Effective impairment of myeloma cells and their progenitors by hyperthermia
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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
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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