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Cancer Chemotherapy and Pharmacology

, Volume 66, Issue 3, pp 455–466 | Cite as

Targeted proteasome inhibition by Velcade induces apoptosis in human mesothelioma and breast cancer cell lines

  • Ying Wang
  • Arun K. RishiEmail author
  • Vineshkumar T. Puliyappadamba
  • Sunita Sharma
  • Huanjie Yang
  • Adi Tarca
  • Q. Ping Dou
  • Fulvio Lonardo
  • John C. Ruckdeschel
  • Harvey I. Pass
  • Anil Wali
Original Article

Abstract

Introduction

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.

Purpose

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.

Keywords

Malignant pleural mesothelioma Bortezomib (Velcade) Apoptosis Gene expression 

Notes

Acknowledgments

This work was supported by the department of Veterans Affairs Merit Review grants to AKR and AW, Susan G. Komen for the Cure grant to AKR, and MARF support to AW.

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Ying Wang
    • 1
  • Arun K. Rishi
    • 2
    Email author
  • Vineshkumar T. Puliyappadamba
    • 3
  • Sunita Sharma
    • 4
  • Huanjie Yang
    • 5
  • Adi Tarca
    • 6
  • Q. Ping Dou
    • 5
  • Fulvio Lonardo
    • 6
  • John C. Ruckdeschel
    • 7
  • Harvey I. Pass
    • 8
  • Anil Wali
    • 9
    • 10
  1. 1.John D. Dingell VA Medical Center, Karmanos Cancer InstituteWayne State UniversityDetroitUSA
  2. 2.John D. Dingell VA Medical Center, Department of Internal Medicine, Karmanos Cancer InstituteWayne State UniversityDetroitUSA
  3. 3.John D. Dingell VA Medical Center, Karmanos Cancer InstituteWayne State UniversityDetroitUSA
  4. 4.John D. Dingell VA Medical Center, Department of Surgery, Karmanos Cancer InstituteWayne State UniversityDetroitUSA
  5. 5.Department of Pathology, Karmanos Cancer InstituteWayne State UniversityDetroitUSA
  6. 6.Karmanos Cancer InstituteWayne State UniversityDetroitUSA
  7. 7.Nevada Cancer CenterLas VegasUSA
  8. 8.Division of Cardiothoracic SurgeryNew York University Cancer CenterNew YorkUSA
  9. 9.John D. Dingell VA Medical Center, Department of Surgery, Karmanos Cancer InstituteWayne State UniversityDetroitUSA
  10. 10.Center to Reduce Cancer Health Disparities, National Cancer InstituteNational Institutes of HealthRockvilleUSA

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