Prostate Cancer-Specific and Potent Antitumor Effect of a DD3-Controlled Oncolytic Virus Harboring the PTEN Gene

Ding, Miao; Cao, Xin; Xu, Hai; Fan, Jianling; Huang, Heng; Yang, Dong; Li, Yu Hua; Wang, Jian; R, Li; Liu, Xin‐Yuan

doi:10.1371/journal.pone.0035153

Cited by 19 publications

(15 citation statements)

References 44 publications

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“…Development of specific small molecules that target or knock down DRD2 family proteins may result in a favorable outcome. Overexpressing shRNA targeting DRD2 family proteins by oncolytic viruses, particularly specific tumor targeting vectors (22,23), may exhibit a great antitumor effect. However, selective agonist of DRD2 family proteins induced lung cancer cell apoptosis (24,25), and this was contrary with the effect of the function of DRD2 family proteins in leukemia (17).…”

Section: Discussionmentioning

confidence: 99%

Thioridazine, an antipsychotic drug, elicits potent antitumor effects in gastric cancer

et al. 2014

Oncology Reports

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Abstract. Thioridazine, an antipsychotic drug, has been reported to induce apoptosis in various types of cancer cells, with specificity on targeting cancer stem cells (CSCs). However, whether it elicits anticancer effects in gastric cancer has never been reported. In the present study, we examined the ability of thioridazine to induce cell death in the gastric cancer cell lines NCI-N87 and AGS, and detected its in vivo tumor inhibition capacity. Thioridazine elicited cytotoxic effects on NCI-N87 and AGS cells in a dose-dependent manner, and inhibited the colony formation abilitiy of the NCI-N87 and AGS cells. Thioridazine treatment induced nuclear fragmentation, increased the proportion of sub-G1 phase cells, and elevated the percentage of Annexin V-positive cells, suggesting the occurrence of apoptosis. Moreover, thioridazine induced gastric cancer cell apoptosis in a caspase-dependent manner, as shown by a decrease in the precursors of casapse-9, caspase-8 and caspase-3, and by the ability of the caspase inhibitor Z-VAD-FMK to reverse the cytotoxic effect of thioridazine. JC-1 staining further revealed that thioridazine induced gastric cancer cell apoptosis via the mitochondrial pathway. In addition, thioridazine pretreatment inhibited the growth of NCI-N87 cell-derived tumors. The present study demonstrated that the antipsychotic drug thioridazine possesses anti-gastric cancer ability through in vitro and in vivo experiments, suggesting thioridazine as a potential drug in gastric cancer therapy. IntroductionGastric cancer is the fourth most common cancer worldwide with 989,600 new cases diagnosed in 2008, and it is the second leading cause of cancer-related death (1,2). Gastric cancer is either asymptomatic or causes non-specific symptoms at an early stage, and thus the majority of patients present with advanced stage disease at the time of initial diagnosis, leading to the poor prognosis of gastric cancer. Gastric cancer treatment involves surgery, chemotherapy, radiation therapy and their combinations. However, current drugs are confronted with low efficacy due to the high rate of patients at the advanced stage of gastric cancer. Thus, the development of novel effective drugs for gastric cancer therapy is urgently needed.Thioridazine, an antagonist of the dopamine receptor D2 family proteins, was initially developed as an antipsychotic drug, and recently its anticancer function was revealed. Studies have revealed the antiproliferative and apoptosis induction capacities of thioridazine in neuroblastoma, glioma, leukemia, breast cancer, cervical cancer and endometrial cancer (3-6). A gene signature-based approach identified thioridazine as an inhibitor of PI3K/Akt signaling in ovarian cancer cells. It downregulated cell cycle regulators cyclin D1 and CDK4, and upregulated p21, p16 and p-CDC25A, leading to the G0/ G1 phase arrest of the cells (7). Research on cervical and endometrial cancer cells disclosing the involvement of the PI3K/Akt/mTOR pathway in thioridazine-induced apoptosis further supported this fi...

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Section: Discussionmentioning

confidence: 99%

Thioridazine, an antipsychotic drug, elicits potent antitumor effects in gastric cancer

et al. 2014

Oncology Reports

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“…The product, Progensa, has been on the market since 2011 [ 21 ]. In a recent advance, Ding et al [ 19 ] developed an oncolytic viral vector, Ad.DD3.E1A.E1B(Δ55)-(PTEN), under the control of the prostate-specific DD3 promoter and proved its apoptotic effect in prostate cancer cell lines.…”

Section: The Great Past and Bright Future Of Lncrnas Unexpectedly Idementioning

confidence: 99%

PRINS, a primate-specific long non-coding RNA, plays a role in the keratinocyte stress response and psoriasis pathogenesis

