Combined Treatment of Sulfonyl Chromen-4-Ones (CHW09) and Ultraviolet-C (UVC) Enhances Proliferation Inhibition, Apoptosis, Oxidative Stress, and DNA Damage against Oral Cancer Cells.

Sheng-Chieh Wang,Hsueh-Wei Chang,Yen-Yun Wang,Meng-Yang Chang,Li-Ching Lin,Shyng-Shiou F Yuan,Jen-Yang Tang

doi:10.3390/ijms21176443

Abstract

The sensitizing effect of chromone-derived compounds on UVC-induced proliferation inhibition has not been comprehensively investigated so far. The subject of this study was to examine the proliferation change of oral cancer cells while using the combined treatment of UVC (254 nm) with our previously developed sulfonyl chromen-4-ones (CHW09), namely UVC/CHW09. Cell viability, apoptosis, oxidative stress, and DNA damage for the individual and combined treatments for UVC and/or CHW09 were examined in oral cancer Ca9-22 cells. In 24 h MTS assay, UVC (30 J/m2; UVC30), or CHW09 (25 and 50 µg/mL; namely, CHW09-25 and CHW09-50) show 54%, 59%, and 45% viability. The combined treatment (UVC30/CHW09-25 and UVC30/CHW09-50) show lower cell viability (45% and 35%). Mechanistically, UVC/CHW09 induced higher apoptosis than individual treatments and untreated control, which were supported by the evidence of flow cytometry for subG1, annexin V/7-aminoactinomycin D, pancaspase and caspases 3/7 activity, and western blotting for cleaved poly(ADP-ribose) polymerase. Moreover, this cleaved PARP expression was downregulated by pancaspase inhibitor Z-VAD-FMK. UVC/CHW09 showed higher oxidative stress than individual treatments and untreated control in terms of flow cytometry for reactive oxygen species, mitochondrial membrane potential, and mitochondrial mass. Furthermore, UVC/CHW09 showed higher DNA damage than individual treatments and untreated control in terms of flow cytometry for H2A histone family member X and 8-oxo-2’-deoxyguanosine. In conclusion, combined treatment UVC/CHW09 suppresses proliferation, and promotes apoptosis, oxidative stress, and DNA damage against oral cancer cells, providing a novel application of sulfonyl chromen-4-ones in order to sensitize UVC induced proliferation inhibition for oral cancer therapy.

Highlights

Radiotherapy is commonly combined with anticancer drugs to enhance radiosensitivity [1,2] and it has become the standard care for several types of cancer treatment
Ultraviolet C (UVC)/CHW09 treatments (UVC30/CHW09-25 and UVC30/CHW09-50) show slightly higher ROS levels than UVC alone (Figure 5B), it shows a dramatically higher induction of Membrane Potential (MMP) depletion than individual treatments (Figure 6B). These results suggest that UVC/CHW09 treatments may cooperatively enhance oxidative stress in oral cancer cells
UVC/CHW09 treatment (UVC30/CHW09-50) shows slightly higher γH2AX level than individual treatments (Figure 8B), it shows moderate induction for 8-oxodG generation (Figure 9B). These results suggest that UVC/CHW09 treatments may cooperatively enhance more oxidative DNA damage (8-oxodG) than γH2AX DNA damage in oral cancer cells

Summary

Introduction

Radiotherapy is commonly combined with anticancer drugs to enhance radiosensitivity [1,2] and it has become the standard care for several types of cancer treatment. Both radiation and anticancer drugs may have side effects. Cytotoxicity to normal cells partly contributes to this side effect. Chemical agents with low cytotoxic effects on normal cells are developed as potential radiosensitizers for cancer therapy. Some drugs can modulate UVC induced proliferation inhibition by its prevention or enhancement, as reported in X-ray studies. Combined treatment of metformin and resveratrol prevents UVC-induced proliferation inhibition in lung cancer A549 cells [4]. The combined treatments of cisplatin/UVC [5] and methanolic extracts of Cryptocarya concinna/UVC [6], respectively, suppresses the proliferation of colorectal and oral cancer cells

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