tailieunhanh - báo cáo khoa học: "The anti-myeloma activity of a novel purine scaffold HSP90 inhibitor PU-H71 is via inhibition of both HSP90A and HSP90B1"

Tuyển tập báo cáo các nghiên cứu khoa học quốc tế ngành y học dành cho các bạn tham khảo đề tài:The anti-myeloma activity of a novel purine scaffold HSP90 inhibitor PU-H71 is via inhibition of both HSP90A and HSP90B1 | Usmani et al. Journal of Hematology Oncology 2010 3 40 http content 3 1 40 JOURNAL OF HEMATOLOGY ONCOLOGY RESEARCH Open Access The anti-myeloma activity of a novel purine scaffold HSP90 inhibitor PU-H71 is via inhibition of both HSP90A and HSP90B1 c x x u 7 I I r x I 1 D Í X I X X r I ì D X x x -X 2 r r x l-x r I I x l x I r r I r 3 ỉ I l x x I I I4 Saad Z Usmani Robert D Bona Gabriela Chiosis Zihai LI 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. Introduction Multiple