Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer.
Heat shock proteins (HSPs), which are molecular chaperones that stabilize numerous vital proteins, may be attractive targets for cancer therapy. The aim of the present study was to investigate the possible anticancer effect of single or dual targeting of HSP90 and HSP70 and the combination treatment with HSP inhibitors and chemotherapeutic agents in bladder cancer cells. The expression of HSP90 and the anticancer effect of the HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) coupled with cisplatin, docetaxel, or gemcitabine were examined using immunohistochemistry, quantitative real-time PCR, cell growth, flow cytometry, immunoblots and caspase-3/7 assays. The expression of HSP70 under HSP90 inhibition and the additive effect of HSP70 inhibitor pifithrin-μ (PFT-μ) were examined by the same assays and transmission electron microscopy. HSP90 was highly expressed in bladder cancer tissues and cell lines. 17-AAG enhanced the antiproliferative and apoptotic effects of each chemotherapeutic agent. 17-AAG also suppressed Akt activity but induced the upregulation of HSP70. PFT-μ enhanced the effect of 17-AAG or chemotherapeutic agents; the triple combination of 17-AAG, PFT-μ and a chemotherapeutic agent showed the most significant anticancer effect on the T24 cell line. The combination of 17-AAG and PFT-μ markedly suppressed Akt and Bad activities. With HSP90 suppression, HSP70 overexpression possibly contributes to the avoidance of cell death and HSP70 may be a key molecule for overcoming resistance to the HSP90 inhibitor. The dual targeting of these two chaperones and the combination with conventional anticancer drugs could be a promising therapeutic option for patients with advanced bladder cancer.
Department of Urology, Oita University, Yufu, Oita 879-5593, Japan.
Liang
L
Ma
Department of Urology, Oita University, Yufu, Oita 879-5593, Japan.
Fuminori
F
Sato
Department of Urology, Oita University, Yufu, Oita 879-5593, Japan.
Ryuta
R
Sato
Division of Urology, Nakamura Hospital, Beppu, Oita 874‑0937, Japan.
Takanori
T
Matsubara
Department of Urology, Oita University, Yufu, Oita 879-5593, Japan.
Kenichi
K
Hirai
Department of Urology, Oita University, Yufu, Oita 879-5593, Japan.
Mutsushi
M
Yamasaki
Department of Urology, Oita University, Yufu, Oita 879-5593, Japan.
Toshitaka
T
Shin
Faculty of Medicine, Oita University, Yufu, Oita 879-5593, Japan.
Tatsuo
T
Shimada
Division of Urology, Tsurumi Hospital, Beppu, Oita 874-8585, Japan.
Takeo
T
Nomura
Department of Urology, Oita University, Yufu, Oita 879-5593, Japan.
Kenichi
K
Mori
Department of Urology, Oita University, Yufu, Oita 879-5593, Japan.
Yasuhiro
Y
Sumino
Department of Urology, Oita University, Yufu, Oita 879-5593, Japan.
Hiromitsu
H
Mimata
D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D015398:Signal Transduction; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin