6- n-Butoxy-10-nitro-12,13-dioxa-11-azatricyclo[7.3.1.02,7]trideca-2,4,6,10-tetraene Improves the X-ray Sensitivity on Inhibiting Proliferation and Promoting Oxidative Stress and Apoptosis of Oral Cancer Cells

Kun-Han Yang; Ching-Yu Yen; Sheng-Chieh Wang; Fang-Rong Chang; Meng-Yang Chang; Chieh-Kai Chan; Jiiang-Huei Jeng; Jen-Yang Tang; Hsueh-Wei Chang

doi:10.3390/biomedicines12020458

6- n-Butoxy-10-nitro-12,13-dioxa-11-azatricyclo[7.3.1.0^2,7]trideca-2,4,6,10-tetraene Improves the X-ray Sensitivity on Inhibiting Proliferation and Promoting Oxidative Stress and Apoptosis of Oral Cancer Cells

Biomedicines. 2024 Feb 19;12(2):458. doi: 10.3390/biomedicines12020458.

Authors

Kun-Han Yang¹, Ching-Yu Yen^{2

3}, Sheng-Chieh Wang⁴, Fang-Rong Chang¹, Meng-Yang Chang⁵, Chieh-Kai Chan⁶, Jiiang-Huei Jeng^{7

8

9}, Jen-Yang Tang^{10

11}, Hsueh-Wei Chang^{1

4

12

13}

Affiliations

¹ Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
² School of Dentistry, Taipei Medical University, Taipei 11031, Taiwan.
³ Department of Oral and Maxillofacial Surgery, Chi-Mei Medical Center, Tainan 71004, Taiwan.
⁴ Department of Biomedical Science and Environmental Biology, PhD Program in Life Sciences, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁵ Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁶ Department of Chemistry, University of Illinois Urbana, Champaign, IL 61820, USA.
⁷ School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
⁸ Department of Dentistry, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
⁹ Department of Dentistry, National Taiwan University Hospital, Taipei 100225, Taiwan.
¹⁰ School of Post-Baccalaureate Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
¹¹ Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
¹² Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
¹³ Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.

Abstract

This in vitro study examines the anti-oral cancer effects and mechanisms of a combined X-ray/SK2 treatment, i.e., X-ray and 6-n-butoxy-10-nitro-12,13-dioxa-11-azatricyclo[7.3.1.0^2,7]trideca-2,4,6,10-tetraene (SK2). ATP cell viability and flow cytometry-based cell cycle, apoptosis, oxidative stress, and DNA damage assessments were conducted. The X-ray/SK2 treatment exhibited lower viability in oral cancer (Ca9-22 and CAL 27) cells than in normal (Smulow-Glickman, S-G) cells, i.e., 32.0%, 46.1% vs. 59.0%, which showed more antiproliferative changes than with X-ray or SK2 treatment. Oral cancer cells under X-ray/SK2 treatment showed slight subG1 and G2/M increments and induced high annexin V-monitored apoptosis compared to X-ray or SK2 treatment. The X-ray/SK2 treatment showed higher caspase 3 and 8 levels for oral cancer cells than other treatments. X-ray/SK2 showed a higher caspase 9 level in CAL 27 cells than other treatments, while Ca9-22 cells showed similar levels under X-ray and/or SK2. The X-ray/SK2 treatment showed higher reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) depletion than other treatments. Meanwhile, the mitochondrial superoxide (MitoSOX) and glutathione levels in X-ray/SK2 treatment did not exhibit the highest rank compared to others. Moreover, oral cancer cells had higher γH2AX and/or 8-hydroxy-2-deoxyguanosine levels from X-ray/SK2 treatment than others. All these measurements for X-ray/SK2 in oral cancer cells were higher than in normal cells and attenuated by N-acetylcysteine. In conclusion, X-ray/SK2 treatment showed ROS-dependent enhanced antiproliferative, apoptotic, and DNA damage effects in oral cancer cells with a lower cytotoxic influence on normal cells.

Keywords: dioxabicyclo[3.3.1]nonane; oral cancer; oxidative stress; radiosensitization.

Abstract

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