Heat shock protein (Hsp) 90 is a key regulator of a variety of
oncogene products and cell-signaling molecules, and the therapeutic benefit of its inhibition in combination with radiation or
chemotherapy has been investigated. In addition,
hyperthermia has been used for many years to treat various malignant
tumors. We previously described a system in which
hyperthermia was induced using thermosensitive ferromagnetic particles (
FMP) with a Curie temperature (Tc = 43 degrees C) low enough to mediate automatic temperature control, and demonstrated its antitumor effect in a mouse
melanoma model. In the present study, we examined the antitumor effects of combining a Hsp90 inhibitor (
geldanamycin; GA) with
FMP-mediated
hyperthermia. In cultured
B16 melanoma cells, GA exerted an antitumor effect by increasing the cells' susceptibility to
hyperthermia and reducing expression of Akt. In an in vivo study,
melanoma cells were subcutaneously injected into the backs of C57BL/6 mice.
FMP were then injected into the resultant
tumors, and the mice were divided into four groups: group I, no treatment (control); group II, one
hyperthermia treatment; group III, GA alone; and group IV, GA with
hyperthermia. When exposed to a magnetic field, the temperature of tissues containing
FMP increased and stabilized at the Tc. In group IV, complete regression of
tumors was observed in five of nine mice (56%), whereas no
tumor regression was seen in groups I-III. Our findings suggest that inhibition of Hsp90 with
hyperthermia increases its antitumor effect. Thus, the combination of
FMP-mediated, self-regulating
hyperthermia with Hsp90 inhibition has important implications for the treatment of
cancer.