Promising Natural Anticancer Agent Research Articles

Mechanism of melanoma suppression by Prosopis juliflora derived alkaloids: Apoptosis induction and signaling pathway inhibition

BackgroundTraditional medicines remain integral to healthcare worldwide especially in developing countries. Our prior studies highlighted the anti-melanoma potential of Prosopis juliflora leave methanolic extract (PJLME), leading us to further isolate and characterize bioactive compounds from PJLME and evaluate their efficacy against melanoma. In this context, we identified alkaloid fractions derived from PJLME (PJLME-AF) as key agents in PJLME's cytotoxic effect against melanoma cells. PurposeThe purpose of this research was to evaluate the anti-cancer effects and mechanisms of PJLME-AF on melanoma cell lines. MethodsChemical Profiling of PJLME-AF was conducted by using LC-ESI-MS/MS. Cell viability and anti-migratory effects of PJLME-AF were assessed through MTT, wound healing and transwell assays. Mechanistic study of PJLME-AF was explored using ROS generation assay, apoptosis assays (Annexin V) assay, western blot (apoptotic protein, EMT markers, stem cell markers and signalling pathways), qPCR. In-vitro spheroid assay was performed to explored the PJLME-AF cytotoxic effects on tumour spheroid forming ability of melanoma cells. Additionally, the anti-tumor efficacy of PJLME-AF was tested in an in-vivo C57BL/6 mouse model. ResultsPJLME-AF demonstrated potent anti-proliferative, anti-migratory and anti-invasive effects on melanoma cells. Mechanistic study indicates that PJLME-AF strongly induce ROS generation and subsequent apoptotic cell death in melanoma cells. Furthermore, PJLME-AF downregulated epithelial-to-mesenchymal transition (EMT) proteins, stem cell markers and Akt/Erk cell survival proteins providing insights into its molecular mechanisms. Notably, PJLME-AF inhibited spheroid formation and reduced PD-L1 expression. Finally, anti-tumor activity of PJLME-AF was further confirmed in a in-vivo mice model. Additionally, PJLME-AF combined with dacarbazine, exhibited enhanced cytotoxicity on melanoma compared to the drug alone. ConclusionPJLME-AF exhibit promising natural anti-cancer agents for metastatic melanoma treatment. This research contributes to the development of novel, safe, and cost-effective agents for metastatic melanoma treatment and as a potential candidate for further cancer research.

Plant-derived extracellular nanovesicles: a promising biomedical approach for effective targeting of triple negative breast cancer cells.

Introduction: Triple negative breast cancer (TNBC), a highly aggressive subtype accounting for 15-20% of all breast cancer cases, faces limited treatment options often accompanied by severe side effects. In recent years, natural extracellular nanovesicles derived from plants have emerged as promising candidates for cancer therapy, given their safety profile marked by non-immunogenicity and absence of inflammatory responses. Nevertheless, the potential anti-cancer effects of Citrus limon L.-derived extracellular nanovesicles (CLENs) for breast cancer treatment is still unexplored. Methods: In this study, we investigated the anti-cancer effects of CLENs on two TNBC cell lines (4T1 and HCC-1806 cells) under growth conditions in 2D and 3D culture environments. The cellular uptake efficiency of CLENs and their internalization mechanism were evaluated in both cells using confocal microscopy. Thereafter, we assessed the effect of different concentrations of CLENs on cell viability over time using a dual approach of Calcein-AM PI live-dead assay and CellTiter-Glo bioluminescence assay. We also examined the influence of CLENs on the migratory and evasion abilities of TNBC cells through wound healing and 3D Matrigel drop evasion assays. Furthermore, Western blot analysis was employed to investigate the effects of CLENs on the phosphorylation levels of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and extracellular signal- regulated kinase (ERK) expression. Results: We found that CLENs were internalized by the cells via endocytosis, leading to decreased cell viability, in a dose- and time-dependent manner. Additionally, the migration and evasion abilities of TNBC cells were significantly inhibited under exposed to 40 and 80μg/mL CLENs. Furthermore, down-regulated expression levels of phosphorylated phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and extracellular signal-regulated kinase (ERK), suggesting that the inhibition of cancer cell proliferation, migration, and evasion is driven by the inhibition of the PI3K/AKT and MAPK/ERK signaling pathways. Discussion: Overall, our results demonstrate the anti-tumor efficiency of CLENs against TNBC cells, highlighting their potential as promising natural anti-cancer agents for clinical applications in cancer treatment.

