Vorinostat abolishes multicellular resistance of spheroids.
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(A) Four mesothelioma cell lines (M28, REN, SARC and VAMT) were grown as monolayers and spheroids and treated with bortezomib (25 nM), vorinostat (5 µM) or their combination for 24 h. Apoptosis was measured by analysis of nuclear condensation in Hoechst-stained cells. Spheroids grown from all the cell lines acquired multicellular resistance to bortezomib, a resistance that was effectively eliminated by the addition of vorinostat. Both vorinostat and bortezomib induced little apoptosis in spheroids when given alone. (* p<0.05 as compared to bortezomib alone, n = 3) (B) Apoptosis was confirmed by CaspaseGlo 3/7 assay in M28 and REN spheroids, treated with either bortezomib (25 nM), vorinostat (5 µM) or their combination for 24 h. Vorinostat had no effect on spheroids but increased their apoptotic response to bortezomib (* p<0.05 as compared to bortezomib or vorinostat alone, n = 3) (C–D) Bright field 10× images of the edge of M28 and REN spheroids treated with vorinostat, bortezomib or the combination for 24 h. Whereas vorinostat or bortezomib alone induced little or no morphologic change, the combination potently increased the number of cells detaching from the spheroids and floating in the medium. (Focus was adjusted in the lower panels to visualize some of these floating cells).