Research Papers:

Effective impairment of myeloma cells and their progenitors by hyperthermia

Hirokazu Miki, Shingen Nakamura, Asuka Oda, Hirofumi Tenshin, Jumpei Teramachi, Masahiro Hiasa, Ariunzaya Bat-Erdene, Yusaku Maeda, Masahiro Oura, Mamiko Takahashi, Masami Iwasa, Takeshi Harada, Shiro Fujii, Kiyoe Kurahashi, Sumiko Yoshida, Kumiko Kagawa, Itsuro Endo, Kenichi Aihara, Mariko Ikuo, Kohji Itoh, Koichiro Hayashi, Michihiro Nakamura and Masahiro Abe _

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Oncotarget. 2018; 9:10307-10316. https://doi.org/10.18632/oncotarget.23121

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Hirokazu Miki1,*, Shingen Nakamura2,*, Asuka Oda2, Hirofumi Tenshin3, Jumpei Teramachi4, Masahiro Hiasa5, Ariunzaya Bat-Erdene2, Yusaku Maeda2, Masahiro Oura2, Mamiko Takahashi2, Masami Iwasa2, Takeshi Harada2, Shiro Fujii2, Kiyoe Kurahashi2, Sumiko Yoshida2, Kumiko Kagawa2, Itsuro Endo2, Kenichi Aihara2, Mariko Ikuo6, Kohji Itoh6, Koichiro Hayashi7, Michihiro Nakamura8 and Masahiro Abe2

1Division of Transfusion Medicine and Cell Therapy, Tokushima University Hospital, Tokushima, Japan

2Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan

3Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan

4Department of Histology and Oral Histology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan

5Department of Biomaterials and Bioengineering, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan

6Department of Medicinal Biotechnology, Institute for Medicinal Research, Graduate School of Pharmaceutical Science, Tokushima University, Tokushima, Japan

7Division of Materials Research, Institute of Materials and Systems for Sustainability, Nagoya University, Aichi, Japan

8Department of Organ Anatomy, Yamaguchi University Graduate School of Medicine and Nanomedicine, Yamaguchi, Japan

*These authors contributed equally to this work

Correspondence to:

Masahiro Abe, email: [email protected]

Keywords: hyperthermia; plasmacytoma; side population; bortezomib; Pim-2

Received: June 03, 2017     Accepted: November 15, 2017     Published: December 07, 2017


Multiple myeloma (MM) remains incurable, and MM-initiating cells or MM progenitors are considered to contribute to disease relapse through their drug-resistant nature. In order to improve the therapeutic efficacy for MM, we recently developed novel superparamagnetic nanoparticles which selectively accumulate in MM tumors and extirpate them by heat generated with magnetic resonance. We here aimed to clarify the therapeutic effects on MM cells and their progenitors by hyperthermia. Heat treatment at 43°C time-dependently induced MM cell death. The treatment upregulated endoplasmic reticulum (ER) stress mediators, ATF4 and CHOP, while reducing the protein levels of Pim-2, IRF4, c-Myc and Mcl-1. Combination with the proteasome inhibitor bortezomib further enhanced ER stress to potentiate MM cell death. The Pim inhibitor SMI-16a also enhanced the reduction of the Pim-2-driven survival factors, IRF4 and c-Myc, in combination with the heat treatment. The heat treatment almost completely eradicated “side population” fractions in RPMI8226 and KMS-11 cells and suppressed their clonogenic capacity as determined by in vitro colony formation and tumorigenic capacity in SCID mice. These results collectively demonstrated that hyperthermia is able to impair clonogenic drug-resistant fractions of MM cells and enhance their susceptibility to chemotherapeutic drugs.

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