ABAB p53 caffeine doxo - - - 24h 48h - + + - + Casp8 Casp10 FADD FLIP Bcl-2 BIM BID PUMA Bax Bak XIAP cIAP-1 cIAP-2 GAPDH MFI untreated 3,3x10 3 MFI doxo.

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ABAB p53 caffeine doxo h 48h Casp8 Casp10 FADD FLIP Bcl-2 BIM BID PUMA Bax Bak XIAP cIAP-1 cIAP-2 GAPDH MFI untreated 3,3x10 3 MFI doxo 9,8x10 3 MFI untreated 3,3x10 3 MFI caffeine +doxo 8,6x10 3 SHEP Supplementary Figure 1 MFI isotype 1,1x10 2 MFI isotype 1,1x10 3 events DR5-APC isotype untreated doxo events DR5-APC isotype untreated caffeine +doxo

CDCD events DR5-APC events DR5-APC MFI doxo 7,2x10 3 MFI doxo 1,3x10 4 DR5 expression of cells in G0/G1 DR5 expression of cells in G2 SHEP Supplementary Figure 1 SHEP events DR5-FITC specific apoptosis (%) mock DR5 overexpression NS TRAIL     MFI mock 6,7x10 0 MFI DR5 overexpression 3,6x10 1 MFI isotyp 2,7x10 0 isotyp mock DR5 overexpression

specific apoptosis (%) control caffeine untreated TRAIL doxo doxo+TRAIL * NS A * HCT116 Supplementary Figure 2

BCBC Casp8 Casp10 FADD FLIP Bcl-2 Bcl-XL BIM BID NOXA Bax Bak XIAP cIAP-2 GAPDH p53 caffeine doxo h 48h events DR5-APC isotyp untreated doxo events DR5-APC isotyp untreated caffeine +doxo MFI untreated 1,8x10 3 MFI doxo 4,9x10 3 MFI untreated 1,8x10 3 MFI caffeine +doxo 2,8x10 3 HCT116 Supplementary Figure 2 MFI isotyp 1,4x10 2

D events k propidium iodide events k propidium iodide events k propidium iodide events k propidium iodide 25,4%78,4% 24,8%27,2% untreated doxo caffeine caffeine+doxo HCT116 Supplementary Figure 2

E p-HistonH3 Ser k propidium iodide p-HistonH3 Ser k propidium iodide p-HistonH3 Ser k propidium iodide p-HistonH3 Ser k propidium iodide ,6% 21,8% 0,2% 78,2% 3,1% 21,7% 3,8% 23,4% untreated doxo caffeine caffeine+doxo HCT116 Supplementary Figure 2

ABAB events DR5-APC isotype untreated dexa events DR5-APC isotype untreated caffeine +dexa MFI untreated 3,3x10 3 MFI dexa 4,6x10 3 MFI untreated 3,3x10 3 MFI caffeine +dexa 4,3x10 3 events DR5-APC isotype untreated MTX events DR5-APC isotype untreated caffeine +MTX MFI untreated 3,3x10 3 MFI MTX 1,1x10 5 MFI untreated 3,3x10 3 MFI caffeine +MTX 6,4x10 4 SHEP Supplementary Figure 3 MFI isotype 1,1x10 2 MFI isotype 1,1x10 2 MFI isotype 1,1x10 2 MFI isotype 1,1x10 2

HCT116 Supplementary Figure 4 TRAIL 1,0 0,75 0,5 0,25 0 FCS withdrawel 0 0,25 0,5 0,75 1,0 TRAIL 1,0 0,75 0,5 0,25 0 mimosine 0 0,25 0,5 0,75 1,0

HCT116 Supplementary Figure 4 TRAIL 1,0 0,75 0,5 0,25 0 irradiation 0 0,25 0,5 0,75 1,0

Supplementary Figure 5 A B events (%) k propidium iodide mock sicyclinE mock sicyclinB events (%) k propidium iodide cyclinE cyclinB parental sicyclinB sicyclinE GAPDH HCT specific apoptosis (%) mock sicyclinB sicyclinE * TRAIL       *

A B events (%) k propidium iodide mock sicyclinE mock sicyclinB events (%) k propidium iodide cyclinE cyclinB parental sicyclinB sicyclinE GAPDH CEM Supplementary Figure specific apoptosis (%) mock sicyclinB sicyclinE * TRAIL       *

A events k propidium iodide events k propidium iodide events k propidium iodide events k propidium iodide 11,4%19,1% 10,9%10,7% untreated doxo caffeine caffeine+doxo ALL-199 Supplementary Figure 7

BCBC untreated TRAIL doxo doxo+TRAIL * NS specific apoptosis (%) control caffeine specific apoptosis (%) control caffeine untreated TRAIL doxo doxo+TRAIL * NS * * ALL-199 ALL-4S Supplementary Figure 7

D cyclinE cyclinB parental sicyclinB sicyclinE GAPDH ALL-199 Supplementary Figure specific apoptosis (%) mock sicyclinB sicyclinE * TRAIL       *

Supplementary Figure 7 E cyclinE cyclinB parental sicyclinB sicyclinE GAPDH ALL-4S 25 0 specific apoptosis (%) mock sicyclinB sicyclinE * TRAIL       *