HSP90 antagonist, geldanamycin, inhibits proliferation, induces apoptosis and blocks migration of rhabdomyosarcoma cells in vitro and seeding into bone marrow in vivo

Abstract

In this study, geldanamycin (GA) was found to have an antiproliferative effect on both embryonal and alveolar rhabdomyosarcoma (RMS) cell lines. The maximum level of inhibition reached 80% for both embryonal and alveolar RMS. After GA treatment, cells also became apoptotic as judged by Annexin V-positive staining, activation of caspase-3 pathway and poly(ADP ribose) polymerase cleavage. GA was responsible for the arrest of RMS cells in both G1 and G2/M phases of the cell cycle. G1 blockade, however, was transient and was seen only in the first 24 h of GA treatment. RMS often gives distant metastases to various organs including bone marrow. RMS cells express high levels of MET receptor and respond to hepatocyte growth factor with increased motility. In our study, we found that GA decreased the level of MET expression and inhibited the chemotaxis of RMS cells toward the hepatocyte growth factor gradient. GA also blocked the homing of RMS cells into bone marrow of severe combined immune deficient mice. In all our experiments embryonal RMS cell lines were significantly more sensitive, and lower concentrations of GA were sufficient to block embryonal RMS cell proliferation, induce apoptosis and inhibit motility. Our data show that the HSP90 inhibitor GA has the potential to become a new drug in RMS treatment. It blocks RMS proliferation, decreases cell survival and inhibits motility of RMS cells.

17AEP-GA, an HSP90 antagonist, is a potent inhibitor of glioblastoma cell proliferation, survival, migration and invasion

“…This block of tumor cell migration is due to inhibition of MET receptor expression (mRNA expression and FACS analysis in this study). Similar results have been obtained for different tumors (19,22,23,28). GAs are able to inhibit the expression of MAPK and AKT kinases which were shown previously to be involved in activating the motility of tumor cells (26,27).…”

“…In our previous studies on rhabdomyosarcoma cells we showed that HGF induced migration of these cells can be blocked by HSP90 inhibitors (19). Thus, in this study, we tested whether HSP90 inhibitors, such as GAs, can block the ability of GBM cells to migrate and invade.…”

“…GA and its analogs have been shown to block growth of tumor cells and the expression of various oncoproteins including tyrosine kinase receptors (17,19,23). However, most of the studies on GBM cells were conducted using geldanamycin and its analog 17-AAG.…”

“…Several in vitro studies indicate that GAs inhibit the proliferation of a wide range of cancer cells (18,19). The effects of GAs on the growth rate of GBM cell lines (LN18, LN229, T98G) were determined using the CellTiter 96 ® Aqueous One Solution assay at 96 h. GAs were used in 1 and 10 nM concentrations.…”

“…It has been shown that MET receptor is a client protein for HSP90 (14,19). Thus, we checked if incubation of GBM cells with GAs had any effect on the surface expression of MET receptor.…”