Shao-Cheng Liu1, Chih-Ming Huang2, Oluwaseun Adebayo Bamodu3, Chun-Shu Lin4, Bing-Lan Liu5, Yew-Min Tzeng6, Jo-Ting Tsai7, Wei-Hwa Lee8, Tsung-Ming Chen9. 1. Department of Otolaryngology - Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical Center, Taiwan. 2. Department of Otolaryngology, Taitung Mackay Memorial Hospital, Taiwan. 3. Department of Hematology and Oncology, Cancer Center, Taipei Medical University - Shuang Ho Hospital, New Taipei City, Taiwan; Department of Medical Research & Education, Taipei Medical University - Shuang Ho Hospital, New Taipei City, Taiwan. 4. Department of Radiation Oncology, Tri-Service General Hospital, National Defence Medical Centre, Taipei, Taiwan. 5. Department of Appiled Chemistry, Chaoyang University of Technology, Taichung, Taiwan. 6. Department of Appiled Chemistry, Chaoyang University of Technology, Taichung, Taiwan; Center for General Education, National Taitung University, Taitung, Taiwan. 7. Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taiwan; Department of Radiation Oncology, Taipei Medical University - Shuang Ho Hospital, New Taipei City, Taiwan. 8. Department of Pathology, Taipei Medical University - Shuang Ho Hospital, Taipei, Taiwan. Electronic address: whlpath97616@s.tmu.edu.tw. 9. Department of Otolaryngology - Head and Neck Surgery, Shuang Ho Hospital, Taipei Medical University, Taiwan; Department of Otolaryngology, School of Medicine, College of Medicine, Taipei Medical University, Taiwan. Electronic address: 09326@s.tmu.edu.tw.
Abstract
BACKGROUND: Treatment for metastatic nasopharyngeal carcinoma (NPC) is challenging. Till now, a truly effective chemotherapy regimen for NPC has not yet been identified. These clinical observations prompted us to investigate a potential drug as alternative option for treating. PURPOSE: This study evaluated the inhibitory effects of Ovatodiolide (Ova), on tumorigenic and cancer stem cell characteristics of NPC cells. METHODS: Two NPC cell lines (NPC-BM1 and NPC-BM2) were used to examine the anticancer effects of Ova and the molecular mechanism underlying these activities by using sulforhodamine B cytotoxicity assay, western blot, immunofluorescence, migration, colony and tumorsphere formation assays. RESULTS: Ova significantly inhibited the viability of BM1 and BM2 cells, downregulated Bcl-xL and Puma, and upregulated Bax/Bad expression levels. Ova dose-dependent suppressed migratory/invasive potential of NPC cells, and reduced ability to form colonies. Ova-induced apoptosis correlated with increased Bax/Bcl-xL ratio while NPC motility and colony formation inhibition were associated with reduced expression of p-FAK, p-PXN, F-actin, and Slug proteins and increased E-cadherin. Furthermore, ova inhibited NPC tumorsphere formation, associated with decreased SOX2, OCT4 and JAK-STAT signaling pathway. Ova also attenuated NPC stem cell tumorigenicity, inhibited tumor growth, and enhanced the sensitivity of NPC cells to cisplatin treatment, in vivo. CONCLUSIONS: Our results demonstrated the anticancer efficacy of Ova in NPC and its potential as a putative inhibitor of JAK2 and STAT3, which are essential in tumorigenesis of NPC. Further development of Ova is encouraged.
BACKGROUND: Treatment for metastatic nasopharyngeal carcinoma (NPC) is challenging. Till now, a truly effective chemotherapy regimen for NPC has not yet been identified. These clinical observations prompted us to investigate a potential drug as alternative option for treating. PURPOSE: This study evaluated the inhibitory effects of Ovatodiolide (Ova), on tumorigenic and cancer stem cell characteristics of NPC cells. METHODS: Two NPC cell lines (NPC-BM1 and NPC-BM2) were used to examine the anticancer effects of Ova and the molecular mechanism underlying these activities by using sulforhodamine Bcytotoxicity assay, western blot, immunofluorescence, migration, colony and tumorsphere formation assays. RESULTS:Ova significantly inhibited the viability of BM1 and BM2 cells, downregulated Bcl-xL and Puma, and upregulated Bax/Bad expression levels. Ova dose-dependent suppressed migratory/invasive potential of NPC cells, and reduced ability to form colonies. Ova-induced apoptosis correlated with increased Bax/Bcl-xL ratio while NPC motility and colony formation inhibition were associated with reduced expression of p-FAK, p-PXN, F-actin, and Slug proteins and increased E-cadherin. Furthermore, ova inhibited NPC tumorsphere formation, associated with decreased SOX2, OCT4 and JAK-STAT signaling pathway. Ova also attenuated NPC stem cell tumorigenicity, inhibited tumor growth, and enhanced the sensitivity of NPC cells to cisplatin treatment, in vivo. CONCLUSIONS: Our results demonstrated the anticancer efficacy of Ova in NPC and its potential as a putative inhibitor of JAK2 and STAT3, which are essential in tumorigenesis of NPC. Further development of Ova is encouraged.