Aplidine for multiple myeloma treatment
a technology of multiple myeloma and aplidine, which is applied in the field of aplidine and analogues in the treatment of cancer, can solve the problems of renal failure, too many antibodies of one type, and many organ dysfunctions, and achieves potent in vitro activity, confirmed selectivity, and lack of severe myelosuppression.
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MTT Calorimetric Survival Assay
[0042] Cell survival was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT; Sigma Chemical, St Louis, Mo.) colorimetric assay, as previously described (Mitsiades C. S. et al. Blood. 2001, 98, 795-804; Mitsiades N. et al. Proc Natl Acad Sci USA. 2002, 99, 14374-14379; Mitsiades N. et al. Blood. 2003, 101, 2377-2380). Briefly, cells were plated in 48-well plates at 70% to 80% confluence in the presence of 2.5% fetal bovine serum (FBS) and in the presence of Aplidine at final concentration of 0-100 nM or DMSO vehicle control. At the end of each treatment, cells were incubated with 1 mg / mL MTT for 4 hours at 37° C.; a mixture of isopropanol and 1 N HCl (23:2, vol / vol) was then added under vigorous pipetting to dissolve the formazan crystals. Dye absorbance (A) in viable cells was measured at 570 nm, with 630 nm as a reference wavelength. Cell viability was estimated as a percentage of the value of untreated controls. Al...
example 2
Stable Transfections of Bcl-2 and Constitutively Active Akt
[0049] MM-1S cells were stably transfected with plasmid vector encoding myristoylated (constitutively active) Akt or Bcl-2 (Upstate Biotechnologies, Lake Placid, N.Y.) or with empty (neo) vectors, and were performed using Lipofectamine 2000 (Life Technologies), followed by cultures in G418-containing selection media, as previously described (Mitsiades C. S. et al. Oncogene. 2002, 21, 5673-5683; Mitsiades N. et al. Proc Natl Acad Sci USA. 2002, 99, 14374-14379).
Results: Aplidine Overcomes the Anti-Apoptotic Effect of Bcl-2 or Constitutively Active Akt
[0050] Because of the roles of Bcl-2 and the PI-3K / Akt cascade in the regulation of drug-induced apoptosis in MM and other neoplasias, we also characterized the activity of aplidine in MM-1S human MM cells stably transfected with Bcl-2 or myristoylated Akt constructs vs. empty vector-transfected control MM-1S cells. We observed that Bcl-2- or myrAkt-transfected cells did not...
example 3
[0051] Co-Culture Assays of MM Cells with Bone Marrow Stromal Cells (BMSCs)
[0052] When adhering to BMSCs, MM cells have reduced sensitivity to conventional anti-MM therapies, such as dexamethasone or cytotoxic chemotherapeutics (Chauhan D. et al. Blood. 1996, 87, 1104-1112). This form of drug resistance is considered a key reason why MM patients eventually relapse when they receive treatment based on administration of glucocorticoids and / or cytotoxic chemotherapy. In contrast, among recently developed therapies for MM, anti-tumor activity against in cases of chemo-resistant or steroid-resistant MM has been achieved by classes of drugs, e.g. proteasome inhibitors (Hideshima T. et al. Cancer Res. 2001, 61, 3071-3076), which can overcome the protective effects of BMSCs on MM cells. We therefore investigated whether aplidine can also overcome the molecular sequelae of the interaction of BMSCs with MM cells and achieve anti-MM activity in this context. We thus performed in vitro co-cult...
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