Cytotoxicity Enhancement of α-Mangostin with Folate-Conjugated Chitosan Nanoparticles in MCF-7 Breast Cancer Cells.

α-mangostin (AM) is a promising natural anticancer agent that can be used in cancer research. However, its effectiveness can be limited by poor solubility and bioavailability. To address this issue, chitosan-based nanoparticles (CSNPs) have been investigated as a potential delivery system to enhance the cytotoxicity to cancer cells and improve selectivity against normal cells. In this study, we developed folate-conjugated chitosan nanoparticles (F-CS-NPs) using a carbodiimide-based conjugation method to attach folate to chitosan (CS), which have different molecular weights. The NPs were crosslinked using tripolyphosphate (TPP) via ionic gelation. To characterize the F-CS-NPs, we utilized various analytical techniques, including transmission electron microscopy (TEM) to evaluate the particle size and morphology, Fourier-transform infrared spectroscopy (FTIR) to confirm the presence of functional groups, and ultraviolet-visible spectroscopy (UV-Vis) to measure the absorption spectrum and confirm the presence of folate. The particle size of AM-F-CS-NPs ranged from 180 nm to 250 nm, with many having favorable charges ranging from +40.33 ± 3.4 to 10.69 ± 1.3 mV. All NPs exhibited the same spherical morphology. The use of F-CS-NPs increased drug release, followed by a sustained release pattern. We evaluated the cytotoxicity of AM, AM-F-CS-HMW, and AM-F-CS-LMW NPs against MCF-7 cells and found IC50 values of 8.47 ± 0.49, 5.3 ± 0.01, and 4.70 ± 0.11 µg/mL, respectively. These results confirm the improved cytotoxicity of AM in MCF-7 cells when delivered via F-CS-NPs. Overall, our in vitro study demonstrated that the properties of F-CS-NPs greatly influence the cytotoxicity of AM in MCF-7 breast cancer cells (significantly different (p < 0.05)). The use of F-CS-NPs as a drug-delivery system for AM may have the potential to develop novel therapies for breast cancer.

Synergistic effect of docetaxel and gambogic acid on bone metastasis of lung cancer

Gambogic acid (GA) as an active compound isolated from Gamboge, have been investigated for many years and proved to be a promising natural anticancer agent for clinical treatment. This study aimed to investigate the inhibitory effect of docetaxel (DTX) combined with gambogic acid on bone metastasis of lung cancer. The anti-proliferation effect of the combination of DTX and GA on Lewis lung cancer (LLC) cells was determined by MTT assays. The anticancer effect of the combination of DTX and GA on bone metastasis of lung cancer in vivo was explored. Evaluation of the efficacy of drug therapy was performed by comparing the degree of bone destruction and the pathological section of bone tissue of the treated mice with that of the control mice. In vitro cytotoxicity, cell migration, and osteoclast-induced formation assay showed that GA enhanced the therapeutic effect of DTX in Lewis lung cancer cell with a synergistic effect. In an orthotopic mouse model of bone metastasis, the average survival of the DTX+GA combination group (32.61d±1.06 d) was significantly increased compared with that of the DTX group (25.75 d±0.67 d) or GA group (23.99 d±0.58 d), *P<0.01. The combination of DTX and GA has synergistic effect and resulted in more effective inhibition of tumor metastasis, providing a strong preclinical rationale for the clinical development of the DTX+GA combination for treating bone metastasis of lung cancer.

