Induction of apoptosis by BIBF 1000 in MM cells
. | . | . | . | Apoptotic cells . | . | . | . | . | . | . | . | . | . | . | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| MM cell . | Karyotypic abnormalities . | FGFR3 +++ . | ras mutation . | Without BIBF 1000, % . | 500 nM BIBF 1000, % . | Increase over vehicle control, % . | P* . | 500 nM BIBF 1000 + IL-6, % . | P† . | 10 μM Dex, % . | P‡ . | 500 nM BIBF 1000 + 10 μM Dex, % . | Increase over Dex, % . | P§ . | ||||||||||
| KMS-11 | t(4;14), t(14;16) | + (Y373C) | — | 17.8 ± 3.4 | 41.9 ± 8.0 | 24.0 ± 4.8 | .011 | 33.6 ± 5.8 | NS | 22.8 ± 6.1 | NS | 52.2 ± 17.9 | 29.4 ± 7.8 | .025 | ||||||||||
| KMS-18 | t(4;14) | + (G384D) | — | 10.2 ± 2.5 | 37.5 ± 14.3 | 27.3 ± 10.7 | .008 | 31.8 ± 12.1 | NS | NA | NA | NA | ||||||||||||
| OPM-2 | t(4;14) | + (K650E) | — | 13.2 ± 3.5 | 39.1 ± 8.2 | 25.9 ± 6.2 | .026 | 24.0 ± 5.3 | NS | 26.0 ± 5.8 | NS | 70.4 ± 15.1 | 44.4 ± 9.7 | .05 | ||||||||||
| UTMC-2 | t(4;14) | + (wt) | — | 32.2 ± 3.6 | 44.8 ± 2.2 | 12.6 ± 5.9 | .035 | NA | 49.5 ± 1.5 | .018 | 58.6 ± 1.3 | 9.1 ± 3.0 | NS | |||||||||||
| NCI-H929 | t(4;14) | + (wt) | + N13 | 26.2 ± 2.3 | 30.4 ± 2.9 | 4.2 ± 1.4 | NS | NA | 33.5 ± 2.5 | .043 | 41.4 ± 4.0 | 7.8 ± 2.5 | NS | |||||||||||
| Pt 1∥ | t(4;14) | + | — | 21.6 | 32.5 | 10.9 | 26.8 | 28.9 | 40.7 | 11.8 | ||||||||||||||
| Pt 2∥ | t(4;14) | + | — | 9.8 | 54.5 | 44.7 | NA | NA | NA | |||||||||||||||
| Pt 3∥ | t(4;14) | + | — | 38.5 | 49.3 | 10.8 | 28.2 | 53.6 | 64.2 | 10.6 | ||||||||||||||
| MM1.S | t(14;16) | — | — | 20.4 ± 1.7 | 47.0 ± 3.0 | 26.6 ± 3.2 | < .001 | 31.9 ± 4.2 | .027 | 53.8 ± 3.9 | .001 | 82.2 ± 2.7 | 25.2 ± 4.2 | .001 | ||||||||||
| MM1.R | t(14;16) | — | — | 25.5 ± 2.9 | 40.8 ± 5.3 | 15.3 ± 5.3 | .019 | 38.9 ± 9.1 | NS | 25.6 ± 2.4 | NS | 37.8 ± 3.8 | 12.2 ± 2.5 | .050 | ||||||||||
| ANBL-6 | t(14;16) | — | — | 8.1 ± 0.5 | 10.2 ± 1.2 | 2.1 ± 1.1 | NS | NA | 29.2 ± 0.7 | .021 | 46.9 ± 0.9 | 17.7 ± 1.1 | .021 | |||||||||||
| JJN-3 | t(14;16) | — | — | 21.6 ± 3.8 | 17.2 ± 2.6 | —4.4 ± 1.6 | NS | NA | 36.9 ± 5.8 | NS | 44.6 ± 8.4 | 7.7 ± 3.4 | NS | |||||||||||
| OCI-My5 | t(14;16) | — | — | 31.2 ± 3.8 | 32.0 ± 2.7 | 0.8 ± 1.6 | NS | NA | 46.9 ± 10.3 | NS | 55.6 ± 10.0 | 8.7 ± 0.6 | NS | |||||||||||
| RPMI-8226 | t(16;22) | — | + K12 | 8.6 ± 2.7 | 8.7 ± 3.3 | 0.1 ± 3.3 | NS | 10.9 ± 2.4 | NS | 9.5 ± 1.4 | NS | 12.3 ± 1.7 | 2.8 ± 1.7 | NS | ||||||||||
| U-266 | — | — | — | 8.7 ± 1.2 | 10.8 ± 1.4 | 2.1 ± 0.6 | NS | 10.1 ± 1.5 | NS | 9.1 ± 1.5 | NS | 12.0 ± 1.8 | 2.9 ± 0.7 | NS | ||||||||||
| L363 | — | — | + N61 | 23.2 ± 3.2 | 24.5 ± 3.8 | 1.3 ± 1.5 | NS | NA | 22.3 ± 2.9 | NS | 23.2 ± 3.4 | 0.9 ± 0.7 | NS | |||||||||||
