Targeted proteasome inhibition by Velcade induces apoptosis in human mesothelioma and breast cancer cell lines.
BACKGROUND
Thoracic malignancies and human breast cancer (HBC) continue to be aggressive solid tumors that are poor responders to the existing conventional standard chemotherapeutic approaches. Malignant pleural mesothelioma (MPM) is an asbestos-related tumor of the thoracic pleura that lacks effective treatment options. Altered ubiquitin proteasome pathway is frequently encountered in many malignancies including HBC and MPM and thus serves as an important target for therapeutic intervention strategies. Although proteasome inhibitor Velcade (Bortezomib) has been under clinical investigation for a number of cancers, limited preclinical studies with this agent have thus far been conducted in HBC and MPM malignancies.


OBJECTIVE
To study the biological and molecular responses of MPM and HBC cells to Velcade treatments, and to identify mechanisms involved in transducing growth inhibitory effects of this agent.


METHODS
Flow-cytometric analyses coupled with western immunoblotting and gene-array methodologies were utilized to determine mechanisms of Velcade-dependent growth suppression of five MPM (H2595, H2373, H2452, H2461, and H2714) and two breast cancer (MDA MB-468, SKBR-3) cell lines.


RESULTS
Our data revealed significant reduction in cell growth properties that were dose and time dependent. Velcade treatment resulted in G2M phase arrest, increased expression of cyclin-dependent kinase inhibitor p21 and pro-apoptotic protein Bax. Pretreatment of mesothelioma cells with Velcade showed synergistic effect with cisplatin combination regimens. High-throughput gene expression profiling among Velcade treated and untreated mesothelioma cell lines resulted in identification of novel transducers of apoptosis such as CARP-1, XAF1, and Troy proteins.


CONCLUSIONS
Velcade targets cell cycle and apoptosis signaling to suppress MPM and HBC growth in part by activating novel transducers of apoptosis. This pilot study has paved way for further in-depth analysis of the downstream target molecules associated with presensitization of mesothelioma cells in finding effective therapeutic treatment options for both mesothelioma and recalcitrant breast cancers.
Wang
Ying
Y
John D. Dingell VA Medical Center, Karmanos Cancer Institute, Wayne State University, VAMC, 4646 John R., Detroit, MI, 48201, USA.
Rishi
Arun K
AK
Puliyappadamba
Vineshkumar T
VT
Sharma
Sunita
S
Yang
Huanjie
H
Tarca
Adi
A
Dou
Q Ping
QP
Lonardo
Fulvio
F
Ruckdeschel
John C
JC
Pass
Harvey I
HI
Wali
Anil
A
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology; D010865:Pilot Projects; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D002945:Cisplatin