Cytochalasin D, LY294002 and olomoucine synergize in promoting death of melanoma cells through activation of caspase-3 and apoptosis.
Many of the current anticancer therapies rely on the induction of apoptosis, and several mechanisms that protect cells against apoptosis may be upregulated in tumors. A growing body of evidence suggests that single drugs with a clearly defined intracellular target may be less efficient in arresting tumor growth and induction of apoptosis than multitargeted strategies. To prove that this is also the case for melanoma, we studied five cell lines, which represent different stages of tumor progression. We tested cell viability, terminal dUTP nick-end labeling and activation of caspase-3 upon exposure to cytochalasin D, LY294002 and olomoucine, added either alone or in various combinations. The obtained data were compared with effects caused by staurosporine. The results show that whereas staurosporine efficiently induced apoptosis in all tested melanoma cell lines, the other drugs had only moderate effects when administered alone. In contrast, the combinations of drugs were more effective in inducing caspase-3 activity and reducing cell viability. In particular, the triple combination of cytochalasin D+LY294002+olomoucine was almost as effective as staurosporine in inducing caspase-3 activity and apoptosis. These results prove that it is possible to design new pharmacological strategies that will effectively induce caspase-3 activity and apoptosis in melanoma. The possible explanations of the observed synergy between the tested drugs are also discussed.
Małecki
Jedrzej Mieczyslaw
JM
Jagiellonian University, Medical College, Kraków, Poland. jedrek13@yahoo.com
Bentke
Anna
A
Ostrowska
Barbara
B
Laidler
Piotr
P
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000008:administration & dosage / Q000494:pharmacology*; D015638:Cytochalasin D / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D007701:Kinetin / Q000008:administration & dosage / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D019311:Staurosporine / Q000494:pharmacology; D015854:Up-Regulation
D002867:Chromones; D009025:Morpholines; D015638:Cytochalasin D; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C090046:olomoucine; D053148:Caspase 3; D019311:Staurosporine; D007701:Kinetin