| Pt 4∥ | — | — | — | 17.8 | 33.6 | 15.8 | NA | NA | NA | NA | ||||||||||||||
| Pt 5∥ | — | — | — | 6.6 | 37.5 | 30.9 | 14.9 | NA | NA | NA | ||||||||||||||
| Pt 6∥ | — | — | — | 17.3 | 31.6 | 14.3 | NA | 34.8 | 59.5 | 24.7 | ||||||||||||||
| Pt 7∥ | — | — | — | 31.9 | 39.1 | 7.2 | NA | 60.7 | 71.9 | 11.2 | ||||||||||||||
| Pt 8∥ | — | — | — | 23.0 | 15.8 | —7.2 | NA | 29.4 | 27.7 | —1.7 | ||||||||||||||
| Pt 9∥ | — | — | NA | 8.8 | 8.9 | 0.1 | 7.6 | NA | NA | NA | ||||||||||||||
| Pt 10∥ | — | — | — | 25.3 | 28.5 | 3.2 | NA | NA | NA | NA | ||||||||||||||
| Pt 11∥ | — | — | NA | 8.9 | 9.9 | 1.0 | NA | 9.4 | 8.3 | —1.1 | ||||||||||||||
| Pt 12∥ | — | — | — | 6.8 | 9.2 | 2.4 | NA | 41.1 | 48.7 | 7.6 | ||||||||||||||
| Pt 13∥ | — | — | NA | 6.7 | 7.4 | 0.7 | 5.9 | 14.2 | 10.2 | —4.0 | ||||||||||||||
. | . | . | . | Apoptotic cells . | . | . | . | . | . | . | . | . | . | . | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| MM cell . | Karyotypic abnormalities . | FGFR3 +++ . | ras mutation . | Without BIBF 1000, % . | 500 nM BIBF 1000, % . | Increase over vehicle control, % . | P* . | 500 nM BIBF 1000 + IL-6, % . | P† . | 10 μM Dex, % . | P‡ . | 500 nM BIBF 1000 + 10 μM Dex, % . | Increase over Dex, % . | P§ . | ||||||||||
| KMS-11 | t(4;14), t(14;16) | + (Y373C) | — | 17.8 ± 3.4 | 41.9 ± 8.0 | 24.0 ± 4.8 | .011 | 33.6 ± 5.8 | NS | 22.8 ± 6.1 | NS | 52.2 ± 17.9 | 29.4 ± 7.8 | .025 | ||||||||||
| KMS-18 | t(4;14) | + (G384D) | — | 10.2 ± 2.5 | 37.5 ± 14.3 | 27.3 ± 10.7 | .008 | 31.8 ± 12.1 | NS | NA | NA | NA | ||||||||||||
| OPM-2 | t(4;14) | + (K650E) | — | 13.2 ± 3.5 | 39.1 ± 8.2 | 25.9 ± 6.2 | .026 | 24.0 ± 5.3 | NS | 26.0 ± 5.8 | NS | 70.4 ± 15.1 | 44.4 ± 9.7 | .05 | ||||||||||
| UTMC-2 | t(4;14) | + (wt) | — | 32.2 ± 3.6 | 44.8 ± 2.2 | 12.6 ± 5.9 | .035 | NA | 49.5 ± 1.5 | .018 | 58.6 ± 1.3 | 9.1 ± 3.0 | NS | |||||||||||
| NCI-H929 | t(4;14) | + (wt) | + N13 | 26.2 ± 2.3 | 30.4 ± 2.9 | 4.2 ± 1.4 | NS | NA | 33.5 ± 2.5 | .043 | 41.4 ± 4.0 | 7.8 ± 2.5 | NS | |||||||||||
| Pt 1∥ | t(4;14) | + | — | 21.6 | 32.5 | 10.9 | 26.8 | 28.9 | 40.7 | 11.8 | ||||||||||||||
| Pt 2∥ | t(4;14) | + | — | 9.8 | 54.5 | 44.7 | NA | NA | NA | |||||||||||||||
| Pt 3∥ | t(4;14) | + | — | 38.5 | 49.3 | 10.8 | 28.2 | 53.6 | 64.2 | 10.6 | ||||||||||||||
| MM1.S | t(14;16) | — | — | 20.4 ± 1.7 | 47.0 ± 3.0 | 26.6 ± 3.2 | < .001 | 31.9 ± 4.2 | .027 | 53.8 ± 3.9 | .001 | 82.2 ± 2.7 | 25.2 ± 4.2 | .001 | ||||||||||
| MM1.R | t(14;16) | — | — | 25.5 ± 2.9 | 40.8 ± 5.3 | 15.3 ± 5.3 | .019 | 38.9 ± 9.1 | NS | 25.6 ± 2.4 | NS | 37.8 ± 3.8 | 12.2 ± 2.5 | .050 | ||||||||||
