Nanoparticle-facilitated Intratumoral Delivery of Bcl-2/IGF-1R siRNAs and p53 Gene Synergistically Inhibits Tumor Growth in Immunocompetent Mice

Kunnath, Anil Philip; Kamaruzman, Nur Izyani; Chowdhury, Ezharul Hoque

doi:10.4172/2157-7439.1000278

Cited by 5 publications

(6 citation statements)

References 39 publications

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“…Indeed, it has been reported that the knockdown of Survivin, with siRNA in mutant TP53 lung cancer cells, increased their sensitivity to doxorubicin . Furthermore, in immunocompetent mice with breast cancers, nanoparticle‐facilitated intra‐tumoral delivery of siRNAs targeting IGF‐1R and Bcl‐2 gene transcripts and the plasmid DNA containing wild‐type TP53 gene was shown to synergistically inhibit tumor growth and increase the chemosensitivity . Therefore, a combination of IGF‐1R/Bcl‐2/Survivin knockdown and targeting mutant TP53 might be an option that warrants further evaluation in preclinical trials to establish the therapeutic potential for the treatment of osteosarcomas.…”

Section: Discussionmentioning

confidence: 99%

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Targeting mutant TP53 as a potential therapeutic strategy for the treatment of osteosarcoma

Tang

Seebacher

et al. 2019

Journal Orthopaedic Research

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Mutant TP53 is a promising therapeutic target in cancers. Considering the current challenges facing the clinical treatment of cancer, as well as the urgent need to identify novel therapeutic targets in osteosarcomas, we aimed to evaluate the clinical significance of mutant TP53 in osteosarcoma patients and to explore the therapeutic effect of targeting mutant TP53 in osteosarcomas. We performed a meta‐analysis to investigate the relationship between mutant TP53 and the overall survival of patients with osteosarcoma. A CRISPR‐Cas9 system and a TP53 inhibitor, NSC59984, were also used to specifically knock‐out and inhibit mutant TP53 in the human osteosarcoma cell lines, KHOS, and KHOSR2. The meta‐analysis demonstrated that mutations in the TP53 gene could be used to predict a poor 2‐year survival in osteosarcoma patients. We also demonstrated that the expression of mutant TP53 in human osteosarcoma cell lines can be efficiently knocked‐out using CRISPR‐Cas9, and this decreased the proliferation, migration, and tumor formation activity of these osteosarcoma cells. Moreover, drug sensitivity to doxorubicin was increased in these TP53 knock‐out osteosarcoma cells. NSC59984 also showed similar anti‐tumor effects as CRISPR‐Cas9 targeted TP53 in the osteosarcoma cells in vitro. We have also demonstrated that the knock‐out or inhibition of mutant TP53 decreased the expression of the oncogene IGF‐1R, anti‐apoptotic proteins Bcl‐2, and Survivin in osteosarcoma cells. Collectively, these results suggest that mutant TP53 is a promising therapeutic target in osteosarcomas. Therefore, further studies exploring novel strategies to target mutant TP53 may help improve the treatment outcomes of osteosarcoma patients in the clinic. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

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Section: Discussionmentioning

confidence: 99%

“…increase the chemosensitivity. 50 Therefore, a combination of IGF-1R/Bcl-2/Survivin knockdown and targeting mutant TP53 might be an option that warrants further evaluation in preclinical trials to establish the therapeutic potential for the treatment of osteosarcomas.…”

Section: Discussionmentioning

confidence: 99%

Targeting mutant TP53 as a potential therapeutic strategy for the treatment of osteosarcoma

Tang

Seebacher

et al. 2019

Journal Orthopaedic Research

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“…Selective silencing of these GFR genes by using exogenous synthetic small interfering RNAs (siRNAs) to suppress growth of cancer cells demands a suitable carrier to deliver the anionic siRNA through the negatively charged cell membrane. The pH sensitive carbonate apatite nanoparticles (NPs) having strong affinity towards anionic nucleic acids (DNA or siRNA) with excellent biocompatibility, favorable pharmacokinetics, high tumor accumulation capacity and rapid, intracellular release rate through proton-driven self-dissolution, recently emerged as an attractive nano-career to efficiently carry siRNAs in diverse cancer cell lines and animal models to silence particular endogenous genes (Hossain et al., 2010 ; Chua et al., 2013 ; Kunnath et al., 2014a , b ), and, therefore, have been employed here to carry the single or multiple siRNA(s) in breast cancer cells as well as in breast tumors subcutaneously induced in mice mammary pads. It has been revealed that silencing of GFR genes reduced cell viability (CV), with the highest cytotoxicity observed with the siRNAs targeting egfr1 and erbb2 genes, enhanced apoptotic signal in the cells and also reduced the tumor volume in mice, with exception of igf1r gene knockdown.…”

Section: Introductionmentioning

confidence: 99%

Carbonate apatite nanoparticles carry siRNA(s) targeting growth factor receptor genes egfr1 and erbb2 to regress mouse breast tumor

