Jacaranone Induces Apoptosis in Melanoma Cells via ROS-Mediated Downregulation of Akt and p38 MAPK Activation and Displays Antitumor Activity In Vivo

Abstract

BackgroundMalignant 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 FindingsThe 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/SignificanceThe results provide evidence for the mechanisms of action of jacaranone and emphasize the potential use of this quinone for the treatment of melanoma.

AC‐1001 H3 CDR peptide induces apoptosis and signs of autophagy in vitro and exhibits antimetastatic activity in a syngeneic melanoma model

“…Alternatively, caspase‐8 could be triggered by ROS, mediating the mitochondrial pathway and bypassing CD95/Fas engagement 25, 38, 39. It has also been reported the possibility of an interdependence of caspase‐2, ‐8, ‐9, and ‐3 in an apoptotic process mediated by ROS 17, 40. Once we also had mitochondrial transmembrane‐potential dissipation and increased ROS production, the apoptosis induced by AC‐1001 H3 likely occurred via the intrinsic pathway and caspase‐8 activation was induced by ROS.…”

Protection or cytotoxicity mediated by a novel quinonoid-polyphenol compound?

“…The lack of DCF fluorescence at the maximum concentration tested might be explained by a loss of barrier ability of the membrane (probably due to massive cell death as well as advanced membrane lipid oxidation) and probe leakage into the medium. Furthermore, unlike the weaker electron-acceptors quinone and quercetin, CHNQ induced cell death predominantly via apoptosis, a phenomenon typical for biologically relevant quinones (Qiu et al 1998;Gomez-Monterrey et al 2010;Massaoka et al 2012). Similarly to pro-apoptotic effects of other quinones (such as jacaranone and thymoquinone (El Mahdy et al 2005;Massaoka et al 2012)), the apoptosis induced by CHNQ involved caspase-8 activation and loss of mitochondrial membrane potential (MMP).…”

“…Furthermore, unlike the weaker electron-acceptors quinone and quercetin, CHNQ induced cell death predominantly via apoptosis, a phenomenon typical for biologically relevant quinones (Qiu et al 1998;Gomez-Monterrey et al 2010;Massaoka et al 2012). Similarly to pro-apoptotic effects of other quinones (such as jacaranone and thymoquinone (El Mahdy et al 2005;Massaoka et al 2012)), the apoptosis induced by CHNQ involved caspase-8 activation and loss of mitochondrial membrane potential (MMP). Mitochondrial dysfunction, characterized by a loss of MMP and opening of mitochondrial permeability transition pores, is an effect caused by many apoptotic stimuli including ROS (Kuwana et al 2005;Le Bras et al 2005).…”

“…In consequence, mitochondria release various intermembrane space proteins to the cytosol including cytochrome c leading to activation of the caspase cascade, including activation of the key caspase-3. It has been clearly shown that ROS trigger activation of caspases, including caspase-2, -8, -9 and -3, during apoptosis Massaoka et al 2012). Activation of caspase-8 during CHNQ-induced apoptosis draws attention to the role of deathreceptor-mediated pathway.…”

Synthesis and Determination of Antitumor Activity of Jacaranone and Synthetic Analogs

“…These quinones have the ability to form oxygen reactive species (ROS) [16], a group of highly reactive chemicals controlled by intracellular antioxidants. Low levels of ROS may produce cell proliferation and genetic instability, but at high concentration can promote apoptosis, and act as cancer suppressor species [7]. This controversial capacity may be due to the varying antioxidant capacities of different cancers [17].…”