Ophiopogonin D increase apoptosis by activating p53 via ribosomal protein L5 and L11 and inhibiting the expression of c-Myc via CNOT2.

Ophiopogonin D (OP-D), which is extracted from the root tuber of Ophiopogon japonicus, is well known for its anti-inflammatory, anti-oxidant, and anti-cancer effects. It is also therapeutic for various diseases such as diabetic myocardial injuries, obesity, atopic dermatitis, and osteoporosis. However, there are insufficient reports on the anti-cancer effects and molecular mechanisms of OP-D in colorectal cancer. Therefore, this study aimed to investigate the anti-cancer-modulating effect of OP-D on colorectal cancer. The study proved that OP-D (20-40 uM) has significant cell viability inhibition and anti-proliferative effects in Cell Counting Kit-8 (CCK-8) assay and colony formation assay. In addition, our immunofluorescence analysis data showed that OP-D (40 uM) inhibited the expression of Ki67, a cell proliferation marker, and confirmed that OP-D could induce nucleolar stress by depletion of IPO7 and XPO1. Furthermore, our western blot data showed that OP-D induced p53 expression via ribosomal protein (RP) L5 or L11 and inhibited c-Myc expression through CNOT2 in a dose-dependent manner. Additionally, OP-D regulated cyclin D1 and CDK4, which are well known as cell cycle regulatory proteins. OP-D consistently inhibited the phosphorylation of AKT expression in a dose-dependent manner. Furthermore, OP-D shortened c-Myc's half-life in a time-dependent manner. Furthermore, CNOT2 knockdown enhanced the inhibitory effect of OP-D on c-Myc in colon cancer cells. Besides that, we confirmed that OP-D has a combinational anti-cancer effect of 5-FU or doxorubicin to reduce cell viability and induce apoptosis through p53 and c-Myc regulation. Altogether, our results suggest that OP-D regulates colon cancer cell proliferation and induces apoptosis by inhibiting c-Myc expression via activation of p53 and CNOT2 regulation. The study demonstrated that OP-D may be a promising natural anti-cancer agent for the treatment of colorectal cancer.

In Vitro Induction of Apoptosis in Isolated Acute Myeloid Leukemia Cells: The Role of Anastatica hierochuntica Methanolic Extract.

Anastatica hierochuntica L. (Cruciferae) has been known in Egyptian folk medicine as a remedy for gastrointestinal disorders, diabetes and heart diseases. Despite the wide usage, A. hierochuntica research provides insufficient data to support its traditional practice. The cytotoxicity of A. hierochuntica methanolic extract was investigated on acute myeloid leukemia blasts (AML) and normal human peripheral leucocytes (NHPL). The phytochemical identification of bioactive compounds using 1H-NMR and LC-ESI-MS was also performed. A. hierochuntica extract caused non-significant cytotoxicity on NHPL, while the cytotoxicity on AML was significant (IC50: 0.38 ± 0.02 μg/mL). The negative expression of p53, upregulation of Caspase-3 and increase in the BAX/BCL-2 ratio were reported at the protein and mRNA levels. The results suggest that A. hierochuntica extract induced AML cell death via the p53-independent mitochondrial intrinsic pathway and further attention should be paid to this plant as a promising natural anticancer agent.

Eugenol-Induced Autophagy and Apoptosis in Breast Cancer Cells via PI3K/AKT/FOXO3a Pathway Inhibition.

