Aloe emodin decreases the ERK-dependent anticancer activity of cisplatin.
The present study describes the ability of an anthraquinone derivative aloe emodin (AE) to reduce the cytotoxic activity of the platinum(II)-based anticancer agent cisplatin toward murine L929 fibrosarcoma and C6 glioma cell lines. The protective effect of AE was demonstrated by MTT and crystal violet assays for cell viability, and involved supression of cisplatin-induced apoptosis and necrosis, as assessed by lactate dehydrogenase release and flow cytometric analysis of DNA fragmentation or phosphatidylserine exposure. Cell-based ELISA and Western blot analysis revealed that AE abolished cisplatin-triggered activation of extracellular signal-regulated kinase (ERK) in tumor cells, while activation of c-Jun N-terminal kinase was not significantly altered. A selective blockade of ERK activation with PD98059 mimicked the protective effect of AE treatment in both tumor cell lines. Moreover, AE failed to protect tumor cells against the ERK-independent toxicity of the Pt(IV)-based complex tetrachloro(O,O-dibutyl-ethylenediamine-N,N'-di-3-propanoate)platinum(IV). Taken together, these data indicate that herbal anthraquinone AE can downregulate the anticancer activity of cisplatin by blocking the activation of ERK in tumor cells.
Mijatovic
S
S
Department of Neurobiology and Immunology, Institute for Biological Research, 11000 Belgrade, Serbia and Montenegro.
Maksimovic-Ivanic
D
D
Radovic
J
J
Miljkovic
D
D
Kaludjerovic
G N
GN
Sabo
T J
TJ
Trajkovic
V
V
D000818:Animals; D000880:Anthraquinones; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004642:Emodin / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D005419:Flavonoids / Q000494:pharmacology; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D010984:Platinum / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship
D000880:Anthraquinones; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010984:Platinum; C518327:aloe emodin; D048049:Extracellular Signal-Regulated MAP Kinases; D004642:Emodin; D002945:Cisplatin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one