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

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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[7.3.1.02,7]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.
Funding Information
  • Ministry of Science and Technology (MOST 111-2320-B-037-015-MY3, MOST 110-2314-B-037-074-MY3, KMUH111-1R68, KMU-DK(A)113003, KMU-TC112A04)
  • Kaohsiung Medical University Chung-Ho Memorial Hospital (MOST 111-2320-B-037-015-MY3, MOST 110-2314-B-037-074-MY3, KMUH111-1R68, KMU-DK(A)113003, KMU-TC112A04)
  • Kaohsiung Medical University (MOST 111-2320-B-037-015-MY3, MOST 110-2314-B-037-074-MY3, KMUH111-1R68, KMU-DK(A)113003, KMU-TC112A04)
  • Kaohsiung Medical University Research Center (MOST 111-2320-B-037-015-MY3, MOST 110-2314-B-037-074-MY3, KMUH111-1R68, KMU-DK(A)113003, KMU-TC112A04)

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