Hyewon Jeong1, Junseong Park1, Jin-Kyoung Shim1, Jae Eun Lee1, Nam Hee Kim2, Hyun Sil Kim2, Jong Hee Chang1, Jong In Yook2, Seok-Gu Kang3. 1. Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei- ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. 2. Department of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, 03722, Republic of Korea. 3. Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei- ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. seokgu9@gmail.com.
Abstract
INTRODUCTION: Glioblastoma (GBM) is the most common and aggressive human primary brain malignancy. The key properties of GBM, stemness and invasiveness, are known to be associated with a highly unfavorable prognosis. Notably, the process of epithelial-mesenchymal transition (EMT) is closely related to the progression of GBM. On the basis of reports that 2'-hydroxycinnamaldehyde (HCA) and its derivative, 2'-benzoyloxycinnamaldehyde (BCA), suppresses EMT in several human cancer cells, we sought to evaluate the therapeutic efficacy of HCA and BCA, alone and in combination with temozolomide (TMZ), on GBM tumorspheres (TSs). METHODS: Two human GBM TSs were treated with HCA, BCA, or TMZ. Therapeutic effects were evaluated by measuring ATP levels, neurosphere formation, 3D-invasion in collagen matrix, and viability. Protein expression profiles after drug treatment were evaluated by western blotting. In vivo anticancer efficacy of drugs was examined in a mouse orthotopic xenograft model. RESULTS: Combined treatment of GBM TSs with HCA or BCA and TMZ significantly reduced cell viability, stemness, and invasiveness. Expression levels of stemness-, invasiveness-, and mesenchymal transition-associated markers, Zeb1, N-cadherin, and β-catenin, were also substantially decreased by the combined treatment. The combined treatment also reduced tumor growth in a mouse orthotopic xenograft model. CONCLUSION: Our findings suggest that HCA and BCA, combined with TMZ, are potential therapeutic agents in the treatment of GBM.
INTRODUCTION:Glioblastoma (GBM) is the most common and aggressive human primary brain malignancy. The key properties of GBM, stemness and invasiveness, are known to be associated with a highly unfavorable prognosis. Notably, the process of epithelial-mesenchymal transition (EMT) is closely related to the progression of GBM. On the basis of reports that 2'-hydroxycinnamaldehyde (HCA) and its derivative, 2'-benzoyloxycinnamaldehyde (BCA), suppresses EMT in several humancancer cells, we sought to evaluate the therapeutic efficacy of HCA and BCA, alone and in combination with temozolomide (TMZ), on GBM tumorspheres (TSs). METHODS: Two human GBM TSs were treated with HCA, BCA, or TMZ. Therapeutic effects were evaluated by measuring ATP levels, neurosphere formation, 3D-invasion in collagen matrix, and viability. Protein expression profiles after drug treatment were evaluated by western blotting. In vivo anticancer efficacy of drugs was examined in a mouse orthotopic xenograft model. RESULTS: Combined treatment of GBM TSs with HCA or BCA and TMZ significantly reduced cell viability, stemness, and invasiveness. Expression levels of stemness-, invasiveness-, and mesenchymal transition-associated markers, Zeb1, N-cadherin, and β-catenin, were also substantially decreased by the combined treatment. The combined treatment also reduced tumor growth in a mouse orthotopic xenograft model. CONCLUSION: Our findings suggest that HCA and BCA, combined with TMZ, are potential therapeutic agents in the treatment of GBM.