| ANBL-6 | t(14;16) | — | — | 8.1 ± 0.5 | 10.2 ± 1.2 | 2.1 ± 1.1 | NS | NA | 29.2 ± 0.7 | .021 | 46.9 ± 0.9 | 17.7 ± 1.1 | .021 | |||||||||||
| JJN-3 | t(14;16) | — | — | 21.6 ± 3.8 | 17.2 ± 2.6 | —4.4 ± 1.6 | NS | NA | 36.9 ± 5.8 | NS | 44.6 ± 8.4 | 7.7 ± 3.4 | NS | |||||||||||
| OCI-My5 | t(14;16) | — | — | 31.2 ± 3.8 | 32.0 ± 2.7 | 0.8 ± 1.6 | NS | NA | 46.9 ± 10.3 | NS | 55.6 ± 10.0 | 8.7 ± 0.6 | NS | |||||||||||
| RPMI-8226 | t(16;22) | — | + K12 | 8.6 ± 2.7 | 8.7 ± 3.3 | 0.1 ± 3.3 | NS | 10.9 ± 2.4 | NS | 9.5 ± 1.4 | NS | 12.3 ± 1.7 | 2.8 ± 1.7 | NS | ||||||||||
| U-266 | — | — | — | 8.7 ± 1.2 | 10.8 ± 1.4 | 2.1 ± 0.6 | NS | 10.1 ± 1.5 | NS | 9.1 ± 1.5 | NS | 12.0 ± 1.8 | 2.9 ± 0.7 | NS | ||||||||||
| L363 | — | — | + N61 | 23.2 ± 3.2 | 24.5 ± 3.8 | 1.3 ± 1.5 | NS | NA | 22.3 ± 2.9 | NS | 23.2 ± 3.4 | 0.9 ± 0.7 | NS | |||||||||||
| Pt 4∥ | — | — | — | 17.8 | 33.6 | 15.8 | NA | NA | NA | NA | ||||||||||||||
| Pt 5∥ | — | — | — | 6.6 | 37.5 | 30.9 | 14.9 | NA | NA | NA | ||||||||||||||
| Pt 6∥ | — | — | — | 17.3 | 31.6 | 14.3 | NA | 34.8 | 59.5 | 24.7 | ||||||||||||||
| Pt 7∥ | — | — | — | 31.9 | 39.1 | 7.2 | NA | 60.7 | 71.9 | 11.2 | ||||||||||||||
| Pt 8∥ | — | — | — | 23.0 | 15.8 | —7.2 | NA | 29.4 | 27.7 | —1.7 | ||||||||||||||
| Pt 9∥ | — | — | NA | 8.8 | 8.9 | 0.1 | 7.6 | NA | NA | NA | ||||||||||||||
| Pt 10∥ | — | — | — | 25.3 | 28.5 | 3.2 | NA | NA | NA | NA | ||||||||||||||
| Pt 11∥ | — | — | NA | 8.9 | 9.9 | 1.0 | NA | 9.4 | 8.3 | —1.1 | ||||||||||||||
| Pt 12∥ | — | — | — | 6.8 | 9.2 | 2.4 | NA | 41.1 | 48.7 | 7.6 | ||||||||||||||
| Pt 13∥ | — | — | NA | 6.7 | 7.4 | 0.7 | 5.9 | 14.2 | 10.2 | —4.0 | ||||||||||||||
Data represent means ± SE of 3 independent experiments for each type of myeloma cell lines (unless there was only a single experiment for each patient sample). PBBLs indicate peripheral blood B lymphocytes obtained from 5 healthy volunteers; Dex, dexamethasone; IL-6, interleukin-6, FGFR3, fibroblast growth factor receptor 3. Data for apoptotic PBBLs: without BIBF 1000, 4.6% ± 1.0%; with 250 nM BIBF 1000, 5.0% ± 0.5%; with 500 nM BIBF 1000, 5.1% ± 0.5%; and with 1000 nm BIBF 1000, 5.9% ± 0.7%.
NA indicates not available; NS, not significant; —, negative for t(4;14), t(14;16), and t(16;22) (column 2); FGFR3 not overexpressed (column 3); or not ras mutated (column 4).
P value of 500 nM BIBF 1000 versus vehicle control
P value of 500 nM BIBF 1000 + IL-6 versus 500 nM BIBF 1000
P value of 10 μM Dex versus vehicle control
P value of 500 nM BIBF 1000 + 10 μM Dex versus Dex alone (10 μM)
CD138+ sorted cells from patients with MM