4-Methylumbelliferone administration enhances radiosensitivity of human fibrosarcoma by intercellular communication

Abstract

Hyaluronan synthesis inhibitor 4-methylumbelliferone (4-MU) is a candidate of radiosensitizers which enables both anti-tumour and anti-metastasis effects in X-ray therapy. The curative effects under such 4-MU administration have been investigated in vitro; however, the radiosensitizing mechanisms remain unclear. Here, we investigated the radiosensitizing effects under 4-MU treatment from cell experiments and model estimations. We generated experimental surviving fractions of human fibrosarcoma cells (HT1080) after 4-MU treatment combined with X-ray irradiation. Meanwhilst, we also modelled the pharmacological effects of 4-MU treatment and theoretically analyzed the synergetic effects between 4-MU treatment and X-ray irradiation. The results show that the enhancement of cell killing by 4-MU treatment is the greatest in the intermediate dose range of around 4 Gy, which can be reproduced by considering intercellular communication (so called non-targeted effects) through the model analysis. As supposed to be the involvement of intercellular communication in radiosensitization, the oxidative stress level associated with reactive oxygen species (ROS), which leads to DNA damage induction, is significantly higher by the combination of 4-MU treatment and irradiation than only by X-ray irradiation, and the radiosensitization by 4-MU can be suppressed by the ROS inhibitors. These findings suggest that the synergetic effects between 4-MU treatment and irradiation are predominantly attributed to intercellular communication and provide more efficient tumour control than conventional X-ray therapy.

4-Methylumebelliferone Enhances Radiosensitizing Effects of Radioresistant Oral Squamous Cell Carcinoma Cells via Hyaluronan Synthase 3 Suppression

“…DCFDA staining and 4-MU administration were simultaneously performed 30 min before irradiation. The increment of the ROS level at 0 h was similar to that observed in our previous report [ 21 ]. The gating strategy was similar to that of the CD44 and CD24 analyses; after removal of the doublets and debris gated on the target population based on FSC and SSC dot plots, this gating was reflected in the histogram of each treatment group, and the MFI of DCFDA was evaluated.…”

“…In recent decades, 4-MU has been shown to exert anti-tumor and anti-invasive/-metastatic effects through suppressing HA synthase (HAS) expression in various cancer cells and mouse models [ 17 , 18 ]. Furthermore, our previous studies have indicated that 4-MU treatment with X-ray irradiation promotes anti-inflammatory effects by suppressing interleukin (IL) −6 and −1β and inhibiting intercellular communication involved in anti-oxidant activities [ 19 , 20 , 21 ]. Elevated expressions of IL-6 and nuclear factor-kappa B (NF-κB), a master regulator of the inflammatory response, have been suggested to enhance resistance to apoptosis and superoxide dismutase (SOD) in cancer cells and induce radioresistance [ 22 , 23 , 24 , 25 ].…”

Anti-Inflammatory and Mineralization Effects of an ASP/PLGA-ASP/ACP/PLLA-PLGA Composite Membrane as a Dental Pulp Capping Agent

“…When studying the effect of anti-inflammatory drugs on cells in an inflammatory state, in vitro inflammatory models are usually used. LPS is often used to establish an inflammatory microenvironment in vitro [ 48 , 49 , 50 ]. According to previous studies, treating human dental pulp cells (HDPCs) with LPS with a concentration of 1 µg/mL is the appropriate method to simulate an inflammatory microenvironment in vitro [ 51 ].…”

Targeting the Tumor Extracellular Matrix by the Natural Molecule 4-Methylumbelliferone: A Complementary and Alternative Cancer Therapeutic Strategy

“…Specifically, they revealed that 4-MU increased the sensitivity of fibrosarcoma cells to X-ray radiation by inhibiting the production of the pro-inflammatory cytokines IL-1b, IL-6 (87), IL-1a, IL-36g and IL-37 (56). Recently, the authors demonstrated that the radio-sensitizing effects of 4-MU are intrinsically related to the suppression of antioxidant activity through previously discovered anti-inflammatory effects (57).…”

“…Regarding fibrosarcoma, another of the most common bonederived tumors, some reports have also shown a positive effect of 4-MU treatment on the sensitivity of cells to radiotherapy (56,57,86,87). In primary solid tumors, external radiotherapy is generally effective and non-invasive and improves local control in the target region.…”