Therapeutic potential of antiviral drugs targeting chemorefractory colorectal adenocarcinoma cells overexpressing endogenous retroviral elements

Abstract

BackgroundEndoretroviruses account for circa 8 % of all transposable elements found in the genome of humans and other animals. They represent a genetic footprint of ancestral germ-cell infections of exoviruses that is transmittable to the progeny by Mendelian segregation. Traces of human endogenous retroviruses are physiologically expressed in ovarial, testicular and placental tissues as well as in stem cells. In addition, a number of these fossil viral elements have also been related to carcinogenesis. However, a relation between endoretroviruses expression and chemoresistance has not been reported yet.MethodsTwenty colorectal carcinoma patient samples were scrutinized for HERV-WE1 and HERV-FRD1 endoretroviruses using immunohistochemical approaches. In order to search for differential expression of these elements in chemotherapy refractory cells, a resistant HCT8 colon carcinoma subline was developed by serial etoposide exposure. Endoretroviral elements were detected by immunocytochemical staining, qPCR and ELISA. IC50-values of antiviral and cytostatic drugs in HCT8 cells were determined by MTT proliferation assay. The antivirals-cytostatics interaction was evaluated by the isobologram method.ResultsIn this work, we show for the first time that HERV-WE1, HERV-FRD1, HERV-31, and HERV-V1 are a) simultaneously expressed in treatment-naïve colon carcinoma cells and b) upregulated after cytostatic exposure, suggesting that these retroviral elements are intimately related to chemotherapy resistance. We found a number of antiviral drugs to have cytotoxic activity and the ability to force the downregulation of HERV proteins in vitro. We also demonstrate that the use of different antiviral compounds alone or in combination with anticancer agents results in a synergistic antiproliferative effect and downregulation of different endoretroviral elements in highly chemotherapy-resistant colorectal tumor cells.ConclusionsEnhanced HERV-expression is associated with chemoresistance in colon carcinomas which can be overcome by antiviral drugs alone or in combination with anticancer drugs. Therefore, the introduction of antiviral compounds to the current chemotherapy regimens potentially improves patient outcomes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0199-5) contains supplementary material, which is available to authorized users.

Drug repurposing in oncology: Compounds, pathways, phenotypes and computational approaches for colorectal cancer

“…Diaz-Carballo et al . tested the antiviral drugs, amantadine and pleconaril, which target HERV components expressed in chemotherapy-naïve and chemoresistant CRC cell lines [ 63 ]. The mechanism of action of both medications is still poorly understood.…”

Type W Human Endogenous Retrovirus (HERV-W) Integrations and Their Mobilization by L1 Machinery: Contribution to the Human Transcriptome and Impact on the Host Physiopathology

“…Both treatments are known to influence HERV transcription with no specificity for tumor environment [ 78 ]. Similarly, Díaz-Caballo et al reported a HERV-W hyperexpression in HCT8 colon carcinoma cells, and proposed a correlation with the induction of a chemotherapy-refractory state [ 77 ]. Such increased transcription, however, is possibly the consequence of the experimental induction of a cytostatic stress.…”

Do the Human Endogenous Retroviruses Play a Role in Colon Cancer?

“…This scenario can provide the rationale for inclusion of HERV-H Xp22.3 into clinical vaccination protocols. A study conducted by Díaz-Carballo et al 119 demonstrated that the expression of various HERVs proteins was not only detectable in colon cancer cells but might also have therapeutic implications for the patients, especially in chemorefractory tumors. In particular, several retroviral transcripts resulted overexpressed in HCT8 colon cancer cell line up to three times in chemotherapy refractory HCT8 cells, suggesting a relationship to chemoresistance.…”

“…This evidence proposed the HERVs' overexpression as a tool for monitoring the therapy resistance. 119 Bronte et al 120 reported that the inoculation of a DNA plasmid encoding mouse gp70 or p15E (two products of the env gene of an endogenous murine leukemia virus) elicited the T-lymphocyte response and resulted in partial protection of the mouse tumors possessing these antigens. Furthermore, systemic administration of agonistic anti-CD40 monoclonal antibodies increased the therapeutic potential of the DNA vaccine uniquely when administrated during the tumor rejection phase.…”