Naslov
Anti-proliferative and pro-apoptotic action of the combined cytostatic/immunosuppressive treatment of myeloma cell lines in vitro

Autori
Zelić, Ana ; Ivčević, Sanja ; Kovačić, Nataša ; Kušec, Rajko ; Grčević, Danka

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, ostalo

Izvornik
Liječnički Vijesnik / Anić, Branimir - Zagreb, 2011, 104-104

Skup
Leukemia and Lymphoma

Mjesto i datum
Dubrovnik, Hrvatska, 17.09.2011. - 21.09.2011

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
multiple myeloma; drug treatment; apoptosis; proliferation

Sažetak
Background: Multiple myeloma (MM) is B-lymphocyte neoplasia, characterized by the slow proliferation of malignant plasma cells in the bone-marrow (BM). Multiple anti-apoptotic signaling mechanisms contribute to the accumulation of myeloma cells within the BM and account for their resistance to chemotherapy. Therefore, investigation of the effects of different agents on the balance between pro- and anti-apoptotic factors in the malignant clone would contribute to the development of novel therapeutic strategies in MM. Aim: We determined the effects of several currently used anti-myeloma agents and their possible additive action on the inhibition of proliferation and enhancement of apoptosis of different human myeloma cell lines. Material and methods: Human myeloma cell lines NCI-H929, RPMI 8226 and JJN3 (ADCC-LGC and DSMZ cell line collection) and Theil (a gift from Dr. K. Pulford, University of Oxford, UK) were treated with bortezomib (Millenium Pharmaceuticals), dexamethasone, cyclosporine and thalidomide (Sigma-Aldrich) for 48 hrs. Cell line proliferation was assessed by the colorimetric MTT assay, whereas viability and apoptosis were evaluated by annexin V/propidium iodide staining. Gene expression of pro-apoptotic (Bax and p21) and pro-survival molecules (Bcl-2 and c-Myc) was assessed by real-time AB7500 instrument (Applied Biosystems). Additionally, we assessed the expression of SPARC (secreted protein acidic and rich in cysteine), involved in the cell de-adhesion from BM matrix and tumor pathogenesis. Results: Anti-myeloma agents (dexamethasone, bortezomib and thalidomide) achieve their effects by different cellular mechanisms. In addition, cyclosporine was included for its ability to increase cell sensitivity to other cytostatics. Each cell line, representing different biological variant of MM, has shown unique pattern of the expression of pro- and anti-apoptotic genes and, in addition, responded differently to anti-myeloma treatment. The most potent additive effect of drug combinations, including thalidomide/bortezomib, thalidomide/cyclosporine and bortezomib/cyclosporine, was noticed on the cellular and molecular level, as suppressed proliferation and shift in the balance of pro- and anti-apoptotic genes. Conclusion: Resistance to apoptosis, common in myeloma cells, depends on the constitutive expression of molecules acting at cell-cycle checkpoints and activated intracellular pathways in the particular circumstances. We observed that the susceptibility of myeloma cells to specific treatment is determined by their intrinsic balance between pro-survival and pro-apoptotic factors. Certain drug combinations, specifically thalidomide or bortezomib with cyclosporine, decreased Bcl-2/Bax ratio, a key indicator of enhanced apoptosis. Our findings suggest that the insight into the molecular events in the affected clone could enable administration of a specific individualized therapy which would be more effective in eradicating the malignant clone.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

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