Antitumor Activity from the Combined Application of Poly(I:C) and Chemotherapeutics in Human Metastatic Pharyngeal Cell Lines

Abstract

Background: Toll-like receptor 3 (TLR3) activation in tumor cells induces apoptosis. We investigated the effect of TLR3 ligand (poly(I:C)) in combination with chemotherapeutics applied to human pharyngeal carcinoma cells as a possible antitumor therapy. Methods:Human pharyngeal cancer cell lines were studied (FaDu and Detroit 562). Cytotoxicity assays and apoptosis assays (annexin V staining and caspase 3/7 activity measurements) were used to investigate the cytotoxic effects. By using TLR3 siRNA we confirmed that the observed effect is TLR3-dependent. Results: We found that the combined application of poly(I:C) and chemotherapeutics (cisPt, HU, 5-FU and MTX) has a stronger inhibitory effect on cell growth in tumor cells expressing functional TLR3 as compared with a single treatment. This is a result of TLR3-dependent apoptosis. Conclusion: Our study showed that a combined application of the two agents already being used in tumor therapy could lower the necessary dosage of chemotherapeutics, leading to fewer side effects.

Radio-sensitization of head and neck cancer cells by a combination of poly(I:C) and cisplatin through downregulation of survivin and c-IAP2

“…The combined use of TLR3 activation with poly(I:C) and cisplatin in cancer has been previously investigated. We and the others have shown that poly(I:C) and cisplatin act synergistically to induce cell death [16,21,22]. The results of a very recent study confirmed our hypothesis and showed that pre-treatment with poly(I:C) increased the amount of cisplatin in the cytoplasm, and greatly increased the low-dose cisplatin-induced cell death in TLR3-and caspase-3-dependent manner [21].…”

“…Caspase 3/7 enzyme activity was determined using the Caspase-Glo 3/7 assay (Promega, Madison, USA) as previously described [16]. Briefly, SQ20B cells at a concentration of 1.5 ×10 4 cells/well were plated in a whitewalled 96-well plate in 100 μl culture medium and treated with 10 µg/ml poly(I:C) or 1µM cisplatin for 45 minutes, irradiated and caspase 3/7 activity was determined after 24 hours.…”

“…Some studies reported the pro-apoptotic effects of TLR3 agonists but these effects were generally obtained using very high concentrations of agonists which were not compatible with clinical use [14][15][16][17]. In contrast, other studies dealing with low concentrations of agonists showed evidence of their contribution to carcinogenesis and promotion of tumor growth and invasiveness [18][19][20].…”

Toll‐like receptor 3 agonist poly I:C reinforces the potency of cytotoxic chemotherapy via the TLR3‐UNC93B1‐IFN‐β signaling axis in paclitaxel‐resistant colon cancer

“…As our experimental results showed, poly I:C also elevated the expression levels of RIG-1 and MDA-5 along with IFN-β production, and this effect was stronger with impaired TLR3- With attempts to optimize practical results, combination chemotherapy regimens for neoplastic cell treatment are frequently favored over single agents. Recent studies display that poly I:C in combination with anticancer agents like cycloheximide, 5-fluorouracil, or PTX for chemo-immunotherapy appears to offer promising effects (Jiang et al, 2008;Matijević, Kirinec, & Pavelić, 2011;Park et al, 2012)…”

Stimulation of the toll-like receptor 3 promotes metabolic reprogramming in head and neck carcinoma cells

“…In a somehow paradoxical manner, many investigators have emphasized the role of TLR3 as a factor of vulnerability for malignant cells. Initially Poly(I:C) was used as an artificial ligand of TLR3 and was shown in several studies to induce apoptosis of various types of malignant cells in vitro [12, 14, 16, 17]. However, these studies have met two limitations.…”