Apoptin as a Tumor-Specific Therapeutic Agent: Current Perspective on Mechanism of Action and Delivery Systems

Malla, Waseem Akram; Arora, Richa; Khan, Raja Ishaq Nabi; Mahajan, Sumit; Tiwari, Ashok Kumar

doi:10.3389/fcell.2020.00524

Cited by 30 publications

(22 citation statements)

References 173 publications

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“…Very interesting is the notion that two de novo proteins are known to exert functions that are not virus-specific. They are the apoptin of Chicken anemia virus, which induces cell death in a broad range of human tumour cell lines but not in normal cells [57,58], and the protein X of Borna disease virus, which shows protective properties against neurodegeneration in vitro and in vivo [59,60]. Symmetric evolution (similar selection pressures on the two proteins) was found in the remaining 37 overlaps of the dataset [51].…”

Section: Symmetric and Asymmetric Evolution In Viral Overlapping Genesmentioning

confidence: 99%

Origin, Evolution and Stability of Overlapping Genes in Viruses: A Systematic Review

Pavesi

2021

Genes

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During their long evolutionary history viruses generated many proteins de novo by a mechanism called “overprinting”. Overprinting is a process in which critical nucleotide substitutions in a pre-existing gene can induce the expression of a novel protein by translation of an alternative open reading frame (ORF). Overlapping genes represent an intriguing example of adaptive conflict, because they simultaneously encode two proteins whose freedom to change is constrained by each other. However, overlapping genes are also a source of genetic novelties, as the constraints under which alternative ORFs evolve can give rise to proteins with unusual sequence properties, most importantly the potential for novel functions. Starting with the discovery of overlapping genes in phages infecting Escherichia coli, this review covers a range of studies dealing with detection of overlapping genes in small eukaryotic viruses (genomic length below 30 kb) and recognition of their critical role in the evolution of pathogenicity. Origin of overlapping genes, what factors favor their birth and retention, and how they manage their inherent adaptive conflict are extensively reviewed. Special attention is paid to the assembly of overlapping genes into ad hoc databases, suitable for future studies, and to the development of statistical methods for exploring viral genome sequences in search of undiscovered overlaps.

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Section: Symmetric and Asymmetric Evolution In Viral Overlapping Genesmentioning

confidence: 99%

Origin, Evolution and Stability of Overlapping Genes in Viruses: A Systematic Review

Pavesi

2021

Genes

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“…Oncolytic Adenoviruses are novel and highly effective gene delivery vectors which can be modified to express specific genes in the target cancer cell, eventually causing cell lysis and death [1].Our laboratory developed an Ad-vp3 (Ad5-apoptin) that expresses apoptin. Another Ad-vt (Ad5-apoptin-hTERTp-E1a) that can continuously express apoptin in the cancer cell via an hTERT promoter-driven was also developed.…”

Section: Introductionmentioning

confidence: 99%

Apoptin induces pyroptosis of colorectal cancer cells via the GSDME-dependent pathway

Liu¹,

Li²,

Zhu³

et al. 2022

Int. J. Biol. Sci.

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Apoptin is a small molecular weight protein encoded by the VP3 gene of chicken anemia virus (CAV). It can induce apoptosis of tumor cells and play anti-tumorigenic functions. In this study, we identified a time-dependent inhibitory role of apoptin on the viability of HCT116 cells. We also demonstrated that apoptin induces pyroptosis through cleaved caspase 3, and with a concomitant cleavage of gasdermin E (GSDME) rather than GSDMD. GSDME knockdown switched the apoptin-induced cell death from pyroptosis to apoptosis in vitro. Furthermore, we demonstrated that the effect of apoptin on GSDME-dependent pyroptosis could be mitigated by caspase-3 and caspase-9 siRNA knockdown. Additionally, apoptin enhanced the intracellular reactive oxygen species (ROS), causing aggregation of the mitochondrial membrane protein Tom20. Moreover, bax and cytochrome c were released to the activating caspase-9, eventually triggering pyroptosis. Therefore, GSDME mediates the apoptin-induced pyroptosis through the mitochondrial apoptotic pathway. Finally, using nude mice xenografted with HCT116 cells, we found that apoptin induces pyroptosis and significantly inhibits tumor growth. Based on this mechanism, apoptin may provide a new strategy for colorectal cancer therapy.

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“…For example, a recent study indicated that the infection induced by avian smallpox virus (without the ability of proliferation, functioning as a vector for the apoptin gene) resulted in significant apoptosis induction in hepatoma cells, suggesting the inhabitation of subcutaneously implanted tumor cells in mice. 30 While the apoptin protein can function with specificity in the apoptosis induction of the transformed (cancerous) cells, the healthy cells are not affected by this process. 1 The specificity of apoptin depends on where it is found inside the cell; therefore, its specificity to the cancer cell is increased compared to other healthy cells, due to the transmission of this molecule from the outside of the cell to the nucleus during the process of attachment to the cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Antiproliferative Effects of Recombinant Apoptin on Lung and Breast Cancer Cell Lines

et al. 2020

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Background: Selective therapy has always been the main challenge in cancer treatments. Various non-replicative oncolytic viral systems have revealed the safety and efficacy of using viruses and these products. The aim of this paper is to examine the impact of recombinant apoptin on the proliferation of lung cancer and breast cancer cell lines. Methods: The present study consisted of two steps of expression of recombinant apoptin and its anti-proliferative effects on normal and cancer cells. In the first step, following bioinformatics and optimizing apoptin gene sequencing and synthesis, it was expressed using vector PET28a and E. coli BL21 (DE3). The expressed recombinant apoptin was confirmed by analytical SDSPAGE and then purified using Ni affinity chromatography. In the second step, the antiproliferative effects of recombinant apoptin on lung cancer, breast cancer and primary cell lines were determined using MTT assay. Results: According to the results of SDS-PAGE gel assay, recombinant apoptin was visible in the 14 kDa band. Also, the MTT assay results indicated that the antiproliferative effects of recombinant apoptin in cancer cell lines was different compared with the primary cell line, and followed a dose-dependent manner in both cell lines. The highest cytotoxicity (lowest cell viability) groups were 0.2 mg/mL in lung cancer (0.32 ± 0.015) (P<0.001), and in breast cancer (0.33 ± 0.031) (P<0.001) and 0.032 mg/mL in primary cells (0.17 ± 0.004) (P<0.01), as compared to the control groups. Conclusion: Our results confirmed that recombinant apoptin can induce antiproliferative effects in lung cancer and breast cancer cell lines, but not in normal monkey kidney cell line Vero; thus, it can be introduced as a promising novel specific antitumor agent after further evaluation in clinical trials.

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Apoptin as a Tumor-Specific Therapeutic Agent: Current Perspective on Mechanism of Action and Delivery Systems

Cited by 30 publications

References 173 publications

Origin, Evolution and Stability of Overlapping Genes in Viruses: A Systematic Review

Origin, Evolution and Stability of Overlapping Genes in Viruses: A Systematic Review

Apoptin induces pyroptosis of colorectal cancer cells via the GSDME-dependent pathway

Antiproliferative Effects of Recombinant Apoptin on Lung and Breast Cancer Cell Lines

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