ABSTRACT
BACKGROUND: Glioblastoma (GBM) is the most aggressive type of primary malignant brain tumour. The interaction between high-mobility group box 1 (HMGB1) and receptor for advanced glycation end-products (RAGE) is important for tumour cell growth. Previously, we identified an anticancer candidate, papaverine, that inhibited the HMGB1-RAGE interaction. MATERIALS AND METHODS: Our study assessed the anticancer effects of papaverine alone or in combination with temozolomide on U87MG and T98G human GBM cells using clonogenicity assays, as well as in a U87MG xenograft mouse model. The radiosensitizing efficacy of papaverine was measured based on the clonogenicity of T98G cells. RESULTS: Papaverine significantly inhibited the clonogenicity of U87MG and T98G cells. Compared with single treatment, the combination of papaverine and temozolomide more highly suppressed the clonogenicity of T98G cells and delayed tumour growth in the U87MG xenograft mouse model. Furthermore, papaverine increased the radiosensitivity of T98G cells. CONCLUSION: Papaverine is a potential anticancer drug in GBM treatment.
Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/drug therapy , Cell Proliferation/drug effects , Glioblastoma/drug therapy , Papaverine/therapeutic use , Temozolomide/therapeutic use , Animals , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Brain Neoplasms/radiotherapy , Cell Line, Tumor , Glioblastoma/metabolism , Glioblastoma/pathology , Glioblastoma/radiotherapy , HMGB1 Protein/antagonists & inhibitors , HMGB1 Protein/metabolism , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Radiation Tolerance/drug effects , Receptor for Advanced Glycation End Products/antagonists & inhibitors , Receptor for Advanced Glycation End Products/metabolism , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
The interaction between high-mobility group box 1 protein (HMGB1) and receptor for advanced glycation end products (RAGE) is important for tumor cell growth. We investigated the tumor biological effects of HMGB1 and RAGE interaction. Previously, we identified an inhibitor of HMGB1/RAGE interaction, papaverine (a non-narcotic opium alkaloid), using a unique drug design system and drug repositioning approach. In the present study, we examined the anticancer effects of papaverine in human glioblastoma (GBM) temozolomide (TMZ; as a first-line anticancer medicine)-sensitive U87MG and TMZ-resistant T98G cells. HMGB1 supplementation in the culture medium promoted tumor cell growth in T98G cells, and this effect was canceled by papaverine. In addition, papaverine in T98G cells suppressed cancer cell migration. As an HMGB1/RAGE inhibitor, papaverine also significantly inhibited cell proliferation in U87MG and T98G cells. The effects of papaverine were evaluated in vivo in a U87MG xenograft mouse model by determining tumor growth delay. The results indicate that papaverine, a smooth muscle relaxant, is a potential anticancer drug that may be useful in GBM chemotherapy.
Subject(s)
Antineoplastic Agents/pharmacology , Glioblastoma/drug therapy , Papaverine/therapeutic use , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Glioblastoma/pathology , HMGB1 Protein/metabolism , Heterografts , Humans , Mice , Opiate Alkaloids , Papaverine/pharmacology , Receptor for Advanced Glycation End Products/metabolism , Temozolomide/pharmacologyABSTRACT
Receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor implicated in the pathogenesis of certain types of cancer. In the present study, papaverine was identified as a RAGE inhibitor using the conversion to small molecules through optimized-peptide strategy drug design system. Papaverine significantly inhibited RAGE-dependent nuclear factor κ-B activation driven by high mobility group box-1, a RAGE ligand. Using RAGE- or dominant-negative RAGE-expressing HT1080 human fibrosarcoma cells, the present study revealed that papaverine suppressed RAGE-dependent cell proliferation and migration dose-dependently. Furthermore, papaverine significantly inhibited cell invasion. The results of the present study suggested that papaverine could inhibit RAGE, and provided novel insights into the field of RAGE biology, particularly anticancer therapies.
