- 作者：Emir Hadzijusufovic ; Laura Rebuzzi ; Karoline V. Gleixner ; Veronika Ferenc ; Barbara Peter ; Rudin Kondo ; Alex ; er Gruze ; Michael Kneidinger ; Maria-Theresa Krauth ; Matthias Mayerhofer ; Puchit Samorapoompi
- 刊名：Experimental Hematology
- 出版年：2008
- 出版时间：November 2008
- 年：2008
- 卷：36
- 期：11
- 页码：1461-1470
- 全文大小：673 K
Objective
Advanced mast cell (MC) neoplasms are usually resistant to conventional therapy. Therefore, current research focuses on new targets in neoplastic MC and development of respective targeted drugs. Mastocytomas in dogs often behave as aggressive tumors. We report that heat-shock protein 32 (Hsp32), also known as heme oxygenase-1, is a survival-enhancing molecule and new target in canine mastocytoma cells.Materials and Methods
As assessed by reverse transcriptase polymerase chain reaction, Northern blotting, immunocytochemistry, and Western blotting, primary neoplastic dog MC, and the canine mastocytoma-derived cell line C2 expressed Hsp32 mRNA and the Hsp32 protein in a constitutive manner.
Results
The KIT-targeting drug midostaurin inhibited expression of Hsp32, as well as survival in C2 cells. Confirming the functional role of Hsp32, the inhibitory effect of midostaurin on C2 cells was markedly reduced by the Hsp32-inductor hemin. Two pharmacologic Hsp32-inhibitors, styrene maleic-acid micelle-encapsulated ZnPP (SMA-ZnPP) and pegylated zinc-protoporphyrin (PEG-ZnPP) were applied. Both drugs were found to inhibit proliferation of C2 cells as well as growth of primary neoplastic canine MC. The growth-inhibitory effects of SMA-ZnPP and PEG-ZnPP were dose- and time-dependent (IC50: 1–10 μM) and found to be associated with induction of apoptosis.
Conclusions
Hsp32 is an important survival factor and interesting new target in neoplastic canine MC. Trials with Hsp32-targeted drugs are now warranted to define the clinical efficacy of these drugs.