased abilities of proliferation, migration, and invasion, induced cell-cycle changes and apoptosis, and markedly changed the cellular mRNA and miRNA expression profiles in HCC cells. The optimal antitumor effect was also demonstrated on HCC cell line xenograft models and HCC patient-derived xenograft (PDX) tumor models in nude mice. This strategy has established a technology platform with a reliable therapeutic effect for HCC therapy.

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“…The replication of AdSur and AdSur‐SYE is regulated by the survivin promoter, which has been reported to exhibit a higher activity only in a variety of cancers but not in normal tissues . To confirm the relevance of the survivin promoter to the PNET cell lines, cells were transfected with the pSur‐Luc and pRL‐SV40 plasmids.…”

Section: Resultsmentioning

confidence: 99%

“…To regulate the replication of the adenovirus, we used the survivin promoter in the AdSur‐SYE construct. Survivin is one of antiapoptotic proteins involved in mitotic regulation during embryonic and fetal development, but its expression is generally undetectable in somatic cells . Thus, survivin is a broad‐spectrum molecular target for cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Strong antitumor efficacy of a pancreatic tumor‐targeting oncolytic adenovirus for neuroendocrine tumors

et al. 2017

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Although oncolytic adenoviruses are promising cancer therapy agents, for effective oncolytic activity, viruses need to specifically infect and effectively replicate in cancer cells but not in normal cells. We have previously identified a pancreatic cancer‐targeting ligand, SYENFSA (SYE), by screening an adenovirus library displaying random peptides against human pancreatic cancer cells and reported that a survivin promoter‐regulated adenovirus, displaying the SYE ligand (AdSur‐SYE), provided effective oncolysis of pancreatic ductal adenocarcinoma (PDAC) in a preclinical study. As we examined the infectivity of AdSur‐SYE in human surgical specimens of various pancreatic tumors, we unexpectedly found that AdSur‐SYE showed high gene transduction efficiency for pancreatic neuroendocrine tumors (PNETs) as well as for PDAC, 9.1‐ and 6.2‐fold, respectively, compared to that of the nontargeting virus (AdSur). The infectivity of both vectors was almost the same in other cancers and organs such as the pancreas. Immunostaining indicated that the cells infected with AdSur‐SYE were PNET cells but not stromal cells. AdSur‐SYE showed a significantly higher oncolytic potency than that of AdSur in human PNET cell lines, and intratumoral infection with AdSur‐SYE completely diminished subcutaneous tumors in a murine model, in which AdSur‐SYE effectively proliferated and spread. AdSur‐SYE exerted a stronger oncolytic effect in primary PNET cells cocultured with mouse embryonic fibroblasts than AdSur did. Thus, AdSur‐SYE shows promise as a next‐generation therapy for PNET.

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Survivin promoter-regulated oncolytic adenovirus with Hsp70 gene exerts effective antitumor efficacy in gastric cancer immunotherapy

Cited by 36 publications

References 32 publications

Targeting Hsp70: A possible therapy for cancer

Targeting Hsp70: A possible therapy for cancer

An Artificially Designed Interfering lncRNA Expressed by Oncolytic Adenovirus Competitively Consumes OncomiRs to Exert Antitumor Efficacy in Hepatocellular Carcinoma

Strong antitumor efficacy of a pancreatic tumor‐targeting oncolytic adenovirus for neuroendocrine tumors

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