2017

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Cancer cells lose their control on cell cycle by numerous genetic and epigenetic alterations. In a tumor, these cells highly express growth factor receptors (GFRs), eliciting growth, and cell division. Among the GFRs, epidermal growth factor receptor-1 (EGFR1) (Her1/ERBB1) and epidermal growth factor receptor-2 (EGFR2) (Her2/ERBB2) from epidermal growth factor (EGF) family and insulin-like growth factor-1 receptor (IGF1R) are highly expressed on breast cancer cells, thus contributing to the aggressive growth and invasiveness, have been focused in this study. Moreover, overexpression of these receptors is related to suppression of cell death and conferring resistance against the classical drugs used to treat cancer nowadays. Therefore, silencing of these GFRs-encoding genes by using selective small interfering RNAs (siRNAs) could be a powerful approach to treat breast cancer. The inorganic pH sensitive carbonate apatite nanoparticles (NPs) were used as a nano-carrier to deliver siRNA(s) against single or multiple GFR genes in breast cancer cells as well as in a mouse model of breast carcinoma. Silencing of egfr1 and erbb2 simultaneously led to a reduction in cell viability with an increase in cell death signal in the cancer cells and regression of tumor growth in vivo.

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“…Fourier transform-infrared (FT-IR) spectroscopy of generated carbonate apatite particles was performed using Varian 440 FTIR (Santa Clara, CA, USA). CA nanoparticles were prepared as discussed earlier [41]. Additionally, 44mM of sodium bicarbonate and DMEM powder was mixed using mili-Q water with pH adjusted to 7.4.…”

Section: Methodsmentioning

confidence: 99%

“…CA nanoparticles were prepared as discussed earlier [41]. Briefly, 44 mM sodium bicarbonate and DMEM powder was mixed using mili-Q water, with pH adjusted to 7.4.…”

Section: Methodsmentioning

confidence: 99%

Targeting Cell Adhesion Molecules via Carbonate Apatite-Mediated Delivery of Specific siRNAs to Breast Cancer Cells In Vitro and In Vivo

et al. 2019

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While several treatment strategies are applied to cure breast cancer, it still remains one of the leading causes of female deaths worldwide. Since chemotherapeutic drugs have severe side effects and are responsible for development of drug resistance in cancer cells, gene therapy is now considered as one of the promising options to address the current treatment limitations. Identification of the over-expressed genes accounting for constitutive activation of certain pathways, and their subsequent knockdown with specific small interfering RNAs (siRNAs), could be a powerful tool in inhibiting proliferation and survival of cancer cells. In this study, we delivered siRNAs against mRNA transcripts of over-regulated cell adhesion molecules such as catenin alpha 1 (CTNNA1), catenin beta 1 (CTNNB1), talin-1 (TLN1), vinculin (VCL), paxillin (PXN), and actinin-1 (ACTN1) in human (MCF-7 and MDA-MB-231) and murine (4T1) cell lines as well as in the murine female Balb/c mice model. In order to overcome the barriers of cell permeability and nuclease-mediated degradation, the pH-sensitive carbonate apatite (CA) nanocarrier was used as a delivery vehicle. While targeting CTNNA1, CTNNB1, TLN1, VCL, PXN, and ACTN1 resulted in a reduction of cell viability in MCF-7 and MDA-MB-231 cells, delivery of all these siRNAs via carbonate apatite (CA) nanoparticles successfully reduced the cell viability in 4T1 cells. In 4T1 cells, delivery of CTNNA1, CTNNB1, TLN1, VCL, PXN, and ACTN1 siRNAs with CA caused significant reduction in phosphorylated and total AKT levels. Furthermore, reduced band intensity was observed for phosphorylated and total MAPK upon transfection of 4T1 cells with CTNNA1, CTNNB1, and VCL siRNAs. Intravenous delivery of CTNNA1 siRNA with CA nanoparticles significantly reduced tumor volume in the initial phase of the study, while siRNAs targeting CTNNB1, TLN1, VCL, PXN, and ACTN1 genes significantly decreased the tumor burden at all time points. The tumor weights at the end of the treatments were also notably smaller compared to CA. This successfully demonstrates that targeting these dysregulated genes via RNAi and by using a suitable delivery vehicle such as CA could serve as a promising therapeutic treatment modality for breast cancers.

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Nanoparticle-facilitated Intratumoral Delivery of Bcl-2/IGF-1R siRNAs and p53 Gene Synergistically Inhibits Tumor Growth in Immunocompetent Mice

Cited by 5 publications

References 39 publications

Targeting mutant TP53 as a potential therapeutic strategy for the treatment of osteosarcoma

Targeting mutant TP53 as a potential therapeutic strategy for the treatment of osteosarcoma

Carbonate apatite nanoparticles carry siRNA(s) targeting growth factor receptor genes egfr1 and erbb2 to regress mouse breast tumor

Targeting Cell Adhesion Molecules via Carbonate Apatite-Mediated Delivery of Specific siRNAs to Breast Cancer Cells In Vitro and In Vivo

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