Naturally occurring, tumor-specific, therapeutic proteins

Abstract

The emerging approach to cancer treatment known as targeted therapies offers hope in improving the treatment of therapy-resistant cancers. Recent understanding of the molecular pathogenesis of cancer has led to the development of targeted novel drugs such as monoclonal antibodies, small molecule inhibitors, mimetics, antisense and small interference RNA-based strategies, among others. These compounds act on specific targets that are believed to contribute to the development and progression of cancers and resistance of tumors to conventional therapies. Delivered individually or combined with chemo- and/or radiotherapy, such novel drugs have produced significant responses in certain types of cancer. Among the most successful novel compounds are those which target tyrosine kinases (imatinib, trastuzumab, sinutinib, cetuximab). However, these compounds can cause severe side-effects as they inhibit pathways such as epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor, which are also important for normal functions in non-transformed cells. Recently, a number of proteins have been identified which show a remarkable tumor-specific cytotoxic activity. This toxicity is independent of tumor type or specific genetic changes such as p53, pRB or EGFR aberrations. These tumor-specific killer proteins are either derived from common human and animal viruses such as E1A, E4ORF4 and VP3 (apoptin) or of cellular origin, such as TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) and MDA-7 (melanoma differentiation associated-7). This review aims to present a current overview of a selection of these proteins with preferential toxicity among cancer cells and will provide an insight into the possible mechanism of action, tumor specificity and their potential as novel tumor-specific cancer therapeutics.

Human Gyrovirus Apoptin shows a similar subcellular distribution pattern and apoptosis induction as the chicken anaemia virus derived VP3/Apoptin

“…20 A number of viral and cellular proteins have been described that show tumour-specific toxicity, including Apoptin, Trail, mda-7 (etc). 21 The therapeutic potential of such proteins and their cellular targets is of immense interest. Recently, a HGyV has been identified encoding a viral protein resembling the CAV-derived Apoptin.…”

Antitumor effect of human TRAIL on adenoid cystic carcinoma using magnetic nanoparticle–mediated gene expression

“…[6][7][8][9][10] Although the mechanism for this cancer-specific action of TRAIL is poorly understood, it is recognized that TRAIL has the potential to become a promising antitumor therapy reagent and may provide a novel approach for cancer treatment. 11,12 The human telomerase reverse transcriptase (hTERT) is highly active in 85-90% of human cancer, whereas its activity is lower or undetectable in most human normal somatic cells. 13,14 Because the hTERT promoter was considered as a tumor-specific promoter, many studies have used the hTERT promoter to drive antitumor gene expression selectively in cancer cells, with little or no effect on normal cells, so as to restrict or limit unwanted side effects.…”

Nonviral gene therapy in vivo with PAM-RG4/apoptin as a potential brain tumor therapeutic

“…[26][27][28][29][30] Therefore, we expected a difference in the EGFR-staining intensity between the PAM-RG4/pJDK-apoptin-treated group and the control groups, because if apoptin was actually active, less glioma cells had to be present in the therapeutic group leading to weaker EGFR-staining intensity compared to the control groups. Indeed, strong EGFR-staining intensity can be easily observed in the control groups B and D, but not in the therapeutic group, F. Since there are no correlations between apoptin and EGFR expression levels, 31 this can be inferred as a result of a decrease in the number of glioma cells, due to the apoptotic effect of apoptin. Although a small lump was observed in the PAM-RG4/pJDK-apoptin-treated group ( Figure 3A), no signs of tumor could be observed according to the H&E staining results (E), where the two outer dermal layers were tightly bound to each other and converged well, and the EGFR staining results (F), where strong binding of the EGFR antibody was absent.…”