The use of natural compounds is promising in approaches to prevent and treat cancer. The long-term application of most currently employed chemotherapy techniques has toxic side effects. Eugenol, a phenolic phytochemical extracted from certain essential oils, has an anti-cancer effect. The modulation of autophagy can promote either the survival or apoptosis of cancer cells. Triple-negative (MDA-MB-231) and HER2 positive (SK-BR-3) breast cancer cell lines were treated with different doses of eugenol. Apoptosis was detected by a flow-cytometry technique, while autophagy was detected by acridine orange. Real-time PCR and Western blot assays were applied to investigate the effect of eugenol on the gene and protein expression levels of autophagy and apoptotic genes. Treating cells with different concentrations of eugenol significantly inhibited cell proliferation. The protein levels of AKT serine/threonine kinase 1 (AKT), forkhead box O3 (FOXO3a), cyclin dependent kinase inhibitor 1A (p21), cyclin-dependent kinase inhibitor (p27), and Caspase-3 and -9 increased significantly in Eugenol-treated cells. Eugenol also induced autophagy by upregulating the expression levels of microtubule-associated protein 1 light chain 3 (LC3) and downregulating the expression of nucleoporin 62 (NU p62). Eugenol is a promising natural anti-cancer agent against triple-negative and HER2-positive breast cancer. It appears to work by targeting the caspase pathway and by inducing autophagic cell death.

Tangeretin as an adjuvant and chemotherapeutic sensitizer against various types of cancers: a comparative overview.

Cancer is a leading cause of disabling morbidities and death worldwide. Although there are various strategies for the management of cancer, the severe adverse effects negatively impact the patient's quality of life. In addition, the development of resistance limits the efficacy of many chemotherapeutics. Many natural agents are capable of reducing the adverse effects associated with chemotherapy and improving the therapeutic outcome. Tangeretin, a polymethoxy flavone, is one of the promising natural anticancer agents. Tangeretin not only targets various malignancies but also synergizes chemotherapeutic agents and reverses cancer resistance. Hence, the application of tangeretin as an adjuvant in cancer chemotherapy would be a promising strategy. This work critically highlighted the proposed anticancer activity of tangeretin and discussed its potential combination with various chemotherapeutic agents. Additionally, it shed light on tangeretin chemical derivatives with improved pharmacokinetic and pharmacodynamic activity. Finally, this review described flavonoid biosynthetic pathways and how bioengineering can be employed to enhance the production yield of tangeretin. Thus, this work paves the way for the rational clinical utilization of tangeretin as a safe and effective adjuvant in chemotherapeutic protocols.

Tannin Nanoparticles (NP99) Enhances the Anticancer Effect of Tamoxifen on ER+ Breast Cancer Cells

Recently, natural substances in the form of nanoparticles are increasingly being used in different field, particularly in medicines to enhance their beneficial effects in treatment and prevention. Cancer cells of the breast (MCF-7) have been chosen to be examined and treated in vitro with conventional drug Tamoxifen (Tam) and tannin nanoparticles extract (NP99) individually or in combination. MTT reagent has been applied to assess the cell viability and propagation percentage, DNA fragmentation and mRNA relative expression of apoptotic genes to study the cell death pathway. The results showed that Tam and tannin NP99 triggered cytotoxic activity towards the MCF-7 cell. They reduce the viability and induced high potent repressive activity on cell proliferation percentage and induced apoptosis as indicated by rising the percentage in DNA fragmentation. Effect of NP99 extract exhibited its effect in a dose and time-varying. The combined treatment of Tam and NP99 were much more efficient than individual drugs. It could be concluded that NP99 is considered a promising natural anticancer agent as a new tool in therapeutic strategies.

Investigation of the in vitro Anticancer Activity of Sorbus aria Extract on Prostate Cancer

Cancer is one of the common diseases observed in our country and worldwide with a high mortality rate. Although cancer has been treated with different applications such as chemotherapy, radiotherapy and surgical operation, the exact remedy of this disease has still not been found, yet. The fact that current treatment methods have severe side effects on patients has increased the interest in natural anticancer agents that are accepted easily and considered as safer by society. The aim of this study is to investigate the anticancer activity of whitebeam (Sorbus aria) that grows in the Central Anatolia Region in Turkey, extract on PC-3 human prostate cancer cells in vitro. The anticancer activity of the ethanol extract obtained from whitebeam fruits evaluated using MTT cell proliferation assay. Also, Folin-Ciocalteu assay and CUPRAC method were performed to determine total phenol content and antioxidant capacity of whitebeam fruits, respectively. Whitebeam fruit extract showed strong anticancer activity on prostate cancer in vitro. The obtained ethanol extract is found to be a promising natural anticancer agent in vitro, and our findings need to be verified with in vivo studies and clinical trials.

