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.
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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 -