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Publications

Journal Article Ppublish

PubMed: 42187533 DOI: 10.1002/ddr.70327

Santamarine Synergizes With Cisplatin via ROS/JNK Axis to Selectively Induce Apoptosis and DNA Damage in Oral Cancer Cells In Vitro.

Drug Dev Res 87(4):e70327

Authors: Hsin-I Lu, Kuan-Liang Chen, Chung-Yi Chen, Ching-Yu Yen, Ammad Ahmad Farooqi, Tsu-Ming Chien, Jiiang-Huei Jeng, Bing-Hung Chen, Hsueh-Wei Chang

Affiliations

  • Department of Biomedical Science and Environmental Biology, PhD Program in Life Sciences, College of Life Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • Department of Dentistry, Chi-Mei Medical Center, Tainan, Taiwan.
  • Department of Healthy Beauty, School of Medical and Health Sciences, Fooyin University, Kaohsiung, Taiwan.
  • School of Dentistry, Taipei Medical University, Taipei, Taiwan.
  • Department of Molecular Oncology, Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan.
  • School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • Department of Urology, Kaohsiung Gangshan Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • Department of Dentistry, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
  • Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan.
  • Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.

Abstract

Santamarine (SAMA), a Michelia compressa-derived sesquiterpene lactone, exhibits ROS‑mediated anticancer activity; however, its potential mechanisms and synergy with cisplatin in oral cancer have not been explored. This study investigated SAMA and cisplatin's combined effects and underlying ROS/MAPK mechanisms of action on oral cancer cells. The combination significantly reduced viability (ATP assay) in oral cancer Ca9‑22 and CAL 27 cells compared with either agent alone, with synergistic indices confirming enhanced antiproliferation. Moreover, this combination markedly suppressed colony formation and cell migration. SAMA/cisplatin induced subG1 accumulation and G2/M arrest, elevated cellular and mitochondrial ROS, and promoted apoptosis, as evidenced by increased annexin V positivity and caspase‑3, -8, and -9 activation, while DNA damage markers γH2AX and 8‑OHdG were also markedly elevated. In contrast, normal oral S‑G cells showed minimal cytotoxic damage and mechanical changes, suggesting selectivity. Mechanistically, JNK inhibition rescued the antiproliferative response and suppressed apoptosis, caspase activation, and DNA damage. Pretreatment with the ROS scavenger NAC attenuated all test effects, confirming ROS dependence. Together, these findings demonstrate that SAMA synergizes with cisplatin to selectively enhance oxidative stress, apoptosis, and DNA damage in oral cancer cells via ROS‑dependent JNK signaling, highlighting its potential as a cisplatin adjunct.

MeSH

Cells, Pharmaceutical Preparations, Neoplasms, Oxidative Stress, Caspases, Apoptosis, Mouth Neoplasms, Dna, Dna Damage