Anticancer effects of a non-narcotic opium alkaloid medicine, papaverine, in human glioblastoma cells.

Mana Inada,Kyousuke Kobayashi,Yohei Yamamoto,Akira Sato,Mika Shindo,Koichi Ichimura,Sei-Ichi Tanuma,Yasuharu Akasaki,Ilya Ulasov

doi:10.1371/journal.pone.0216358

Mana Inada, Kyousuke Kobayashi + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0216358

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Abstract

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.

Highlights

High-mobility group box 1 (HMGB1) is a nonhistone DNA-binding nuclear protein that functions as an extracellular signaling molecule during inflammation, cell differentiation, cell migration, and tumor metastasis [1,2,3,4]
We have been investigating the relationship between the growth and migration of cancer cells and HMGB1/receptor for advanced glycation end products (RAGE) interaction in tumors, and recently we demonstrated that papaverine inhibits RAGE-dependent nuclear factor-κB activation, which is triggered by the RAGE ligand HMGB1 [5]
We studied the association between cell proliferation and HMGB1/RAGE interaction in several tumor cells

Summary

Introduction

High-mobility group box 1 (HMGB1) is a nonhistone DNA-binding nuclear protein that functions as an extracellular signaling molecule during inflammation, cell differentiation, cell migration, and tumor metastasis [1,2,3,4]. We have been investigating the relationship between the growth and migration of cancer cells and HMGB1/RAGE interaction in tumors, and recently we demonstrated that papaverine inhibits RAGE-dependent nuclear factor-κB activation, which is triggered by the RAGE ligand HMGB1 [5]. We assessed the anticancer effects of papaverine in human GBM U87MG and T98G cells as well as a U87MG xenograft mouse model. Papaverine significantly inhibited cell proliferation in U87MG and T98G cells and tumor growth in the U87MG xenograft mouse model. These observations suggest that the HMGB1/RAGE inhibitor papaverine can provide a novel anticancer strategy for GBM

Materials and methods

Results and discussion

Conclusions