Bik/NBK accumulation correlates with apoptosis induction by bortezomib (PS-341, Velcade) and other proteasome inhibitors

06-16-2006

Bik/NBK accumulation correlates with apoptosis induction by bortezomib (PS-341, Velcade) and other proteasome inhibitors.

"Proteasome inhibitors have emerged as promising anticancer therapeutic agents. Bortezomib (PS-341), a specific proteasome inhibitor, exhibits antitumor activity against a wide range of malignancies and has been approved by the U.S. Food and Drug Administration for the treatment of relapsed or refractory multiple myeloma. However, the molecular mechanisms of bortezomib-mediated apoptosis remain unclear," scientists writing in the journal Oncogene report.

"To characterize the mechanisms of apoptosis induction by proteasome inhibitors, we examined levels of Bcl-2 protein family members (Bik/NBK, Bax, Bak, Bcl-2, and Bcl-XL), release of cytochrome c, and activation of caspase-9 and -3 in human colon cancer cell lines DLD1, LOVO, SW620, and HCT116; human lung cancer cell line H1299; and human ovarian cancer cell line SKOV3 after they were treated with bortezomib," stated Hongbo Zhu and collaborators at Zhejiang University in China and the University of Texas M.D. Anderson Cancer Center in the U.S.

The researchers reported, "The result showed that bortezomib induced rapid accumulation of Bik/NBK but not other Bcl-2 family members in all six cell lines. Bortezomib-mediated Bik/NBK accumulation and apoptosis were also observed in human embryonic kidney cells 293 and normal human bronchial epithelial cells. Moreover, dramatic Bik/NBK accumulation and apoptosis induction were observed when cells were treated with proteasome inhibitor MG132 and calpain inhibitor I (ALLN). Furthermore, no detectable changes in I kappa B alpha levels or in NF kappa B functionality were found after treatment with bortezomib."

"Finally, Bik/NBK accumulation was caused by stabilization of the protein from degradation and was associated with bortezomib cytotoxicity and apoptosis induction," noted the investigators.

They concluded, "Pretreatment of DLD1 cells with Bik/NBK siRNA reduced bortezomib-mediated Bik/NBK accumulation and cell death. Our results suggested that Bik/NBK is one of the mediators of proteasome inhibitor-induced apoptosis."

Zhu and associates published their study in Oncogene (Bik/NBK accumulation correlates with apoptosis-induction by bortezomib (PS-341, Velcade) and other proteasome inhibitors. Oncogene, 2005;24(31):4993-4999).

Additional information can be obtained by contacting Bingliang Fang, Department of Thoracic and Cardiovascular Surgery, University of Texas, MD Anderson Cancer Center, Unit 445, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Bfang@mdanderson.org.

This article was prepared by Clinical Oncology Week editors from staff and other reports. Copyright 2006, Clinical Oncology Week via NewsRx.com.