Recombinant Human Ad-p53

Multiple myeloma (MM) is a B-cell malignancy characterized by abnormal proliferation of clonal plasma cells in the bone marrow, the incidence of which has further increased in recent years. In multiple myeloma, wild-type functional p53 is often inactivated or dysregulated. Therefore, this study aimed to investigate the role of p53 knockdown or overexpression in multiple myeloma and the therapeutic effect of recombinant adenovirus-p53 (rAd-p53) in combination with Bortezomib.

SiRNA p53 and rAd-p53 were used to knock down and overexpress p53. RT-qPCR was used to detect gene expression, and western blotting (WB) was used to detect protein expression levels. We also constructed wild-type multiple myeloma cell line-MM1S cell xenograft tumor models and explored the effects of siRNA-p53, rAd-p53, and Bortezomib on multiple myeloma in vivo and in vitro. H&E staining and KI67 immunohistochemical staining were used to assess the anti-myeloma effects of recombinant adenovirus and Bortezomib in vivo.

The designed siRNA p53 effectively led to the knockdown of the p53 gene, while rAd-p53 could significantly achieve p53 overexpression. p53 gene inhibited MM1S cell proliferation and promoted apoptosis of wild-type multiple myeloma cell line MM1S. P53 gene inhibited tumor proliferation in vitro by promoting p21 expression and reducing cell cycle protein B1 expression of MM1S. P53 gene overexpression could inhibit tumor growth in vivo. Injection of rAd-p53 in tumor models inhibited tumor development through p21- and cyclin B1-mediated cell proliferation and apoptosis regulation.

We found that overexpression of p53 inhibits MM tumor cell survival and proliferation in vivo and in vitro. Furthermore, the combination of rAd-p53 and Bortezomib significantly improved the efficacy, which provides a new possibility for more effective treatment of MM.

Viral vectors have proven useful in a broad spectrum of gene therapy applications due to their possibility to accommodate foreign genetic material for both local and systemic delivery. The wide range of viral vectors has enabled gene therapy applications for both acute and chronic diseases. Cancer gene therapy has been addressed by delivery of viral vectors expressing anti-tumor, toxic, and suicide genes for destruction of tumors. Delivery if immunostimulatory genes such as cytokines and chemokines has also been applied for cancer therapy. Moreover, oncolytic viruses specifically replicating in and killing tumor cells have been used as such for tumor eradication or in combination with tumor killing or immunostimulatory genes. In a broad meaning, vaccines against infectious diseases and various cancers can be considered as gene therapy, which has been highly successful not the least for development of effective COVID-19 vaccines. Viral vector-based gene therapy has also demonstrated encouraging and promising results for chronic diseases such as severe combined immunodeficiency (SCID), muscular dystrophy, and hemophilia. Preclinical gene therapy studies in animal models have demonstrated proof-of-concept for a wide range of disease indications. Clinical evaluation of drugs and vaccines in humans has showed high safety levels, good tolerance, and therapeutic efficacy. Several gene therapy drugs such as the adenovirus-based drug Gendicine® for non-small-cell lung cancer, the reovirus-based drug Reolysin® for ovarian cancer, lentivirus-based treatment of SCID-X1 disease, and the rhabdovirus-based vaccine Ervebo against Ebola virus disease, and adenovirus-based vaccines against COVID-19 have been developed.