Gambogic acid inhibits the catalytic activity of human topoisomerase IIalpha by binding to its ATPase domain.
ABSTRACT This study is intended to characterize the cellular target of gambogic acid (GA), a natural product isolated from the gamboge resin of Garcinia hurburyi tree, which possesses potent in vitro and in vivo antitumor activities. The antiproliferative activity of GA was further confirmed here in a panel of human tumor cells and multidrug-resistant cells. We found that GA significantly inhibited the catalytic activity of topoisomerase (Topo) II and, to a comparatively less extent, of Topo I, without trapping and stabilizing covalent topoisomerase-DNA cleavage complexes. Down-regulation of Topo IIalpha but not Topo I and Topo IIbeta, reduced GA-induced apoptosis and the phosphorylation of c-Jun, and restored cell proliferation upon GA treatment. Moreover, GA antagonized etoposide-induced DNA damage and abrogated the antiproliferative activity of etoposide, whereas it did not affect camptothecin-induced DNA damage. By dissecting the actions of GA on the individual steps of Topo IIalpha catalytic cycle, we found that GA inhibited DNA cleavage and ATP hydrolysis. Moreover, GA directly bound to the ATPase domain of Topo IIalpha, and may share common binding sites with ATP. The results reported here show that GA exerts its antiproliferative effect by inhibiting the catalytic activity Topo IIalpha. They also indicate that GA inhibits Topo IIalpha-mediated DNA cleavage and modulate the activity of Topo II poisons, which provide rationale for further clinical evaluation of GA.
Article: Involvement of matrix metalloproteinase 2 and 9 in gambogic acid induced suppression of MDA-MB-435 human breast carcinoma cell lung metastasis.[show abstract] [hide abstract]
ABSTRACT: Cancer cell invasion is one of the crucial events in local spreading, growth, and metastasis of tumors. The present study investigated the antiinvasive and antimetastatic action of gambogic acid (GA) in MDA-MB-435 human breast carcinoma cells. GA caused a concentration-dependent suppression of cell invasion through Matrigel and significantly inhibited lung metastases of the cells transplanted in vivo. The potent effects of GA have been attributed to its ability to reduce the expression of matrix metalloproteinases (MMP) 2 and 9 in vitro and in vivo both at the protein and mRNA levels, which were associated with protein kinase C (PKC) signaling pathway as supported by the diminished antiinvasive effect of GA in the presence of specific activator of the pathway. Collectively, our data demonstrated that GA exhibited antiinvasion properties on highly invasive cancer cells via PKC mediated MMP-2/9 expression inhibition. This indicated that GA can be served as a potential novel therapeutic candidate for the treatment of cancer metastasis.Journal of Molecular Medicine 10/2008; 86(12):1367-77. · 4.67 Impact Factor
Article: Gambogic acid triggers DNA damage signaling that induces p53/p21(Waf1/CIP1) activation through the ATR-Chk1 pathway.[show abstract] [hide abstract]
ABSTRACT: Gambogic acid (GA) has been wildly studied to show potent anti-tumor effects in vivo and in vitro. We have confirmed that GA stabilized and activated p53 through down-regulating the expression of MDM2 in variety of cancer cell lines. However, GA-induced p53 activation could be partially reversed by caffeine, a PI3k inhibitor. Therefore, questions of whether GA induces post-translational modifications of p53 and subsequent activation of p53; and if that is the case, which upstream signaling pathway(s) is (are) responsible for that are proposed. Here, the relationship between p53 activation and its post-translational modifications was investigated in the human cancer cell lines HepG2 and A549 in response to GA or adriamycin treatment. GA induces p53 phosphorylation at sites Ser15 and Ser20 in a concentration- or time-dependent way, which was a direct result of DNA damage, as gamma-HA2X foci and 'comet' DNA fragments were detected. GA induces p53 phosphorylation through activation of an ATM- and Rad3-related pathway, and GA-induced phosphorylation of Chk1 is also involved. Upon treatment with GA, ATR activation is clearly associated with p53 phosphorylation, as well as activation of its target gene p21(Waf/CIP1). Furthermore, we found the dephosphorylation of Cdk1 at Thr161 induced by GA was abrogated, followed by a remarkable disruption of G2/M arrest when the cells were pre-incubated with caffeine. Interestingly, the sensitivity to caffeine enhanced the cytotoxicity of GA as well. Taken together, these data showed an important role of the DNA damage response mediated by ATR-Chk1 in p53/p21(Waf/CIP1) activation and downstream G2/M arrest during GA treatment.Cancer letters 10/2010; 296(1):55-64. · 4.86 Impact Factor
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ABSTRACT: ABSTRACT: In recent years, a number of natural products isolated from Chinese herbs have been found to inhibit proliferation, induce apoptosis, suppress angiogenesis, retard metastasis and enhance chemotherapy, exhibiting anti-cancer potential both in vitro and in vivo. This article summarizes recent advances in in vitro and in vivo research on the anti-cancer effects and related mechanisms of some promising natural products. These natural products are also reviewed for their therapeutic potentials, including flavonoids (gambogic acid, curcumin, wogonin and silibinin), alkaloids (berberine), terpenes (artemisinin, β-elemene, oridonin, triptolide, and ursolic acid), quinones (shikonin and emodin) and saponins (ginsenoside Rg3), which are isolated from Chinese medicinal herbs. In particular, the discovery of the new use of artemisinin derivatives as excellent anti-cancer drugs is also reviewed.Chinese Medicine 01/2011; 6(1):27. · 1.79 Impact Factor