Thermal, Morphological and Cytotoxicity Characterization of Hardwood Lignins Isolated by &amp;lt;i&amp;gt;In-Situ&amp;lt;/i&amp;gt; Sodium Hydroxide-Sodium Bisulfate Method

In the present work, lignin is isolated from three different agro-industrial waste, sweet sorghum, rice straw and sugarcane bagasse using in-situ sodium hydroxide-sodium bisulfate methodology. Characterization was performed using fourier transform infrared analysis (FTIR), scan electron microscopy (SEM), thermo gravimetric analysis (TGA). The SEM micrographs showed sponge-like structure except for sugarcane bagasse lignin reveals rock-like structure. The FTIR indicates the presence of hydroxyl, carbonyl and methoxyl groups in the lignin structure. TGA thermograms were relatively same and sugarcane bagasse lignin was found the most thermally stable up to 201˚C as compared to both of soda and kraft sugarcane bagasse lignin and its maximal temperature degradation rate DTGmax was found at 494˚C while 450˚C, 464˚C in addition to thermal stabilities up to 173˚C and 180˚C for sweet sorghum and rice straw lignins respectively. All lignins exhibited low percentage of bio-char less than 10% remained unvalotilized at the end of the thermogravimetric analysis at 800˚C in nitrogen atmosphere, revealing a high conversion yield into volatiles. Moreover, all lignin samples depicted higher cytotoxic potential towards lung cancer cell line (A549), IC50: 12 - 17 μg/ml. These findings suggest that the in-situ separated lignins would be good candidates for pyrolysis, polymer composites preparations and seem to be promising natural anti-cancer agents despite its main utilization as the caner drug delivery substrates.

Cytotoxicity assessment of mesoporous silica nanoparticles -curcumin against breast and colon cancer cell lines: in vitro study

Curcumin is one of the most promising natural anticancer agents, however, its medical application has been limited by its poor water solubility and bioavailability. Attempts have been made to encapsulate curcumin in different carriers, but the interest in nanocarriers for cancer chemotherapy is growing to develop a biodegradable controlled drug delivery vehicle that improves the bioavailability and solubility of curcumin. Here we focused on designing a biocompatible delivery system to be used as nanocarrier of the natural anticancer curcumin allowing its application either in vitro or in vivo. Therefore, mesoporous silica was prepared as a nanocarrier for curcumin. Characterization of the prepared nanocarriers was investigated using different techniques. Transmission electron microscopy (TEM) revealed the spherical, smooth surface of the nano-formulation. Dynamic light scattering (DLS) was used for measuring the hydrodynamic size of the prepared nanocarrier. The stability was also studied by zeta potential measurement indicating its high stability. Fourier transform infrared spectroscopy (FTIR) assessment revealed that curcumin was successfully loaded into mesoporous nanoparticles. In vitro studies elucidated that curcumin loaded nanoparticles have a more potent therapeutic effect than free curcumin against both HCT-116 and MCF-7 cancer cells. The nanocarrier can provide high therapeutic efficacy represented by the inhibition of cancer cells proliferation. Therefore, the development of such novel curcumin nanocarrier with its better curative effect will bring the nutraceutical nanoformulation to be an alternative to the chemotherapeutic drugs.

Marine guanidine alkaloids crambescidins inhibit tumor growth and activate intrinsic apoptotic signaling inducing tumor regression in a colorectal carcinoma zebrafish xenograft model.

