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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

Jacaranone treatment of B16F10-Nex2 cells inhibited Akt pathway activation through ROS generation.Whole-cell extracts from B16F10-Nex2 exposed to 0 (control), 20 or 50 µM jacaranone (Jac) in the presence (A) or absence (B) of NAC were subjected to Western blotting and probed with phospho-p38, phospho-Akt, total Akt, total p38 and Bax antibodies. Protein levels were normalized to the actin level.
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pone-0038698-g005: Jacaranone treatment of B16F10-Nex2 cells inhibited Akt pathway activation through ROS generation.Whole-cell extracts from B16F10-Nex2 exposed to 0 (control), 20 or 50 µM jacaranone (Jac) in the presence (A) or absence (B) of NAC were subjected to Western blotting and probed with phospho-p38, phospho-Akt, total Akt, total p38 and Bax antibodies. Protein levels were normalized to the actin level.

Mentions: Akt is a serine/threonine kinase that stimulates cell proliferation, inhibits apoptosis and has been associated with melanoma progression and prognosis [21]. In this context, Govindarajan et al. demonstrated that melanoma cells overexpressing Akt led to rapidly growing tumors in vivo[22]. To determine whether downregulation of Akt is involved in jacaranone-induced apoptosis in B16F10-Nex2, we evaluated the phosphorylation status of Akt using Western blotting analysis. As shown (Fig. 5A), phosphorylated Akt (p-Akt) was detected in lysates of non-treated cells and treatment with jacaranone reduced the level of p-Akt in a dose-dependent manner. Interestingly, the expression of total Akt was abolished in cells treated with 50 µM jacaranone, suggesting protein degradation at this concentration.


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)

Jacaranone treatment of B16F10-Nex2 cells inhibited Akt pathway activation through ROS generation.Whole-cell extracts from B16F10-Nex2 exposed to 0 (control), 20 or 50 µM jacaranone (Jac) in the presence (A) or absence (B) of NAC were subjected to Western blotting and probed with phospho-p38, phospho-Akt, total Akt, total p38 and Bax antibodies. Protein levels were normalized to the actin level.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038698-g005: Jacaranone treatment of B16F10-Nex2 cells inhibited Akt pathway activation through ROS generation.Whole-cell extracts from B16F10-Nex2 exposed to 0 (control), 20 or 50 µM jacaranone (Jac) in the presence (A) or absence (B) of NAC were subjected to Western blotting and probed with phospho-p38, phospho-Akt, total Akt, total p38 and Bax antibodies. Protein levels were normalized to the actin level.
Mentions: Akt is a serine/threonine kinase that stimulates cell proliferation, inhibits apoptosis and has been associated with melanoma progression and prognosis [21]. In this context, Govindarajan et al. demonstrated that melanoma cells overexpressing Akt led to rapidly growing tumors in vivo[22]. To determine whether downregulation of Akt is involved in jacaranone-induced apoptosis in B16F10-Nex2, we evaluated the phosphorylation status of Akt using Western blotting analysis. As shown (Fig. 5A), phosphorylated Akt (p-Akt) was detected in lysates of non-treated cells and treatment with jacaranone reduced the level of p-Akt in a dose-dependent manner. Interestingly, the expression of total Akt was abolished in cells treated with 50 µM jacaranone, suggesting protein degradation at this concentration.

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