Mini-reviewTherapeutic potential of gambogic acid, a caged xanthone, to target cancer
Introduction
Cancer is one of the major life-threatening diseases in the world, with a very high incidence and mortality rate. Despite the remarkable advances made in cancer prognosis and treatment, the incidence and mortality rate of cancer have not shown appreciable decrease over the years. GLOBOCAN 2008 reported approximately 12.7 million cancer incidences and 7.6 million deaths (GLOBOCAN 2008), whereas in the year 2012, 14.1 million new cancer cases and almost 8.2 million deaths have been found to occur due to cancer [1]. Extensive research over the past several decades exploring the molecular causes of cancer has led to the development of several chemotherapeutic agents for the treatment of this disease. However, the agents used at present are associated with diverse side effects such as vomiting, hypertension, heart disease, bone marrow suppression, and kidney dysfunction, which, together with chemoresistance, further complicates the process of treatment of this dreadful disease [2,3]. Hence, the development of agents with fewer side effects is immensely critical for the effective management of this disease.
Nature acts as provenance for the development of pharmaceuticals and it needs to be further explored to isolate novel chemotherapeutic agents for enhanced treatment modalities [[4], [5], [6], [7], [8]]. Natural products possess inherent anti-cancer properties that arise from an array of phytochemicals such as flavonoids, diterpenoids, sesquiterpenes, alkaloids, and polyphenolic compounds present in fruits, vegetables, and medicinal plants [[8], [9], [10], [11], [12]]. Furthermore, there is evidence that various herbal medicines have proven to be useful and effective in sensitizing cancers to conventional therapeutic agents, prolonging survival time, preventing side effects of chemotherapy, and improving the quality of life in cancer patients [[13], [14], [15], [16]].
Gambogic Acid (GA) is one such natural compound with a polyprenylated xanthone structure and is derived from dry, brownish to orange gamboge resin exuded from the Garcinia hanburyi and Garcinia morella trees found in Southeast Asia. The medicinal properties of these evergreen trees have been well-documented in various Asian cultures. Historically, the tree resin was used commonly as an anti-inflammatory and anti-microbial agent for wound treatment [17,18]. GA exhibits a huge range of bioactivity, such as anti-tumor, antimicrobial, and anti-proliferative effects on cancer cells [[19], [20], [21], [22], [23], [24], [25]]. Various preclinical studies have demonstrated that GA exhibits its effect on several types of human cancers such as lung cancer, prostate cancer, pancreatic cancer, gastric cancer, leukemia, and hepatocarcinoma [21,[26], [27], [28]]. The plausible anti-cancer mechanisms involved are the induction of apoptosis, decreased cell proliferation, enhanced reactive oxygen species (ROS) accumulation, induction of autophagy, inhibition of telomerase activity, and interception of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway [21,26,[28], [29], [30], [31], [32], [33], [34]]. Interestingly, cancer cell lines are discovered to be more sensitive to GA treatment compared to normal cell lines, presumptively due to the differential ability in redox homeostasis [35]. Several in vivo studies on different adult animal species have demonstrated that GA has a good safety profile, though some adverse effects in fetal development were seen in rats [36]. In a Phase IIa trial in China, forty-seven patients with advanced malignant tumors were enrolled into the study and results similarly showed a favorable safety profile with promising disease control rates [37]. In addition, GA has been approved for the treatment of lung cancer by the Chinese Food and Drug Administration [38].
Section snippets
Gambogic acid—chemistry and biological activities
GA is an amorphous/crystalline orange solid with molecular formula of C38H44O8, molecular weight of 628.75116 g/mol, a boiling point of 808.9 °C, and flash point 251.4 °C, with a maximum absorption wavelength of 365 nm. GA is also known as 2-methyl-4-[(1R,3aS,5S,11R,14aS)-3a,4,5,7tetrahydro-8-hydroxy-3,3,11-trimethyl-13-(3-methyl-2buten-1-yl)-11-(4-methyl-3-penten-1-yl)-7,15-dioxo-1,5methano-1H,3H,11 H-furo [3,4-g] pyrano [3,2-b] xanthen-1yl]-2Z-botanical acid, guttic acid, guttatic acid,
Molecular targets of GA
GA has been known to exert potent anti-cancer effect mediated via different mechanisms (Fig. 1). One of the major mechanisms through which GA functions is the induction of apoptosis in cancer cells via activation of pro-apoptoic genes such as caspases and Bax, and downregulation of the anti-apoptotic gene Bcl-xL [[44], [45], [46]]. GA mediated apoptosis was also found to involve modulation of other oncogenic proteins such as Bcl-2, NF-κB, c-myc, PI3K, and p-AKT, subsequently causing inhibition
Cancer chemopreventive and therapeutic properties of GA
Congregate evidence shows that GA inhibits proliferation, survival, invasion, angiogenesis, metastasis, and chemoresistance of different types of cancers such as brain cancer, breast cancer, colon cancer, gastric cancer, leukemia, liver cancer, lung cancer, multiple myeloma, osteosarcoma, and prostate cancer by targeting multiple signaling pathways. These studies provide substantial evidence that GA has great potential as an effective multi-targeted agent for both the prevention and treatment
Brain cancer
One of the most common and encroaching malignant primary tumors of the adult central nervous system (CNS) is Glioblastoma multiforme (GBM), which is derived from glial cells and has the worst prognosis among all cancers [79]. Two different studies conducted by Thida et al., and He et al., on the effect of GA have shown it to induce anti-proliferative activity against T98G glioblastoma cells and U87 glioma cells. A previous study reported apoptosis-mediated cytotoxicity against T98G glioblastoma
Conclusion
GA a xanthone structure isolated from the dry, brownish gamboge resin secreted from the Garcinia hanburyi tree in Southeast Asia, and has been extensively studied for its many biological activities. Various in vitro and in vivo studies have demonstrated that GA possesses potent anti-cancer activity and holds a huge prospect in the prevention and treatment of cancer. Several studies unraveled the numerous molecular targets associated with GA activity, such as enzymes, kinases, apoptotic
Conflicts of interest
The authors declare no conflict of interests.
Acknowledgments
This work was supported by BT/P/SG/01 grant, Indian Institute of Technology Guwahati, Assam, India awarded to Dr. Ajaikumar B. Kunnumakkara. The author Kishore Banik acknowledges the UGC for providing the fellowship. The author Bethsebie Lalduhsaki. Sailo acknowledges DST- INSPIRE for providing her the fellowship. APK was supported by grants from National Medical Research Council of Singapore, Medical Science Cluster, Yong Loo Lin School of Medicine, National University of Singapore and by the
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