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Jacaranone induces apoptosis in melanoma cells via ROS-mediated downregulation of Akt and p38 MAPK activation and displays antitumor activity in vivo.

Massaoka MH, Matsuo AL, Figueiredo CR, Farias CF, Girola N, Arruda DC, Scutti JA, Romoff P, Favero OA, Ferreira MJ, Lago JH, Travassos LR - PLoS ONE (2012)

Bottom Line: 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.The results provide evidence for the mechanisms of action of jacaranone and emphasize the potential use of this quinone for the treatment of melanoma.

View Article: PubMed Central - PubMed

Affiliation: Unidade de Oncologia Experimental, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil.

ABSTRACT

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.

Methodology/principal findings: 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/significance: The results provide evidence for the mechanisms of action of jacaranone and emphasize the potential use of this quinone for the treatment of melanoma.

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Related in: MedlinePlus

Chemical structure of jacaranone isolated from leaves of P. desiderabilis.
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pone-0038698-g001: Chemical structure of jacaranone isolated from leaves of P. desiderabilis.

Mentions: The cytotoxicity of jacaranone [Methyl (1-hydroxy-4-oxo-2,5-cyclohexandienyl) acetate] (Fig. 1) was determined on human cancer cell lines and the murine melanoma B16F10-Nex2 cell line. In all tested cell lines jacaranone induced cell death in vitro in a dose-dependent manner and showed different degrees of cytotoxicity. As observed in Table 1, IC50 values (the concentration of jacaranone that reduced cell survival by 50%) varied from 9 to 145 µM for human cancer cells. The IC50 for murine melanoma B16F10-Nex2 was 17 µM.


Jacaranone induces apoptosis in melanoma cells via ROS-mediated downregulation of Akt and p38 MAPK activation and displays antitumor activity in vivo.

Massaoka MH, Matsuo AL, Figueiredo CR, Farias CF, Girola N, Arruda DC, Scutti JA, Romoff P, Favero OA, Ferreira MJ, Lago JH, Travassos LR - PLoS ONE (2012)

Chemical structure of jacaranone isolated from leaves of P. desiderabilis.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368838&req=5

pone-0038698-g001: Chemical structure of jacaranone isolated from leaves of P. desiderabilis.
Mentions: The cytotoxicity of jacaranone [Methyl (1-hydroxy-4-oxo-2,5-cyclohexandienyl) acetate] (Fig. 1) was determined on human cancer cell lines and the murine melanoma B16F10-Nex2 cell line. In all tested cell lines jacaranone induced cell death in vitro in a dose-dependent manner and showed different degrees of cytotoxicity. As observed in Table 1, IC50 values (the concentration of jacaranone that reduced cell survival by 50%) varied from 9 to 145 µM for human cancer cells. The IC50 for murine melanoma B16F10-Nex2 was 17 µM.

Bottom Line: 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.The results provide evidence for the mechanisms of action of jacaranone and emphasize the potential use of this quinone for the treatment of melanoma.

View Article: PubMed Central - PubMed

Affiliation: Unidade de Oncologia Experimental, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil.

ABSTRACT

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.

Methodology/principal findings: 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/significance: The results provide evidence for the mechanisms of action of jacaranone and emphasize the potential use of this quinone for the treatment of melanoma.

Show MeSH
Related in: MedlinePlus