No abstract

No abstract

Despite recent advances in the treatment of multiple myeloma, patients with this disease still inevitably relapse and become refractory to existing therapies. Mutations in K-RAS, N-RAS and B-RAF are common in multiple myeloma, affecting 50% of patients at diagnosis and >70% at relapse. However, targeting mutated RAS/RAF via MEK inhibition is merely cytostatic in myeloma and largely ineffective in the clinic. We examined mechanisms mediating this resistance and identified histone deacetylase inhibitors as potent synergistic partners. Combining the MEK inhibitor AZD6244 (selumetinib) with the pan-histone deacetylase inhibitor LBH589 (panobinostat) induced synergistic apoptosis in RAS/RAF mutated multiple myeloma cell lines. Interestingly, this synergy was dependent on the pro-apoptotic protein BIM. We determined that while single-agent MEK inhibition increased BIM levels, the protein remained sequestered by antiapoptotic BCL-2 family members. LBH589 dissociated BIM from MCL-1 and BCL-XL, which allowed it to bind BAX/BAK and thereby initiate apoptosis. The AZD6244/LBH589 combination was specifically active in cell lines with more BIM:MCL-1 complexes at baseline; resistant cell lines had more BIM:BCL-2 complexes. Those resistant cell lines were synergistically killed by combining the BH3 mimetic ABT-199 (venetoclax) with LBH589. Using more specific histone deacetylase inhibitors, i.e. MS275 (entinostat) and FK228 (romidepsin), and genetic methods, we determined that concomitant inhibition of histone deacetylases 1 and 2 was sufficient to synergize with either MEK or BCL-2 inhibition. Furthermore, these drug combinations effectively killed plasma cells from myeloma patients ex vivo. Given the preponderance of RAS/RAF mutations, and the fact that ABT-199 has demonstrated clinical efficacy in relapsed/refractory multiple myeloma, these drug combinations hold prom ise as biomarker-driven therapies.

Graft copolymers and networks of gelatin were synthesized with three acrylamides (acrylamide, 2-acrylamido-2-methyl-1-propanesulfonic acid, and N-iso-propylacrylamide) by using a redox initiator system consisting of ammonium peroxysulfate-ferrous ammonium sulfate in either the absence or the presence of a crosslinker (N,Nmethylene bisacrylamide) at two temperatures. Characterization of synthesized polymers was studied by FTIR and thermal studies to investigate evidence of grafting or interpenetrating network formation and to investigate the effect of reaction conditions and crosslinker concentration on the properties of synthesized polymers. Detailed investigation into water-uptake properties of these hydrogels was carried out as a function of time, temperature, and pH. The inherent properties of the monomer incorporated onto gelatin collectively act as determinant of the water-absorption behavior of the hydrogels. Sorption of Fe ϩ2 , Cr ϩ6 , and Cu ϩ2 ions from their aqueous solutions was also studied on select hydrogels, where it was observed that metal ions are sorbed by effective partitioning between hydrogels and solution phase and apart from the nature of metal ions, and structural aspects of hydrogels also determine the quantum of metal ion uptake.