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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: The jacaranone antitumor activity was shown against several human cancer cell lines in vitro.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.

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 increased survival of B16F10-Nex2 tumor-bearing mice.Animals (5 mice per group) were subcutaneously injected with 5×104 cells and treated with PBS, 0.8 mg/kg or 4 mg/kg of jacaranone on alternate days. Intraperitoneal therapy began one day after inoculation of melanoma cells and was extended for 14 days. Mean survival times were 23.4±2.1 days for untreated tumor control group, 29±4.3 days (p = 0.05) for 0.8 mg/kg of jacaranone-treated group, and 34±3.6 days (*p<0.01) for 4 mg/kg jacaranone-treated group.
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pone-0038698-g006: Jacaranone increased survival of B16F10-Nex2 tumor-bearing mice.Animals (5 mice per group) were subcutaneously injected with 5×104 cells and treated with PBS, 0.8 mg/kg or 4 mg/kg of jacaranone on alternate days. Intraperitoneal therapy began one day after inoculation of melanoma cells and was extended for 14 days. Mean survival times were 23.4±2.1 days for untreated tumor control group, 29±4.3 days (p = 0.05) for 0.8 mg/kg of jacaranone-treated group, and 34±3.6 days (*p<0.01) for 4 mg/kg jacaranone-treated group.

Mentions: To determine the effect of jacaranone on tumor development in vivo, we used a well-established syngeneic murine melanoma model. B16F10-Nex2 cells were injected subcutaneously into the right flanks of C57BL/6 mice and tumor growth was measured daily. Two treatment groups of 5 mice received 0.8 and 4 mg/kg of jacaranone intraperitoneally every other day for 14 days. A control group received 100 μL of normal saline solution. Mice were removed from the therapy study and sacrificed when tumor size exceeded 3,000 mm3. The survival rate (percent value of the number of mice with tumor growth and the total number of mice inoculated in the group) was monitored every day. Treatment of melanoma-bearing mice with 0.8 and 4 mg/kg of jacaranone resulted in a dose-dependent protective effect (Fig. 6). The mean survival times of tumor mice in the 0.8 and 4 mg/kg jacaranone treatment groups were extended to 29±4.3 days (p = 0.05) and 34±3.6 days (*p <0.01), respectively, compared with the 23.4±2.1 days of the control group. Moreover, we noted that jacaranone-treated animals maintained healthy physical appearance, normal activity levels and healthy normal-weight throughout the study period. The result shown with 4 mg/kg of jacaranone was confirmed by a second experiment with a group of 6 animals. A positive control with doxorubicin was included which rendered 84% survival of challenged animals (data not shown). Furthermore, no hemolytic activity was detected with jacaranone treatment as described previously [7].


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 increased survival of B16F10-Nex2 tumor-bearing mice.Animals (5 mice per group) were subcutaneously injected with 5×104 cells and treated with PBS, 0.8 mg/kg or 4 mg/kg of jacaranone on alternate days. Intraperitoneal therapy began one day after inoculation of melanoma cells and was extended for 14 days. Mean survival times were 23.4±2.1 days for untreated tumor control group, 29±4.3 days (p = 0.05) for 0.8 mg/kg of jacaranone-treated group, and 34±3.6 days (*p<0.01) for 4 mg/kg jacaranone-treated group.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038698-g006: Jacaranone increased survival of B16F10-Nex2 tumor-bearing mice.Animals (5 mice per group) were subcutaneously injected with 5×104 cells and treated with PBS, 0.8 mg/kg or 4 mg/kg of jacaranone on alternate days. Intraperitoneal therapy began one day after inoculation of melanoma cells and was extended for 14 days. Mean survival times were 23.4±2.1 days for untreated tumor control group, 29±4.3 days (p = 0.05) for 0.8 mg/kg of jacaranone-treated group, and 34±3.6 days (*p<0.01) for 4 mg/kg jacaranone-treated group.
Mentions: To determine the effect of jacaranone on tumor development in vivo, we used a well-established syngeneic murine melanoma model. B16F10-Nex2 cells were injected subcutaneously into the right flanks of C57BL/6 mice and tumor growth was measured daily. Two treatment groups of 5 mice received 0.8 and 4 mg/kg of jacaranone intraperitoneally every other day for 14 days. A control group received 100 μL of normal saline solution. Mice were removed from the therapy study and sacrificed when tumor size exceeded 3,000 mm3. The survival rate (percent value of the number of mice with tumor growth and the total number of mice inoculated in the group) was monitored every day. Treatment of melanoma-bearing mice with 0.8 and 4 mg/kg of jacaranone resulted in a dose-dependent protective effect (Fig. 6). The mean survival times of tumor mice in the 0.8 and 4 mg/kg jacaranone treatment groups were extended to 29±4.3 days (p = 0.05) and 34±3.6 days (*p <0.01), respectively, compared with the 23.4±2.1 days of the control group. Moreover, we noted that jacaranone-treated animals maintained healthy physical appearance, normal activity levels and healthy normal-weight throughout the study period. The result shown with 4 mg/kg of jacaranone was confirmed by a second experiment with a group of 6 animals. A positive control with doxorubicin was included which rendered 84% survival of challenged animals (data not shown). Furthermore, no hemolytic activity was detected with jacaranone treatment as described previously [7].

Bottom Line: The jacaranone antitumor activity was shown against several human cancer cell lines in vitro.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.

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