Jacaranone induces apoptosis in melanoma cells via ROS-mediated downregulation of Akt and p38 MAPK activation and displays antitumor activity in vivo.
BACKGROUND
Malignant melanoma is a deadly type of metastatic skin cancer with increased incidence over the past 30 years. Despite the advanced knowledge on the biology, immunobiology and molecular genetics of melanoma, the alternatives of treatment are limited with poor prognosis. On clinical trials, natural products and among them redox-active quinones have been tested in the attempt to control the growth of cancer cells. Recently, we isolated jacaranone from Pentacalia desiderabilis, a benzoquinone derivative that showed a broad antitumor activity and protective anti-melanoma effect in a syngeneic model. The purified substance is active at micromolar concentrations, is not hemolytic, and is not toxic in naïve mice.


RESULTS
The jacaranone antitumor activity was shown against several human cancer cell lines in vitro. Moreover, the induction of apoptosis in murine melanoma cells and jacaranone antitumor activity in vivo, in a melanoma experimental model, were also shown. Jacaranone renders antiproliferative and proapoptotic responses in tumor cells, by acting on Akt and p38 MAPK signaling pathways through generation of reactive oxygen species (ROS). The free radical scavenger N-acetyl-cysteine (NAC) was able to completely suppress cell death induced by jacaranone as it blocked Akt downregulation, p38 MAPK activation as well as upregulation of proapoptotic Bax. Notably, treatment of melanoma growing subcutaneously in mice with jacaranone significantly extended the mean survival times in a dose-dependent manner.


CONCLUSIONS
The results provide evidence for the mechanisms of action of jacaranone and emphasize the potential use of this quinone for the treatment of melanoma.
Unidade de Oncologia Experimental, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil.
Mariana H
MH
Massaoka
Alisson L
AL
Matsuo
Carlos R
CR
Figueiredo
Camyla F
CF
Farias
Natália
N
Girola
Denise C
DC
Arruda
Jorge A B
JA
Scutti
Paulete
P
Romoff
Oriana A
OA
Favero
Marcelo J P
MJ
Ferreira
João H G
JH
Lago
Luiz R
LR
Travassos
D000111:Acetylcysteine; D000818:Animals; D017304:Annexin A5; D000970:Antineoplastic Agents / Q000032:analysis / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D019659:Asteraceae / Q000737:chemistry*; D016227:Benzoquinones / Q000032:analysis / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D003124:Colorimetry; D015536:Down-Regulation; D006801:Humans; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D019906:Nuclear Magnetic Resonance, Biomolecular; D008517:Phytotherapy / Q000379:methods*; D010936:Plant Extracts / Q000494:pharmacology*; D011419:Propidium; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013481:Superoxides; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D017304:Annexin A5; D000970:Antineoplastic Agents; D016227:Benzoquinones; D002843:Chromatin; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D013481:Superoxides; D011419:Propidium; C013077:jacaranone; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D000111:Acetylcysteine