Gambogic Acid CAS NO.2752-65-0

Gambogic acid sensitizes ovarian cancer cells to doxorubicin through ROS-mediated apoptosis.[Pubmed: 23436279]

Cell Biochem Biophys. 2013 Sep;67(1):199-206.

Ovarian cancer is one human malignancy which has response portly to doxorubicin. The anti-cancer activity of Gambogic acid has been tested in in vitro and in vivo studies.
METHODS AND RESULTS:
In this study, we showed that Gambogic acid, a natural compound, could potentiate the anticancer activity of doxorubicin in ovarian cancer through ROS-mediated apoptosis. Platinum-resistant human ovarian cancer cell line (SKOV-3) was treated with Gambogic acid, doxorubicin, or the combination of both to investigate cell proliferation and apoptosis. We found that the combination of Gambogic acid and doxorubicin causes synergistic loss of cell viability in SKOV-3 cells and this synergistic effect correlated with increased cellular ROS accumulation. Moreover, in vivo results showed that Gambogic acid and doxorubicin combination resulted in a synergistic suppressing effect on tumor growth in ovarian cancer mice model.
CONCLUSIONS:
Taken together, the results suggested that doxorubicin in combination with Gambogic acid might provide a promising therapeutic strategy to enhance chemosensitivity of ovarian cancer to doxorubicin.

Gambogic acid inhibits angiogenesis and prostate tumor growth by suppressing vascular endothelial growth factor receptor 2 signaling.[Pubmed: 18339865 ]

Cancer Res. 2008 Mar 15;68(6):1843-50.

Gambogic acid (GA), the main active compound of Gamboge hanburyi, has been previously reported to activate apoptosis in many types of cancer cell lines by targeting transferrin receptor and modulating nuclear factor-kappaB signaling pathway. Whether GA inhibits angiogenesis, which is crucial for cancer and other human diseases, remains unknown.
METHODS AND RESULTS:
Here, we found that GA significantly inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, migration, invasion, tube formation, and microvessel growth at nanomolar concentration. In a xenograft prostate tumor model, we found that GA effectively inhibited tumor angiogenesis and suppressed tumor growth with low side effects using metronomic chemotherapy with GA. GA was more effective in activating apoptosis and inhibiting proliferation and migration in HUVECs than in human prostate cancer cells (PC3), suggesting GA might be a potential drug candidate in cancer therapy through angioprevention with low chemotoxicity. Furthermore, we showed that GA inhibited the activations of vascular endothelial growth factor receptor 2 and its downstream protein kinases, such as c-Src, focal adhesion kinase, and AKT.
CONCLUSIONS:
Together, these data suggest that GA inhibits angiogenesis and may be a viable drug candidate in antiangiogenesis and anticancer therapies.

Potent anti-inflammatory and antiproliferative effects of gambogic acid in a rat model of antigen-induced arthritis.[Pubmed: 24623960]

Mediators Inflamm. 2014;2014:195327.

We have previously reported a continuous activation of caspase-1 and increased interleukin (IL)-1β levels in early rheumatoid arthritis (RA). These observations raised the hypothesis that drugs targeting the IL-1β pathway, in addition to tumour necrosis factor (TNF), may be particularly effective for early RA treatment. We have recently identified Gambogic acid as a promising therapeutic candidate to simultaneously block IL-1β and TNF secretion. Our main goal here was to investigate whether Gambogic acid administration was able to attenuate inflammation in antigen-induced arthritis (AIA) rats.
METHODS AND RESULTS:
Gambogic acid was administered to AIA rats in the early and late phases of arthritis. The inflammatory score, ankle perimeter, and body weight were evaluated during the period of treatment. Rats were sacrificed after 19 days of disease progression and paw samples were collected for histological and immunohistochemical evaluation. We found that inflammation in joints was significantly suppressed following Gambogic acid administration. Histological and immunohistochemical evaluation of treated rats revealed normal joint structures with complete abrogation of the inflammatory infiltrate and cellular proliferation.
CONCLUSIONS:
Our results suggest that Gambogic acid has significant anti-inflammatory properties and can possibly constitute a prototype anti-inflammatory drug with therapeutic efficacy in the treatment of inflammatory diseases such as RA.

Gambogic acid is a tissue-specific proteasome inhibitor in vitro and in vivo.[Pubmed: 23260670 ]

Gambogic acid induces EGFR degradation and Akt/mTORC1 inhibition through AMPK dependent-LRIG1 upregulation in cultured U87 glioma cells.[Pubmed: 23665322]

Gambogic acid induced oxidative stress dependent caspase activation regulates both apoptosis and autophagy by targeting various key molecules (NF-κB, Beclin-1, p62 and NBR1) in human bladder cancer cells.[Pubmed: 25218692]

Biochim Biophys Acta. 2014 Dec;1840(12):3374-84.

