Gambogic acid induces apoptosis and sensitizes TRAIL-mediated apoptosis through downregulation of cFLIPL in renal carcinoma Caki cells

Abstract

Gambogic acid (GA) is a natural compound derived from brownish gamboge resin that shows a range of bioactivity, such as antitumor and antimicrobial properties. Although, GA is already known to induce cell death in a variety of cancer cells, the molecular basis for GA-induced cell death in renal cancer cells is unclear. In this study, a treatment with GA induced cell death in human renal carcinoma Caki cells in a dose-dependent manner. Treatment of Caki cells with GA decreased the levels of antiapoptotic proteins, such as Bcl-2 and XIAP in a dose-dependent manner. In addition, GA decreased the expression of the cFLIPL protein, which was downregulated at the transcriptional level without any change in the levels of cFLIPs expression. z-VAD (pan-caspase inhibitor) partially blocked GA-mediated cell death. GA-induced apoptotic cell death in Caki cells is mediated partly by the AIF translocation from the mitochondria into the nucleus via a caspase-independent pathway. In contrast, N-acetylcysteine (NAC), a ROS scavenger, had no effect on GA-induced cell death. The restoration of cFLIPL attenuated GA-induced cell death in Caki cells. Furthermore, a sub-toxic dose of GA sensitized TRAIL-mediated apoptosis in Caki cells. Pretreatment with z-VAD completely blocked GA plus TRAIL-mediated apoptosis. On the contrary, pretreatment with NAC partially inhibited GA plus TRAIL-induced apoptosis. Our findings suggested that GA induces apoptosis via the downregulation of cFLIPL and sensitized TRAIL-mediated apoptosis in Caki cells.

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…It has multiple biological activities such as anti-oxidative, anti-inflammatory, and anti-cancer activities [638,639]. Plenty of evidence shows that GA inhibits cell proliferation, invasion, survival, metastasis and chemoresistance, and induces angiogenesis in many types of cancers such as gastric and prostate cancers, leukemia, multiple myeloma, osteosarcoma, and renal carcinoma through multiple signaling mechanisms [640][641][642][643][644][645][646].…”

Role of gambogic acid and NaI131 in A549/DDP cells

“…GA has also been implicated in several mechanisms of cisplatin resistance (18). Furthermore, it has exhibited detectable effects on patients with lung cancer, colorectal cancer and renal cell carcinoma (19)(20)(21). Thus, GA has been approved for evaluation in a phase II clinical trial for NSCLC in China (approval no.…”

Gambogic acid inhibits HBx-mediated hepatitis B virus replication by targeting the DTX1-Notch signaling pathway

“…GA is a xanthone structure extracted from the dry, brownish gamboge resin secreted by the Garcinia hanburyi tree in Southeast Asia and has inherent anticancer properties ( Banik et al., 2018 ). GA has been shown to inhibit proliferation and increase apoptosis in several types of cancer cells ( Jang et al., 2016 ; Cai et al., 2014 ; Zou et al., 2012 ). In particular, Guo and his partner found that GA could inhibit human telomerase reverse transcriptase gene expression in human hepatoma SMMC-7721 cells, resulting in the inhibition of HCC development ( Nie et al., 2009 ).…”