Antitumor activity of gambogic acid lysinate in human SiHa cells in vitro and in vivo

Background: Cervical cancer is a major cause of death for women worldwide and human papillomavirus (HPV) infection is the main cause of cervical cancer. The purpose of this study was to explore the anti-tumor activity of gambogic acid lysinate and clarify its mechanism in SiHa cells. Methods: In the present study, cell viability was detected by means of an MTT assay, a cell growth curve was drawn with Microsoft Excel 2010, the cell cycle and cell apoptosis were evaluated by flow cytometry, Western blotting was employed to explore the mechanism of gambogic acid lysinate, and caspase-3 activity was determined with a colorimetric Caspase-3 assay kit. Additionally, the in vivo antitumor activity of gambogic acid lysinate was studied through a xenograft tumor model established with nude mice. Results: The results showed that gambogic acid lysinate inhibited the proliferation of both SiHa cells (half-maximal inhibitory concentration (IC50) values: 0.83 μmol/l and 0.77 μmol/l for 48 h and 72 h) and HeLa cells (IC50 >2 μmol/l). In SiHa cells, gambogic acid lysinate (1 and 2 μmol/l) inhibited cell proliferation and 2 μmol/l gambogic acid lysinate induced cell apoptosis and decreased the number of S phase cells. Both 1 and 2 μmol/l gambogic acid lysinate increased the number of G0/G1 phase cells. The results of a Western blot assay demonstrated that P53 and P21 were involved in SiHa cell G0/G1 phase arrest and that Bcl-2 and BAX were involved in SiHa cell apoptosis. An in vivo study showed that the growth of SiHa cell xenograft tumors was inhibited by gambogic acid lysinate (2.5 mg/kg body weight), however, gambogic acid lysinate (2.5 mg/kg body weight) had no significant effect on mouse weight gain. Conclusions: gambogic acid lysinate is a promising candidate for cervical cancer therapy.

Novel Xanthone Derivatives Impair Growth and Invasiveness of Colon Cancer Cells In Vitro

Natural xanthones are a large group of compounds from which promising anticancer properties could be further developed by chemical modifications. This study aimed to investigate the influence of four novel xanthone derivatives based on a naturally occurring xanthone skeleton on the invasiveness of colon cancer cells in vitro. First, the concentrations required to inhibit growth of three colorectal cancer cell lines to 50% (GI50) of all the studied compounds, as well as the natural xanthones used as a reference (gambogic acid and α-mangostin), have been established (MTS reduction test). Next, the assays determining several aspects of the GI25 xanthones influence on colorectal cancer cells, including cytotoxicity, migration and invasion potential, interaction with extracellular matrix and endothelial cells, as well as expression of selected invasiveness related genes have been performed. Our results demonstrate that these novel xanthone derivatives impair colorectal cancer proliferation, motility, adhesion to extracellular matrix and to endothelial cells, and also induce apoptosis and cell death. Moreover, their activity is comparable to cisplatin and 5-fluorouracil, used as reference compounds. Conducted research indicates our compounds for further research and development as novel drugs in colorectal cancer treatment.

Molecularly engineered carrier-free co-delivery nanoassembly for self-sensitized photothermal cancer therapy

