Irinotecan (CPT-11) Canonical Anti-Cancer Drug Can also Modulate Antiviral and Pro-Inflammatory Responses of Primary Human Synovial Fibroblasts

Abstract

Alphaviruses are a group of arboviruses that generate chronic inflammatory rheumatisms in humans. Currently, no approved vaccines or antiviral therapies are available to prevent or treat alphavirus-induced diseases. The aim of this study was to evaluate the repositioning of the anti-cancer molecule irinotecan as a potential modulator of the antiviral and inflammatory responses of primary human synovial fibroblasts (HSF), the main stromal cells of the joint synovium. HSF were exposed to O’nyong-nyong virus (ONNV) and polyinosinic-polycytidylic acid (PIC) to mimic, respectively, acute and chronic infectious settings. The cytokine IL-1β was used as a major pro-inflammatory cytokine to stimulate HSF. Quantitative RT-PCR analysis revealed that irinotecan at 15 µM was able to amplify the antiviral response (i.e., interferon-stimulated gene expression) of HSF exposed to PIC and reduce the expression of pro-inflammatory genes (CXCL8, IL-6 and COX-2) upon IL-1β treatment. These results were associated with the regulation of the expression of several genes, including those encoding for STAT1, STAT2, p53 and NF-κB. Irinotecan did not modulate these responses in both untreated cells and cells stimulated with ONNV. This suggests that this drug could be therapeutically useful for the treatment of chronic and severe (rather than acute) arthritis due to viruses.

Drug-microbiota interactions: an emerging priority for precision medicine

“…Chemotherapeutic agents such as CPT-11 are commonly for treating several cancers, however, their use can be limited by the occurrence of severe diarrhea as ADRs. [239][240][241][242] This side effect can be attributed to the influence of gut microbiota, which can convert the less toxic SN-38-glucuronide (SN-38-G) metabolite back into the extremely toxic 7-ethyl-10hydroxycamptothecin (SN-38), leading to intestinal damage. 243,244 Specifically, certain strains (e.g., E. coli, Staphylococcus, and Clostridium) that express high levels of β-glucuronidase (GUSs), a microbial enzyme that eliminates SN-38-G, have been shown to exacerbate this problem.…”

In Vitro Analyses of the Multifocal Effects of Natural Alkaloids Berberine, Matrine, and Tabersonine against the O’nyong-nyong Arthritogenic Alphavirus Infection and Inflammation

“…In addition to this common antiviral strategy based on virus-targeting inhibitors (‘direct-acting antivirals’) or host-targeting inhibitors to abrogate the essential host cell functions for the virus life cycle (‘host-targeting antivirals’), immunomodulatory drugs have gained growing interest as regulators of the immune response [ 37 , 38 ]. In primary human synovial fibroblast cells (HSF) infected by ONNV, we demonstrated the antiviral and immunomodulatory activity of the anticancer drug Irinotecan (CPT-11), derived from the natural quinoline alkaloid camptothecin [ 39 ]. As we recently discussed in a literature survey of in vitro and/or in vivo robust experimental data, some common plant-derived alkaloids have dual antiviral and immunomodulatory effects on both RNA and DNA viruses, as well as on inflammatory-related diseases, including cancer and rheumatic disorders [ 40 ].…”