Gambogic acid is a potent anticancer agent and has been found effective against various types of cancer cells.
METHODS AND RESULTS:
The present study was addressed to explore the cytotoxic potential of Gambogic acid and the modulation of autophagy and apoptosis in bladder cancer cells T24 and UMUC3. Gambogic acid induces reactive oxygen species, and elicits a strong autophagic response by activating JNK at earlier time points, which is inhibited at later time points with the activation of caspases. Reactive oxygen species mediated caspase activation causes degradation of autophagic proteins, cleavage of molecular chaperones (Hsp90 and GRP-78) and adaptor proteins (p62 and NBR1). Gambogic acid treatment results in mitochondrial hyperpolarization and cytochrome c release and activates caspases involved in both extrinsic and intrinsic apoptotic pathways. Gambogic acid abrogates NF-κB activation by ROS mediated inhibition of IκB-α phosphorylation. Functionally Gambogic acid induced autophagy acts as a strong cell survival response and delays caspase activation.
CONCLUSIONS:
Our study provides the new insights about the mechanism of Gambogic acid induced modulation of autophagy and apoptosis in bladder cancer cells. All the molecular events responsible for Gambogic acid induced autophagy and apoptosis are mediated by reactive oxygen species. Since Gambogic acid targets various cell survival molecules therefore, it may be considered as a potential anticancer agent against bladder cancer.

Biochem Biophys Res Commun. 2013 Jun 7;435(3):397-402.

Glioblastoma multiforme (GBM) is the most common malignant tumor in adults' central nervous system (CNS). The development of novel anti-cancer agents for GBM is urgent. In the current study, we found that Gambogic acid induced growth inhibition and apoptosis in cultured U87 glioma cells, which was associated with Akt/mTORC1 (mTOR complex 1) signaling in-activation.
METHODS AND RESULTS:
To restore Akt activation by introducing a constitutively active (CA) Akt attenuated Gambogic acid-induced cytotoxicity against U87 cells. For mechanism study, we found that Gambogic acid induced LRIG1 (leucine-rich repeat and Ig-like domain-containing-1) upregulation, which was responsible for EGFR (epidermal growth factor receptor) degradation and its downstream Akt/mTORC1 inhibition. Further, we provided evidence to support that AMPK (AMP-activated protein kinase) activation mediated Gambogic acid-induced LRIG1 upregulation, U87 cell apoptosis and growth inhibition, while AMPK inhibition by shRNA or compound C reduced Gambogic acid-induced EGFR/Akt inhibition and cytotoxicity in U87 cells.
CONCLUSIONS:
We here proposed novel signaling mechanism mediating Gambogic acid-induced cytotoxic effects in glioma cells.

Cell Rep. 2013 Jan 31;3(1):211-22.

Gambogic acid (GA) is a natural compound derived from Chinese herbs that has been approved by the Chinese Food and Drug Administration for clinical trials in cancer patients; however, its molecular targets have not been thoroughly studied.
METHODS AND RESULTS:
Here, we report that GA inhibits tumor proteasome activity, with potency comparable to bortezomib but much less toxicity. First, GA acts as a prodrug and only gains proteasome-inhibitory function after being metabolized by intracellular CYP2E1. Second, GA-induced proteasome inhibition is a prerequisite for its cytotoxicity and anticancer effect without off-targets.
CONCLUSIONS:
Finally, because expression of the CYP2E1 gene is very high in tumor tissues but low in many normal tissues, GA could therefore produce tissue-specific proteasome inhibition and tumor-specific toxicity, with clinical significance for designing novel strategies for cancer treatment.

Gambogic acid induces apoptosis in imatinib-resistant chronic myeloid leukemia cells via inducing proteasome inhibition and caspase-dependent Bcr-Abl downregulation.[Pubmed: 24334603]

Clin Cancer Res. 2014 Jan 1;20(1):151-63.

翻译关闭即时翻译 英语中文德语检测语言 中文(简体)英语日语 翻译 Gambogic acid, a small molecule derived from Chinese herb gamboges, has been approved for phase II clinical trial for cancer therapy by the Chinese Food and Drug Administration (FDA). In this study, we investigated the effect of Gambogic acid on cell survival or apoptosis in CML cells bearing Bcr-Abl-T315I or wild-type Bcr-Abl.
METHODS AND RESULTS:
CML cell lines (KBM5, KBM5-T315I, and K562), primary cells from patients with CML with clinical resistance to imatinib, and normal monocytes from healthy volunteers were treated with Gambogic acid, imatinib, or their combination, followed by measuring the effects on cell growth, apoptosis, and signal pathways. The in vivo antitumor activity of Gambogic acid and its combination with imatinib was also assessed with nude xenografts. Gambogic acid induced apoptosis and cell proliferation inhibition in CML cells and inhibited the growth of imatinib-resistant Bcr-Abl-T315I xenografts in nude mice. Our data suggest that GA-induced proteasome inhibition is required for caspase activation in both imatinib-resistant and -sensitive CML cells, and caspase activation is required for Gambogic acid-induced Bcr-Abl downregulation and apoptotic cell death. <
CONCLUSIONS:
These findings suggest an alternative strategy to overcome imatinib resistance by enhancing Bcr-Abl downregulation with the medicinal compound Gambogic acid, which may have great clinical significance in imatinib-resistant cancer therapy.