Background Photothermal therapy (PTT) has been extensively investigated as a tumor-localizing therapeutic modality for neoplastic disorders. However, the hyperthermia effect of PTT is greatly restricted by the thermoresistance of tumor cells. Particularly, the compensatory expression of heat shock protein 90 (HSP90) has been found to significantly accelerate the thermal tolerance of tumor cells. Thus, a combination of HSP90 inhibitor and photothermal photosensitizer is expected to significantly enhance antitumor efficacy of PTT through hyperthermia sensitization. However, it remains challenging to precisely co-deliver two or more drugs into tumors. Methods A carrier-free co-delivery nanoassembly of gambogic acid (GA, a HSP90 inhibitor) and DiR is ingeniously fabricated based on a facile and precise molecular co-assembly technique. The assembly mechanisms, photothermal conversion efficiency, laser-triggered drug release, cellular uptake, synergistic cytotoxicity of the nanoassembly are investigated in vitro. Furthermore, the pharmacokinetics, biodistribution and self-enhanced PTT efficacy were explored in vivo. Results The nanoassembly presents multiple advantages throughout the whole drug delivery process, including carrier-free fabrication with good reproducibility, high drug co-loading efficiency with convenient dose adjustment, synchronous co-delivery of DiR and GA with long systemic circulation, as well as self-tracing tumor accumulation with efficient photothermal conversion. As expected, HSP90 inhibition-augmented PTT is observed in a 4T1 tumor BALB/c mice xenograft model. Conclusion Our study provides a novel and facile dual-drug co-assembly strategy for self-sensitized cancer therapy. Graphic abstract

Effect of Gambogic Acid–Loaded Porous-Lipid/PLGA Microbubbles in Combination With Ultrasound-Triggered Microbubble Destruction on Human Glioma

Gambogic acid (GA) is a highly effective antitumor agent, and it is used for the treatment of a wide range of cancers. It is challenging to deliver drugs to the central nervous system due to the inability of GA to cross the blood–brain barrier (BBB). Studies have shown that ultrasound-targeted microbubble destruction can be used for transient and reversible BBB disruption, significantly facilitating intracerebral drug delivery. We first prepared GA–loaded porous-lipid microbubbles (GA porous-lipid/PLGA MBs), and an in vitro BBB model was established. The cell viability was detected by CCK-8 assay and flow cytometry. The results indicate that U251 human glioma cells were killed by focused ultrasound (FUS) combined with GA/PLGA microbubbles. FUS combined with GA/PLGA microbubbles was capable of locally and transiently enhancing the permeability of BBB under certain conditions. This conformational change allows the release of GA to extracellular space. This study provides novel targets for the treatment of glioma.

Effect of Gambogic Acid on miR-199a-3p Expression and Cell Biological Behavior in Colorectal Cancer Cells

Colorectal cancer (CC), as a malignancy threatening life and health, has a rising incidence in recent years. It has been reported that gambogic acid (GA) has antitumor activity in various tumors, but its effect on CC remains to be elucidated. In this investigation, the influence of GA nanoparticles on microRNA-199a-3p (miR-199a-3p) in CC was analyzed to provide a reliable reference for future clinical practice. Through PCR detection, we first determined that miR-199a-3p presented low expression in CC and had a significant effect in predicting the onset and prognosis of CC. Through in vitro experiments, the enhanced CC cell viability after inhibition was determined; however, decreased cell viability and increased miR-199a-3p level were also observed after GA nanoparticles addition. Hence, GA nanoparticles may influence CC cell biological behaviors by modulating miR-199a-3p, providing a novel treatment scheme for CC in the future.

Gambogic Acid Relieves Neuropathic Pain in Rats by Regulating CXCR4-TXNIP/NLRP3 Pathway

Neuropathic pain is caused by abnormal sensory processing in the central nervous system (CNS). The immune response of the CNS is related to the function of glial cells and is critical in neuropathic pain. Agents based on cytokines and glial cells in the CNS have potential for the treatment of neuropathic pain. Gambogic acid (GA) is one of the main components of Garcinia cambogia, which has anti-inflammatory, antitumor, and analgesic effects. However, the effect of GA on neuropathic pain and related mechanisms are still unclear. Previous studies indicated that GA could reduce CXCR4 expression in neuropathic pain. In this study, we found that GA could alleviate nerve pain behavior in rats by measuring the incubation period of heat shrinkage and mechanical pain threshold. Also, GA reduced inflammation in chronic constriction injury rats. We further found GA reduced the apoptosis of spinal cord nerve cells in chronic constriction injury rats. Mechanically, we noticed GA relieved neuropathic pain in rats via regulating CXCR4-TXNIP/NLRP3 pathway. Our data confirmed that GA could serve as a promising drug for the treatment of neuropathic pain.