The Heat Shock Protein 90 Inhibitor, 17-Allylamino-17-demethoxygeldanamycin, Enhances Osteoclast Formation and Potentiates Bone Metastasis of a Human Breast Cancer Cell Line

Abstract

Breast cancer metastasis to the bone occurs frequently, causing numerous complications including severe pain, fracture, hypercalcemia, and paralysis. Despite its prevalence and severity, few effective therapies exist. To address this, we examined whether the heat shock protein 90 (Hsp90) inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), would be efficacious in inhibiting breast cancer metastasis to bone. Utilizing the human breast cancer subline, MDA-MB-231SA, previously in vivo selected for its enhanced ability to generate osteolytic bone lesions, we determined that 17-AAG potently inhibited its in vitro proliferation and migration. Moreover, 17-AAG significantly reduced MDA-MB-231SA tumor growth in the mammary-fat pad of nude mice. Despite these findings, 17-AAG enhanced the incidence of bone metastasis and osteolytic lesions following intracardiac inoculation in the nude mouse. Consistent with these findings, 17-AAG enhanced osteoclast formation 2-to 4-fold in mouse bone marrow/osteoblast cocultures, receptor activator of nuclear factor KB ligand (RANKL)-stimulated bone marrow, and RAW264.7 cell models of in vitro osteoclastogenesis. Moreover, the drug enhanced osteoclastogenesis in human cord blood progenitor cells, demonstrating that its effects were not limited to mouse models. In addition to 17-AAG, other Hsp90 inhibitors, such as radicicol and herbimycin A, also enhanced osteoclastogenesis. A pro-osteolytic action of 17-AAG independent of tumor presence was also determined in vivo, in which 17-AAG-treated tumor-naïve mice had reduced trabecular bone volume with an associated increase in osteoclast number. Thus, HSP90 inhibitors can stimulate osteoclast formation, which may underlie the increased incidence of osteolysis and skeletal tumor incidence causedby 17-AAG in vivo. These data suggest an important contraindication to the Hsp90 targeted cancer therapy currently undergoing clinical trial. (Cancer Res 2005; 65(11): 4929-38)

Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

“…Each of the three inhibitors of osteoclastogenesis counteracted this activity. These data support and extend the results of a recent report in which 17-AAG was found to promote differentiation of preosteoclasts and to increase bone metastases in a murine breast cancer model (18).…”

“…In a study by Price et al (18), 17-AAG was reported to promote formation of osteolytic lesions and bone metastases in a murine breast cancer model (18). Because Src kinase is essential for osteoclast maturation (19,20), we examined the possibility that 17-AAG-induced Src activation in osteoclasts may mediate this phenomenon.…”

Low concentration of GA activates a preconditioning response in HepG2 cells during oxidative stress—roles of Hsp90 and vimentin

“…But Hsp90 inhibitors such as geldanamycin and the ansamycin derivative 17-AAG have been reported to show other effects than tumor inhibition (Schumacher et al 2007). Several data demonstrated that GA pretreatment could induce cell protection (Price et al 2005;Gotz et al 2006). These results raise concerns about treating certain kinds of cancers with Hsp90 inhibitors and suggest that it will be important to understand the tissue-specific effects of Hsp90 inhibition.…”

Hsp90 inhibition transiently activates Src kinase and promotes Src-dependent Akt and Erk activation

“…Although Srcdependent activation of Akt and Erk after GA is relatively short-lived, these data raise the concern that in certain contexts Hsp90 inhibition might favor tumor survival and͞or progression. Indeed, a recent study reported that 17-allylamino-17-demethoxygeldanamycin (17-AAG) promotes formation of osteolytic lesions and bone metastases in a murine breast cancer model by potentiating osteoclastic bone resorption, even though the drug reduced tumor growth at the orthotopic site (35). Because Src is essential for osteoclast activity (20) and Src-induced activation of Akt and Erk promotes osteoclast survival (36, 37), 17-AAG-induced Src activation, as described in this study, may be responsible for the reported effects of 17-AAG on bone.…”