The marine environment constitutes an extraordinary resource for the discovery of new therapeutic agents. In the present manuscript we studied the effect of 3 different sponge derived guanidine alkaloids, crambescidine-816, -830, and -800. We show that these compounds strongly inhibit tumor cell proliferation by down-regulating cyclin-dependent kinases 2/6 and cyclins D/A expression while up-regulating the cell cyclin-dependent kinase inhibitors -2A, -2D and -1A. We also show that these guanidine compounds disrupt tumor cell adhesion and cytoskeletal integrity promoting the activation of the intrinsic apoptotic signaling, resulting in loss of mitochondrial membrane potential and concomitant caspase-3 cleavage and activation. The crambescidin 816 anti-tumor effect was fnally assayed in a zebrafish xenotransplantation model confirming its potent antitumor activity against colorectal carcinoma in vivo.Considering these results crambescidins could represent promising natural anticancer agents and therapeutic tools.

Liposomal formulation for co-delivery of paclitaxel and lapatinib, preparation, characterization and optimization

Paclitaxel (PTX) is one of the most promising natural anticancer agents with a wide therapeutic range which is limited by its hydrophobic nature, low therapeutic index and more importantly, the emergence of multidrug resistance (MDR). Lapatinib (LPT) is a dual tyrosine kinase inhibitor with a significant potential to inhibit p-glycoproteins which form one of the main groups of proteins responsible for efflux pump mediated MDR. To overcome the PTX related MDR, a novel liposomal formulation was optimized for co-delivery of PTX and LPT by applying the D-optimal response surface methodology. The encapsulation efficiency (EE%) of the optimized formulation for LPT and PTX was 52 ± 3% and 68 ± 5, respectively. The optimized formulation showed a narrow size distribution with the average of 235 ± 12 nm. The transmission electron microscopy image showed that liposomes were round in shape and discrete. The release profile exhibited 93% and 71% drug release for PTX and LPT after 40 h in the sink condition. The differential scanning calorimetry analysis indicated the conversion of both drugs from crystalline state to molecular state in the optimized lyophilized formulation. The cytotoxicity of the prepared formulation was studied against 4T1 murine mammary cells. The liposomal formulation showed better cytotoxicity in comparison to the binary mixture of free drugs.

Chitosan exerts anticancer activity through induction of apoptosis and cell cycle arrest in oral cancer cells

Chitosan, a multipurpose biomaterial, has been shown to exert effects against several types of cancer including oral cancer. However, the mechanisms underlying the anticancer activities of chitosan on oral squamous cell carcinoma (SCC) cells remain largely unknown. The present study aimed to compare the effects of low-molecular-weight chitosan (LMWC) and cisplatin on oral SCC Ca9-22 and non-cancer keratinocyte HaCaT cell lines. Cell viability and cell cycle profiles were measured by MTT assay and laser scanning cytometry, respectively. Apoptosis was examined by TUNEL assay and electron microscopy, followed by analysis of caspase activity. LMWC exhibited cytotoxic effects on Ca9-22, but not HaCaT cells, whereas cisplatin induced apoptosis in both types of cells. Exposure of Ca9-22 cells to LMWC led to G1/S cell cycle arrest and an increase of TUNEL-positive cells accompanied by an early apoptotic cell morphology and subtle increases of caspase activity. Short-term LMWC exposure was less cytotoxic to HaCaT cells than to Ca9-22 cells, and anticancer activity was exerted through induction of apoptosis and cell cycle arrest, suggesting that LMWC could be a promising natural anticancer agent with fewer side effects on normal cells.

Enhanced suppression of proliferation and migration in highly-metastatic lung cancer cells by combination of valproic acid and coumarin-3-carboxylic acid and its molecular mechanisms of action

