Inhibition of Hsp90 and 70 sensitizes melanoma cells to hyperthermia using ferromagnetic particles with a low Curie temperature.
BACKGROUND
Heat shock protein (Hsp) 90 is a key regulator of various oncogene products and cell-signaling molecules, while Hsp70 protects against heat-induced apoptosis. We previously described a system in which hyperthermia was produced using thermosensitive ferromagnetic particles (FMPs) with a Curie temperature (T c) of 43 °C to mediate automatic temperature control, and demonstrated its antitumor effect in a mouse melanoma model. In the present study, the antitumor effects of combining Hsp90 inhibitor (17DMAG) and Hsp70 inhibitor (quercetin) with FMP-mediated hyperthermia were examined.


METHODS
Expressions of Hsp90/70 and Akt were evaluated using Western blotting in vitro. In an in vivo study, melanoma cells were subcutaneously injected into the backs of C57BL/6 mice. FMPs were then injected into the resultant tumors, and the mice were divided into groups treated with quercetin and/or 17DMAG with/without hyperthermia. When exposed to a magnetic field, the temperature of tissues containing FMPs increased and stabilized at the T c. The TUNEL method was used to determine whether hyperthermia induced apoptosis within tumors.


RESULTS
In the group pretreated with hyperthermia + quercetin + 17DMAG, Akt expression was reduced in vitro, the incidence of apoptosis within tumors was greater, and tumor growth was significantly suppressed 20 days after FMP injection in vivo, compared with other treatment groups. The survival rates among tumor-bearing mice observed for a period of 40 days were significantly higher in the hyperthermia + quercetin + 17DMAG group.


CONCLUSIONS
Combining Hsp90/70 inhibition with hyperthermia appears to increase their antitumor effects. Thus, the combination of FMP-mediated, self-regulating hyperthermia with Hsp90/70 inhibition has important implications for cancer treatment.
Department of Surgery, Division of Thoracic Surgery, Akita University School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
Tomoyuki
T
Miyagawa
Hajime
H
Saito
Yoshihiro
Y
Minamiya
Kazutaka
K
Mitobe
Shinogu
S
Takashima
Naoko
N
Takahashi
Aki
A
Ito
Kazuhiro
K
Imai
Satoru
S
Motoyama
Junichi
J
Ogawa
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000008:administration & dosage*; D015972:Gene Expression Regulation, Neoplastic; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D006979:Hyperthermia, Induced; D047029:Lactams, Macrocyclic / Q000008:administration & dosage*; D059346:Magnets; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011794:Quercetin / Q000008:administration & dosage*
D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D011794:Quercetin