Disease relevance of Bortezomib

• RNA interference and TRAIL receptor blockage experiments revealed that in bortezomib-treated hepatoma cells TRAIL-R1/TRAIL-R2 up-regulation, enhanced TRAIL DISC formation and cFLIPL down-regulation in addition to accumulation of Bak cooperatively sensitized for TRAIL [1].
• Bortezomib received regular approval for the treatment of patients with mantle cell lymphoma in relapse after prior therapy [2].
• Although the role of bortezomib in lung cancer is uncertain, it is likely to have its greatest clinical benefit when given in combination with other therapeutics [3].
• After 12 weeks of treatment, bortezomib also impaired osteosclerosis development through osteoprotegerin inhibition [4].
• Bortezomib also increased SRC-3 levels and phosphorylated Akt, both in vitro and in treated prostate cancer tissues [5].
• Bortezomib treatment inhibited hepatoma cell growth with IC(50) values between 2.4 and 7.7 nmol/L [6].
• Our in vitro and in vivo studies indicate that mechanisms by which bortezomib inhibits tumor growth and reduces osteolysis result from inhibited cell proliferation, necrosis, and decreased expression of factors that promote BrCa tumor progression in bone [7].
• Bortezomib represents a promising new approach to prime neuroblastoma cells toward TRAIL, which warrants further investigation [8].

Associations of Bortezomib with other chemical compounds

• The highest dose level (1.6 mg/m(2) bortezomib plus 40 mg/m(2) docetaxel) was feasible and tolerable; bortezomib plus docetaxel showed antitumor activity [9].
• Weekly bortezomib 1.0 mg/m(2) plus gemcitabine 1,000 mg/m(2) and cisplatin 70 mg/m(2) is the recommended phase 2 schedule, constituting a safe combination, with activity in NSCLC [10].
• The recommended dose of bortezomib for phase II studies with idarubicin and cytarabine is 1.5 mg/m(2) [11].
• Tumor-bearing mice treated with bortezomib plus fenretinide lived statistically significantly longer than mice treated with each drug alone [12].
• In CAG- or KMS11-SCID xenograft models of disseminated MM, milatuzumab more than doubled median survival time, compared with up to a 33% increase in median survival with bortezomib but no significant benefit with doxorubicin [13].
• We have defined phase II doses for this schedule of temozolomide with bortezomib [14].
• Pretreatment with sorafenib enhanced bortezomib-induced apoptotic cell death by restoring bortezomib's ability to inactivate Akt in PLC/PRF/5 cells [15].
• In cell lysates, bortezomib, but not carfilzomib, significantly inhibited the serine proteases cathepsin G (CatG), cathepsin A, chymase, dipeptidyl peptidase II, and HtrA2/Omi at potencies near or equivalent to that for the proteasome [16].
• In resistant cells, gene expression changes in response to bortezomib were limited and upregulation of NOXA was absent [17].

Gene context of Bortezomib

• GX15-070 synergized with bortezomib, sensitizing MCL cells to low doses of this proteasome inhibitor, by neutralizing bortezomib-induced Mcl-1 accumulation and cooperating with Noxa to induce Bak displacement from this protein [18].
• Although bortezomib treatment inhibited NF-kappaB activity, bortezomib had little activity as a single agent in this population [19].
• Bortezomib inhibits NF-kappaB activity in MMe cells and induces cell cycle blockade and apoptosis in vitro as well as tumor growth inhibition in vivo [20].
• Bortezomib inhibited expression of cIAP-1, cIAP-2, and XIAP, which are regulated by NF-kappaB and function as inhibitors of apoptosis [21].
• Whereas high-dose bortezomib induced direct cytotoxicity that correlated with decreased NF-kappaB activity, low-dose bortezomib sensitized HL cells against a variety of cytotoxic drugs without altering NF-kappaB action [22].
• Treatment of IL-6-dependent and IL-6-independent multiple myeloma cell lines with CNTO 328 enhanced the cytotoxicity of bortezomib in a sequence-dependent fashion [23].
• The effect of bortezomib was muted in cells lacking both alleles of CTR1, showing that bortezomib was working primarily through its effect on blocking hCTR1 degradation [24].
• Bortezomib antagonized cetuximab- and radiation-induced cytotoxicity, degradation of EGFR, and enhanced prosurvival signal pathway activation in SCCHN tumor biopsies and UMSCC-1 [25].

References