Valproic acid (VPA) as a broad-spectrum inhibitor of histone deacetylase, has been used in cancer therapy. Recently, the combination of VPA with other anticancer agents has been considered as a useful and necessary strategy to inhibit tumor growth and progression. The coumarin derivates from natural plants have been shown to be the promising natural anticancer agents. However, no literature is available on the anticancer effects of the combination of VPA and coumarin-3-carboxylic acid (HCCA). Here we show that this combination significantly increases inhibitory effects against the proliferation and migration in highly-metastatic lung cancer cells by inducing apoptosis and cell cycle arrest as well as regulating related protein expressions. Our results indicate that this combination of VPA with HCCA not only enhances the protein levels of Bax, cytosolic cytochrome c, caspase-3 and PARP-1 but also reduces the protein expressions of Bcl-2, cyclin D1 and NF-κB as well as inhibits the phosphorylation and expressions of Akt, EGFR, VEGFR2 and c-Met in the cancer cells. Our results suggest that the combination of VPA with HCCA suppresses the proliferation and migration of lung cancer cells via EGFR/VEGFR2/c-Met-Akt-NF-κB signaling pathways; this combination may have a wide therapeutic and/or adjuvant therapeutic application in the treatment of lung cancer.

Curcumin p38-dependently enhances the anticancer activity of valproic acid in human leukemia cells

Valproic acid (VPA) is a broad-spectrum inhibitor of histone deacetylase, which has been used in cancer therapy. Recently, the combination of VPA with other anticancer agents has been considered as a useful and necessary strategy to specifically induce anticancer gene expression. Curcumin (Cur) is a promising natural anticancer agent that can specifically regulate the expression of NF-κB, bcl-2, and bax in leukemia cells. However, no literature is available on the anticancer effects of the combination of VPA and Cur. Here we show that this combination significantly increases Sp1 binding, histone H3 and H4 acetylation in the promoter region of bax, but not in that of bcl-2. This specifically up-regulates bax expression and leads to HL-60 cell proliferation arrest, sub-G1 DNA accumulation and cell death. Further studies reveal that Cur specifically activates p38 MAPK, an essential factor for Sp1 binding at the bax promoter. Moreover, both inhibition of p38 MAPK and knock-down of bax expression significantly prevent VPA and Cur-induced proliferation arrest and death in HL-60 cells. These results suggest that Cur could p38-dependently promote bax expression and hence enhance the anticancer activity of VPA in human leukemia cells.

Studies on the toxicity of gambogic acid in rats

Aim To study the chronic toxicity of gambogic acid (GA), the major active ingredient of gamboges, a brownish to orange resin extracted from the Garcinia hanburyi (family Guttiferae) in Southeast Asia, using Sprague–Dawley rat as an animal model and provide further theoretical support for clinical applications of this promising natural anticancer agent. Methods GA was administered orally at dosages of 120, 60 and 30 mg/kg once every other day for a total of 13 weeks. Then we carried out the chronic toxicity studies including general body parameters, hematological, serum biochemistry, histopathological, and viscera examination. Results The results from the studies demonstrated that rats treated with high dose (120 mg/kg) of GA for a long time can lead to the damage on the kidney and liver. An innocuous dose was established to be 60 mg/kg after administration to rats for a total of 13 weeks at a frequency of one administration every other day. This dose was approximately 18.0 (body weight) or 9.6 (body surface area) times higher then that of the dose (200 mg/60 kg, every other day) used for human trials. Conclusions The studies demonstrated that the toxicity targets in the rats were the kidney and liver. These results provide further theoretical support for clinical applications of this promising natural anticancer agent.

Toxicological Studies of Gambogic Acid and its Potential Targets in Experimental Animals

Acute and chronic toxicity of gambogic acid, a promising novel anticancer agent, was determined using albino mice and Beagle dogs as model animals. Histopathological examination and viscera parameter investigation were also carried out after autopsy. The LD50 of gambogic acid was found to be 45 approximately 96 mg/kg and the 95% confidence limit was determined to be 43.18 approximately 48.45 mg/kg. The results from the chronic toxicity studies demonstrated that the toxicity targets in the experimental animals were liver and kidney. The innocuous dose was established to be 4 mg/kg after administration to dogs for a total of 13 weeks at a frequency of one injection every other day. This dose (4 mg/kg) was approximately 9.6 (body weight) or 5.1 (body surface area) times the dosage (25 mg/60 kg, every other day) recommended for human trials. Our results provide the theoretical foundation for clinical applications of this promising natural anticancer agent and will likely bring about considerable economic and social benefits.