Targeting sphingolipid metabolism with the sphingosine kinase inhibitor SKI-II overcomes hypoxia-induced chemotherapy resistance in glioblastoma cells: effects on cell death, self-renewal, and invasion

Table 1 Combination analysis of temozolomide (TMZ) and the sphingosine kinase inhibitor SKI-II

Drug Combo	TMZ (µM)	SKI-II (µM)	21% O₂			3% O₂
Drug Combo	TMZ (µM)	SKI-II (µM)	Fa	CI	Degree	Fa	CI	Degree
A1	24.0	0.33	0.52	0.43	+ + +	0.32	0.97	±
A2	48.0	0.33	0.64	0.24	+ + + +	0.44	0.51	+ + +
A3	96.0	0.33	0.70	0.18	+ + + +	0.49	0.48	+ + +
B1	24.0	0.66	0.60	0.39	+ + +	0.41	0.84	+ +
B2	48.0	0.66	0.65	0.33	+ + +	0.46	0.75	+ +
B3	96.0	0.66	0.71	0.26	+ + + +	0.48	0.79	+ +
C1	24.0	1.33	0.60	0.70	+ +	0.50	1.02	±
C2	48.0	1.33	0.67	0.51	+ + +	0.53	0.95	±
C3	96.0	1.33	0.69	0.50	+ + +	0.54	0.95	±
D1	24.0	2.66	0.76	0.52	+ + +	0.76	0.57	+ + +
D2	48.0	2.66	0.79	0.45	+ + +	0.78	0.51	+ + +
D3	96.0	2.66	0.81	0.40	+ + +	0.80	0.44	+ + +
E1	24.0	5.32	0.86	0.50	+ + +	0.87	0.50	+ + +
E2	48.0	5.32	0.87	0.49	+ + +	0.86	0.54	+ + +
E3	96.0	5.32	0.87	0.48	+ + +	0.87	0.51	+ + +

NCH82 cells were treated with 15 combinations of TMZ and SKI-II for 5 days under normoxia (21% O2) and hypoxia (3% O2). Combination Index (CI) was calculated from the CI equation algorithms using CompuSyn software. CI = 1, < 1 and > 1 indicates additive effect, synergism and antagonism, respectively. Fraction affected (Fa) and CI values of each drug combination were obtained from the average of three independent experiments. Graded symbols were attributed to the CI values to depict the degree of synergism of each combination, as suggested by Ting-Chau Chou (27): + + + + , strong synergism; + + + , synergism; + + , moderate synergism; ± , nearly additive

ISSN: 1471-2407