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; Masahiro Abe

doi:10.18632/oncotarget.23121

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 ItohKoichiro Hayashi, Michihiro Nakamura, Masahiro Abe

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

Multiple myeloma (MM) remains incurable, and MM-initiating cells or MM progenitors are considered to contribute to disease relapse through their drugresistant 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.

Original language	English
Pages (from-to)	10307-10316
Number of pages	10
Journal	Oncotarget
Volume	9
Issue number	12
DOIs	https://doi.org/10.18632/oncotarget.23121
Publication status	Published - 2018
Externally published	Yes

Keywords

Bortezomib
Hyperthermia
Pim-2
Plasmacytoma
Side population

ASJC Scopus subject areas

Oncology

Access to Document

10.18632/oncotarget.23121

Cite this

Miki, H., Nakamura, S., Oda, A., Tenshin, H., Teramachi, J., Hiasa, M., Bat-Erdene, A., Maeda, Y., Oura, M., Takahashi, M., Iwasa, M., Harada, T., Fujii, S., Kurahashi, K., Yoshida, S., Kagawa, K., Endo, I., Aihara, K., Ikuo, M., ... Abe, M. (2018). Effective impairment of myeloma cells and their progenitors by hyperthermia. Oncotarget, 9(12), 10307-10316. https://doi.org/10.18632/oncotarget.23121

Miki, H, Nakamura, S, Oda, A, Tenshin, H, Teramachi, J, Hiasa, M, Bat-Erdene, A, Maeda, Y, Oura, M, Takahashi, M, Iwasa, M, Harada, T, Fujii, S, Kurahashi, K, Yoshida, S, Kagawa, K, Endo, I, Aihara, K, Ikuo, M, Itoh, K, Hayashi, K, Nakamura, M & Abe, M 2018, 'Effective impairment of myeloma cells and their progenitors by hyperthermia', Oncotarget, vol. 9, no. 12, pp. 10307-10316. https://doi.org/10.18632/oncotarget.23121

@article{78c0be21e5d04b139ab22e6e28a67083,

title = "Effective impairment of myeloma cells and their progenitors by hyperthermia",

abstract = "Multiple myeloma (MM) remains incurable, and MM-initiating cells or MM progenitors are considered to contribute to disease relapse through their drugresistant 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.",

keywords = "Bortezomib, Hyperthermia, Pim-2, Plasmacytoma, Side population",

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

note = "Funding Information: This work was supported in part by Grants-in-Aid for Young Scientists (B) to H.M., and S.N. Grants-in-aid for Scientific Research (C) to M.A., and a Grant-in-aid for Cancer Research (17-16) to M.A. from the Ministry of Health, Labor and Welfare of Japan. The funders had no Publisher Copyright: {\textcopyright} Miki et al.",

year = "2018",

doi = "10.18632/oncotarget.23121",

language = "English",

volume = "9",

pages = "10307--10316",

journal = "Oncotarget",

issn = "1949-2553",

publisher = "Impact Journals",

number = "12",

}

TY - JOUR

T1 - Effective impairment of myeloma cells and their progenitors by hyperthermia

AU - Miki, Hirokazu

AU - Nakamura, Shingen

AU - Oda, Asuka

AU - Tenshin, Hirofumi

AU - Teramachi, Jumpei

AU - Hiasa, Masahiro

AU - Bat-Erdene, Ariunzaya

AU - Maeda, Yusaku

AU - Oura, Masahiro

AU - Takahashi, Mamiko

AU - Iwasa, Masami

AU - Harada, Takeshi

AU - Fujii, Shiro

AU - Kurahashi, Kiyoe

AU - Yoshida, Sumiko

AU - Kagawa, Kumiko

AU - Endo, Itsuro

AU - Aihara, Kenichi

AU - Ikuo, Mariko

AU - Itoh, Kohji

AU - Hayashi, Koichiro

AU - Nakamura, Michihiro

AU - Abe, Masahiro

N1 - Funding Information: This work was supported in part by Grants-in-Aid for Young Scientists (B) to H.M., and S.N. Grants-in-aid for Scientific Research (C) to M.A., and a Grant-in-aid for Cancer Research (17-16) to M.A. from the Ministry of Health, Labor and Welfare of Japan. The funders had no Publisher Copyright: © Miki et al.

PY - 2018

Y1 - 2018

N2 - Multiple myeloma (MM) remains incurable, and MM-initiating cells or MM progenitors are considered to contribute to disease relapse through their drugresistant 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.

AB - Multiple myeloma (MM) remains incurable, and MM-initiating cells or MM progenitors are considered to contribute to disease relapse through their drugresistant 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.

KW - Bortezomib

KW - Hyperthermia

KW - Pim-2

KW - Plasmacytoma

KW - Side population

UR - http://www.scopus.com/inward/record.url?scp=85041952629&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85041952629&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.23121

DO - 10.18632/oncotarget.23121

M3 - Article

C2 - 29535808

AN - SCOPUS:85041952629

SN - 1949-2553

VL - 9

SP - 10307

EP - 10316

JO - Oncotarget

JF - Oncotarget

IS - 12

ER -

Effective impairment of myeloma cells and their progenitors by hyperthermia

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this