Multiple antimelanoma potential of dry olive leaf extract.
Various constituents of the olive tree (Olea europaea) have been traditionally used in the treatment of infection, inflammation, prevention of chronic diseases, cardiovascular disorders and cancer. The anticancer potential of dry olive leaf extract (DOLE) represents the net effect of multilevel interactions between different biologically active compounds from the extract, cancer cells and conventional therapy. In this context, it was of primary interest to evaluate the influence of DOLE on progression of the highly malignant, immuno- and chemoresistant type of skin cancer-melanoma. DOLE significantly inhibited proliferation and subsequently restricted clonogenicity of the B16 mouse melanoma cell line in vitro. Moreover, late phase tumor treatment with DOLE significantly reduced tumor volume in a syngeneic strain of mice. DOLE-treated B16 cells were blocked in the G(0) /G(1) phase of the cell cycle, underwent early apoptosis and died by late necrosis. At the molecular level, the dying process started as caspase dependent, but finalized as caspase independent. In concordance, overexpression of antiapoptotic members of the Bcl-2 family, Bcl-2 and Bcl-XL, and diminished expression of their natural antagonists, Bim and p53, were observed. Despite molecular suppression of the proapoptotic process, DOLE successfully promoted cell death mainly through disruption of cell membrane integrity and late caspase-independent fragmentation of genetic material. Taken together, the results of this study indicate that DOLE possesses strong antimelanoma potential. When DOLE was applied in combination with different chemotherapeutics, various outcomes, including synergy and antagonism, were observed. This requires caution in the use of the extract as a supplementary antitumor therapeutic.
Mijatovic
Sanja A
SA
Department of Immunology, Institute for Biological Research, Belgrade University, Belgrade, Serbia. sanjamama@yahoo.com
Timotijevic
Gordana S
GS
Miljkovic
Djordje M
DM
Radovic
Julijana M
JM
Maksimovic-Ivanic
Danijela D
DD
Dekanski
Dragana P
DP
Stosic-Grujicic
Stanislava D
SD
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D008297:Male; D008546:Melanoma, Experimental / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D031658:Olea / Q000737:chemistry*; D010936:Plant Extracts / Q000494:pharmacology*; D018515:Plant Leaves / Q000737:chemistry*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000473:pathology / Q000517:prevention & control*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D010936:Plant Extracts; D012333:RNA, Messenger; D020169:Caspases