Széll

Danis

Bata‐Csörgő

et al. 2016

Pflugers Arch - Eur J Physiol

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In the last few years with the recent emergence of high-throughput technologies, thousands of long non-coding RNAs (lncRNAs) have been identified in the human genome. However, assigning functional annotation and determining cellular contexts for these RNAs are still in its infancy. As information gained about lncRNA structure, interacting partners, and roles in human diseases may be helpful in the characterization of novel lncRNAs, we review our knowledge on a selected group of lncRNAs that were identified serendipitously years ago by large-scale gene expression methods used to study human diseases. In particular, we focus on the Psoriasis-susceptibility-Related RNA Gene Induced by Stress (PRINS) lncRNA, first identified by our research group as a transcript highest expressed in psoriatic non-lesional epidermis. Results gathered for PRINS in the last 10 years indicate that it is conserved in primates and plays a role in keratinocyte stress response. Elevated levels of PRINS expression in psoriatic non-lesional keratinocytes alter the stress response of non-lesional epidermis and contribute to disease pathogenesis. Finally, we propose a categorization for the PRINS lncRNA based on a recently elaborated system for lncRNA classification.

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“…Moreover, the use of a tumor-specific promoter as a replacement for the E1A endogenous promoter improves the targeting of the oncolytic virus. The human telomerase reverse transcriptase (hTERT) promoter [31] , the α-fetoprotein (AFP) promoter [32,33] and the differential display code 3 (DD3) promoter [34] have been extensively utilized in targeted cancer therapy. Survivin is a cancer gene and could potentially be useful for cancer diagnosis and therapy [20,21,35] .…”

Section: Discussionmentioning

confidence: 99%

Tumor suppressor in lung cancer-1 (TSLC1) mediated by dual-regulated oncolytic adenovirus exerts specific antitumor actions in a mouse model

et al. 2013

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Aim:The tumor suppressor in lung cancer-1 (TSLC1) is a candidate tumor suppressor of lung cancer, and frequently inactivated in primary non-small cell lung cancer (NSCLC). In this study, we investigated the effects of TSLC1 mediated by a dual-regulated oncolytic adenovirus on lung cancer, and the mechanisms underlying the antitumor actions. Methods: The recombinant virus Ad·sp-E1A (∆24) -TSLC1 was constructed by inserting the TSLC1 gene into the dual-regulated Ad·sp-E1A (∆24) vector, which contained the survivin promoter and a 24 bp deletion within E1A. The antitumor effects of Ad·sp-E1A (∆24) -TSLC1 were evaluated in NCI-H460, A549, and H1299 lung cancer cell lines and the normal fibroblast cell line MRC-5, as well as in A549 xenograft model in nude mice. Cell viability was assessed using MTT assay. The expression of TSLC1 and activation of the caspase signaling pathway were detected by Western blot analyses. The tumor tissues from the xenograft models were examined using H&E staining, IHC, TUNEL, and TEM analyses. Results: Infection of A549 lung cancer cells with Ad·sp-E1A (∆24) -TSLC1 induced high level expression of TSLC1. Furthermore, the Ad·sp-E1A (∆24) -TSLC1 virus dose-dependently suppressed the viability of NCI-H460, A549, and H1299 lung cancer cells, and did not affect MRC-5 normal fibroblast cells. Infection of NCI-H460, A549, and H1299 lung cancer cells with Ad·sp-E1A (∆24) -TSLC1 induced apoptosis, and increased activation of caspase-8, caspase-3 and PARP. In A549 xenograft model in nude mice, intratumoral injection of Ad·sp-E1A (∆24) -TSLC1 significantly suppressed the tumor volume, and increased the survival rate (from less than 15% to 87.5% at d 60). Histological studies showed that injection of Ad·sp-E1A (∆24) -TSLC1 caused tumor cell apoptosis and virus particle propagation in tumor tissues. Conclusion: The oncolytic adenovirus Ad·sp-E1A (∆24) -TSLC1 exhibits specific antitumor effects, and is a promising agent for the treatment of lung cancer.

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Prostate Cancer-Specific and Potent Antitumor Effect of a DD3-Controlled Oncolytic Virus Harboring the PTEN Gene

Cited by 19 publications

References 44 publications

Thioridazine, an antipsychotic drug, elicits potent antitumor effects in gastric cancer

Thioridazine, an antipsychotic drug, elicits potent antitumor effects in gastric cancer

PRINS, a primate-specific long non-coding RNA, plays a role in the keratinocyte stress response and psoriasis pathogenesis

Tumor suppressor in lung cancer-1 (TSLC1) mediated by dual-regulated oncolytic adenovirus exerts specific antitumor actions in a mouse model

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