It is at present unclear whether the high expression of bcl-2 in human myeloma is the result of a deregulated expression associated with the malignant phenotype or a mere reflection of the bcl-2 expression typical of normal plasma cells.
To ascertain if multiple myeloma cells surviving exposure to chemotherapy alter their BCL-2 expression, we treated the myeloma cell lines 8226, IM-9, and U266 as well as a primary myeloma cell culture with various injurious agents.
We studied eight myeloma cell lines for the presence of Bcl-2, which inhibits apoptosis, of Bax, which counteracts Bcl-2, of Bcl-x(L) and Bcl-x(S), which act in an anti- and pro-apoptotic fashion, respectively, and of Apo-1/Fas, which induces programmed cell death, when activated by the Apo-1/Fas ligand or the relevant monoclonal antibody (mab).
We studied the cytotoxic effect of TAX and GEM on MM cells expressing varying levels of the antiapoptotic protein bcl-2, which is overexpressed in the majority of myeloma cell from MM patients.
We tested the role of bcl-2 by transfecting 2 low bcl-2-expressing myeloma cell lines, ARP-1 and 8226, with a bcl-2 expression vector and compared the effects of DEX and MEL on apoptosis, cell cycle distribution and the levels of proapoptotic (bax) and antiapoptotic (bcl-2, bclx) proteins.
Forced expression of bcl-2 in 8226 and ARP-1 multiple myeloma (MM) cell lines expressing relatively low levels of bcl-2, resulted in 1-2 log increase in resistance to dexamethasone (DEX)-induced apoptosis.
Collectively, our data suggest that the protective effects of bcl-2 in MM cells act upstream in the NF-kappaB activation-signaling pathway and the potential use of NF-kappaB as a biomarker in progressive MM.
Regulation of Bcl-2-family proteins in myeloma cells by three myeloma survival factors: interleukin-6, interferon-alpha and insulin-like growth factor 1.
CD34(+) cells were resistant to Ad-p53-mediated apoptosis, and CFU-GM and BFU-E colony formation was not affected by treatment with Ad-p53.Ad-p53 is a potent inducer of apoptosis in MM cell lines and in freshly isolated myeloma cells expressing low levels of bcl-2.
Replication deficient Ad-p53 and human recombinant Apo2L/TRAIL were used.Myeloma cells with mutated/w.t. p53 and varying expression of bcl-2 were used to test the effect of Ad-p53, Apo2L/TRAIL, or both, on apoptosis, measured by annexin V.
MM cells express multiple Bcl-2 family members, including Bcl-2, Bcl-XL, and Mcl-1, which are thought to play a key role in the survival and drug resistance of myeloma.
To conclude, we suggest that the expression pattern of the Bcl-2 family of proteins separates the malignant phenotype of MM from normal plasma cells, and that the protecting effect of IL-6 may be conducted via an altered balance between these proteins.
In summary, our data demonstrates that loss of p53 function leads to myeloma cell progression and resistant phenotype through bcl-2-related mechanisms.
Accelerated plasmacytomagenesis in strain C.BCL2 may be useful for designing and testing BCL2 inhibition strategies in human plasma cell tumors overexpressing BCL2, such as Waldenström's macroglobulinemia and multiple myeloma.
The study aim was to investigate Stat 3 activation in a series of multiple myeloma (MM) cases and its effect on downstream targets such as the anti-apoptotic proteins Bcl-xL, Mcl-1, and Bcl-2, and the cell-cycle protein cyclin D1.Forty-eight cases of MM were analyzed.
Bcl-2 antisense therapy with G3139 (oblimersen sodium; Genasense, Genta Inc, Berkeley Heights, NJ) is in clinical trials for a number of malignancies, including an ongoing trial in myeloma.
Ongoing clinical trials are exploring the role of Bcl-2 downregulation with oblimersen (Bcl-2 antisense) in patients with non-Hodgkin's lymphoma, chronic lymphocytic leukemia and multiple myeloma.