Figure 1: Examples of clinically used anti-multiple myeloma drugs
|
HEK COX-1 |
untreated |
MOF |
DEX |
THA |
DEX+MOF |
THA+MOF |
NCI-H929 |
1(100) |
0.06(6) |
0.085(8.5) |
0.13(13) |
0.10(10) |
0.09(9) |
0.17(17) |
SK-MM-2 |
1(100) |
0.03(3) |
0.09(9) |
0.60(60) |
0.25(25) |
0.28(28) |
0.50(50) |
Table 1: COX-1 expression in treated NCI-H929 and SK-MM-2 cell lines
Values are related to the positive control HEK-COX-1, to which the value 1 was assigned. In parenthesis, the percentage (%) of COX-1 expression with respect to the 100% of HEK-COX-1 is reported
EC50 (μM)a |
|||||
|
ATP |
Pappc |
|||
|
MDR1 |
MRP1 |
BCRP (%)b |
|
|
MOF |
NA |
NA |
NA |
NO |
2.3 ± 0.2 |
ASA |
NA |
NA |
NA |
NO |
1.9 ± 0.3 |
CEL |
87 ± 1.2 |
3.47 ± 0.3 |
37b |
NO |
5.9 ± 1.1 |
SC |
30.8 ± 1.5 |
24.5 ± 0.4 |
32b |
NO |
6.3 ± 0.8 |
Table 2: P-gp interacting mechanism of COX inhibitors.
aValues are the means ± SEM of three independent experiments carried out in triplicate. bPercentage of activity. cApparent permeability ratio (the value is from two independent experiments). NA: not active; NO: no ATP consumption.
Figure 1: Examples of clinically used anti-multiple myeloma drugs
Figure 2: Chemical structures of some COXs inhibitors and their Selectivity Index (SI). SI corresponds to the ratio COX-2 IC50/COX-1 IC50. SI values higher than 1 means that the compound is a selective COX-1 inhibitor [8-10]
Figure 3: Adjusted image of Western blotting experiments depicting the expression of COX-1 and COX-2 isoenzymes determined by Western blotting. Original gel blots are reported in Supplementary Materials
Figure 4: Hypotesis of COX activation in a BMSCs milieu, in turn permissive for MM cells proliferation, angiogenesis inducer, metastasis and drug resistrance development. COXs structures used are PDB: 6Y3C for COX-1 [46] and PDB:1CVU for COX-2 [47]
Figure 5: Expression of COXs in BMSCs upon treatment with mofezolac alone or in combination with BRZ, DEX or THA. Cells were incubated for 48 hours with (+) or without (-) 100 μM MOF, 100 μM CEL, 100 μM DEX, 100 μM THA, 300 nM BRZ. 30 μg of protein extract were applied to Western blot. The protein level of β-actin was used as the loading control. HEK-293 COX-1 cells are the positive control. Original blots are in the Supporting Materials
Figure 6: Anti-proliferative activity of anti-MM drugs alone or added with COXs inhibitors on hBMSCs growth
Tables at a glance
Figures at a glance