In Silico Evaluation of Two Targeted Chimeric Proteins Based on Bacterial Toxins for Breast Cancer Therapy Publisher



Goleij Z¹ ; Hosseini HM¹ ; Amin M² ; Amani J¹ ; Behzadi E³ ; Fooladi AAI¹ Show Affiliations
Source: International Journal of Cancer Management Published:2019

Abstract

Background: Despite major advances in cancer research, breast cancer still remains the most common cancer in women. Breast cancer is a heterogeneous disease, including at least 5 subtypes. Overexpression of human epidermal growth factor receptor 2 (HER2) in the patients denotes poor prognosis leading to a reduced survival rate compared to other subtypes of breast cancer. Therefore, HER2 can be a potential therapeutic target. To enhance the potency of HER2 blockers, the conjugation of specific cytotoxic agents with these types of anticancer agents may be successful. Application of antibody-based agents are important emerging anticancer therapies. One novel approach to increase the potency of monoclonal antibodies (mAbs) is combining them with toxic molecules. Objectives: Pseudomonas exotoxin A (PE), ricin toxin (RT), and others in very minor quantities can be more potent and biologically active for this purpose. Methods: In this study, we used trastuzumab as a ligand for HER2 receptor along with Pseudomonas exotoxin A (PE38) and A subunit of Shiga toxin 2a (Stx2a). This fusion protein selectively bound to the HER2 receptor. Upon uptake by the target cells, apoptosis and cell eradication was observed. An in silico method was used before the in vitro study to illustrate the properties and construction of the protein. Physicochemical properties, structure, stability, and ligand-receptor interaction of this chimeric protein were predicted by means of computational and bioinformatics tools and servers. Results: The results of this study showed that codon adaptation index of s1 and p2 fusion gene has improved to 0.98 and .99, respectively. The mfold result has revealed that s1 and p2 mRNA were stable sufficient for efficient translation in the new host. Based on Ramachandran plot, s1 and p2 were categorized as constant fusion protein. Conclusions: Finally, based on docking software analysis, the binding ability of Herceptin was robust enough to its receptor, so these constructs could be assigned as a new antitumor candidate in cancer therapy. The results suggested that s1 and p2 were stable fusion proteins with accurate affinity to the overexpressed receptors making them potential candidates for inducing apoptosis in breast cancer cells. © 2019, Author(s).