The anti-myeloma activity of a novel purine scaffold HSP90 inhibitor PU-H71 is via inhibition of both HSP90A and HSP90B1 Journal Article
| Authors: | Usmani, S. Z.; Bona, R. D.; Chiosis, G.; Li, Z. |
| Article Title: | The anti-myeloma activity of a novel purine scaffold HSP90 inhibitor PU-H71 is via inhibition of both HSP90A and HSP90B1 |
| Abstract: | Background. Heat shock protein 90 (HSP90) inhibitors have emerged as a promising class of anti-cancer drugs in both solid and hematologic malignancies. The HSP90 family includes the cytosolic HSP90 (HSP90AA1), the ER paralogue gp96 (HSP90B1) and the mitochondrial member TRAP1 (HSP90L). We evaluated the in vitro anti-tumor activity and mechanism of action of PU-H71, a novel purine scaffold HSP90 inhibitor in human multiple myeloma cell lines. Methods. Multiple human myeloma cell lines including cells that are resistant to corticosteroids and bortezimab were treated with PU-H71, followed by analysis of cell viability, cell cycle progression and apoptosis, by flow cytometry and caspase 3 immunoblot. Induction of unfolded protein response was studied by XBP-1 s immunoblot. The role of gp96 was further assessed by small hairpin RNA knockdown of gp96 before treatment with PU-H71. Results. PU-H71 has potent in vitro anti-myeloma activity in both drug-sensitive and drug-resistant cell lines. PU-H71 activates the unfolded protein response and induces caspase-dependent apoptosis. The stable gp96 knockdown human myeloma cell line was found to be more resistant to PU-H71 and other HSP90 inhibitors including 17-AAG and 17-DMAG, even though these cells are more sensitive to conventional anti-myeloma drugs. Conclusion. We conclude that PU-H71 is a promising drug for the treatment of myeloma. Our finding further suggests that PU-H71 and the geldanamycin analogues work in part by inhibiting the endoplasmic reticulum gp96 along with the cytosolic HSP90. © 2010 Usmani et al; licensee BioMed Central Ltd. |
| Keywords: | signal transduction; controlled study; unclassified drug; human cell; antineoplastic agents; flow cytometry; antineoplastic agent; protein function; cell viability; cell cycle progression; cell cycle s phase; apoptosis; bortezomib; multiple myeloma; x box binding protein 1; caspase 3; antineoplastic activity; cancer cell culture; in vitro study; drug effect; chemosensitivity; cell line, tumor; physiology; cancer resistance; endoplasmic reticulum; drug antagonism; drug mechanism; membrane glycoproteins; membrane protein; tumor cell line; immunoblotting; protein induction; 17 demethoxy 17 (2 dimethylaminoethylamino)geldanamycin; heat shock protein 90 inhibitor; pu h71; tanespimycin; heat shock protein 90; hsp90 heat-shock proteins; target cell; benzodioxoles; purines; purine derivative; corticosteroid; short hairpin rna; cell cycle g1 phase; g1 phase; s phase; concentration response; cytosol; geldanamycin; unfolded protein response; 1,3 benzodioxole derivative; pu h 71; glycoprotein gp 96; heat shock protein 90a; heat shock protein 90b1; endoplasmin; myeloma cell |
| Journal Title: | Journal of Hematology & Oncology |
| Volume: | 3 |
| ISSN: | 1756-8722 |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2010-10-26 |
| Start Page: | 40 |
| Language: | English |
| DOI: | 10.1186/1756-8722-3-40 |
| PUBMED: | 20977755 |
| PROVIDER: | scopus |
| PMCID: | PMC2974653 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 20 April 2011" - "Art. No.: 40" - "Source: Scopus" |
