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

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

doi:10.1371/journal.pone.0216358

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

PLoS One. 2019 May 17;14(5):e0216358. doi: 10.1371/journal.pone.0216358. eCollection 2019.

Authors

Mana Inada¹, Mika Shindo^{1

2}, Kyousuke Kobayashi¹, Akira Sato¹, Yohei Yamamoto³, Yasuharu Akasaki³, Koichi Ichimura⁴, Sei-Ichi Tanuma^{1

5}

Affiliations

¹ Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
² National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.
³ Department of Neurosurgery, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
⁴ Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
⁵ Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Noda, Chiba, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Glioblastoma / drug therapy*
Glioblastoma / pathology
HMGB1 Protein / metabolism
Heterografts
Humans
Mice
Opiate Alkaloids
Papaverine / pharmacology
Papaverine / therapeutic use*
Receptor for Advanced Glycation End Products / metabolism
Temozolomide / pharmacology

Substances

Antineoplastic Agents
HMGB1 Protein
Opiate Alkaloids
Receptor for Advanced Glycation End Products
Papaverine
Temozolomide

Grants and funding

This work was supported by a JSPS KAKENHI grant number 26670648 (T.A.) and an Education Research Fund for Tokyo University of Science (A.S. and S.T.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.