Mundulea Sericea Research Articles

Callus of Mundulea sericea as potential anti-diabetic agents; an in silico approach

Mundulea sericea, a rare plant of the fabaceae family, has high medicinal value but a low regeneration rate in its natural habitat. The present study aims to conduct in vitro propagation and screen the potential bioactive compounds in the callus through in silico analysis. The explants were collected, sterilized, and inoculated in a standardized MS media with growth regulators in vitro to obtain sterile plants. The experiment resulted in the formation of a greenish-brown callus at a rate of 82.41 % on MS medium supplemented with BAP (6.66 µM L−1). The callus was powdered and subjected to GC–MS analysis. A total of 31 compounds were identified in the methanolic extract, along with their corresponding peak values. The compounds underwent ADME analysis for toxicity predictions. Eight compounds were chosen further based on pharmacokinetic and pharmacodynamic properties. The selected ligands were docked with anti-diabetic targets α-amylase and α-glucosidase. As a result, the compound CID 5283663 exhibited a strong binding affinity of −9.3 with the α-amylase receptor. The ligand CID 33010 exhibits a strong interaction of −7.5 with the α-glucosidase receptor. Glibenclamide and acarbose were used as standards. This study is the first attempt to identify compounds in the callus extract that could inhibit α-amylase and α-glucosidase enzymes. The findings from molecular docking analysis suggest these compounds could become potent treatments for diabetics, showcasing the promise of natural sources in drug discovery.

Phytochemical Characterization of Mundulea sericea Leaf Extracts and Analysis of Antioxidant and Antidiabetic Activities

Many developing countries are focusing on the plant-based drug for various human diseases for less or no side effects, low cost and are easily available. Hence, we need to find the new phytochemicals and their biological activities. For this reason, the present study was designed to screen the phytochemical constituents of various solvent-based leaf extracts of Mundulea sericea for antioxidant and antidiabetic activities. Through preliminary phytochemical qualitative screening, Fourier transform infrared (FTIR), and gas chromatography–mass spectrometry (GC–MS) spectrum analysis with standard procedures, phytochemical analysis of M. sericea leaf hexane (MSLH), M. sericea leaf petroleum ether (MSLPE), M. sericea leaf chloroform (MSLC), M. sericea leaf ethyl acetate (MSLEA), M. sericea leaf ethanol (MSLE), M. sericea leaf methanol (MSLM) extracts was studied. Further, MSLE extract was examined for free radical scavenging of DPPH, ABTS, nitric oxide, and hydrogen peroxide antioxidant methods and also evaluated antidiabetic activity by α-amylase and α-glucosidase assays. As a result of the phytochemical analysis, several phytochemical compounds were identified. Among the extracts, MSLE and MSLM extracts contain more secondary metabolites than other extracts. Furthermore, those secondary metabolites chemical compound constituents were identified through FTIR and GC–MS spectrum analysis. At a higher concentration, MSLE extract showed good antioxidant activity which is similar to the one found in standard antioxidant tests. The maximum antioxidant activity was reported in nitric oxide (79.37%) at 250 μg/ml concentration. Furthermore, MSLE extracts were showed good antidiabetic activity in α-glucosidase (70.70%) at 500 μg/ml concentration. As per the study, MSLE extract has effective phytochemical constituents and also acts as a novel antioxidant and antidiabetic activity. Further, investigation is needed to confirm ethanol extract as a novel therapeutic drug.

Effects of Various Phytochemical Fractions of Mundulea sericea on Free Radical Scavenging and Inhibition of Inflammatory Agents

Antioxident and antiinflammatory activities of Mundulea sericea (Willd.) A. Chev. is a medicinally important species belong to the family Fabaceae. This species contains various phytocompounds of entire parts which act as antimicrobial activity, anti-inflammatory activity, anticancer activity, antidiabetic activity, etc. Hence, the present study was aimed to analysis of phytochemical constitutes through Fourier transform infrared (FTIR) and gas chromatography mass spectrometry (GCMS) analysis by six various solvent extracts of hexane (MSBH), petroleum ether (MSBPE), chloroform (MSBC), ethyl acetate (MSBEA), ethanol (MSBE), and methanol (MSBM). The result of phytochemical analysis reported that the MSBE and MSBM extracts are contain more phytochemical constitutes than other extracts. In FTIR and GCMS study, MSBE and MSBM extracts are reported various phytochemical constitutes and out that many bioactive compounds are present of these extracts. Further, MSBE extract was subjected antioxidant and anti-inflammatory activities. In antioxidant activity, four different type assays such as 2,2-diphenyl-1-picryl-hydrazyl-hydrate radical scavenging, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate), hydrogen peroxide, and nitric oxide (NO) were used. Among this antioxidant study, NO was reported 74.63 inhibition percentage of free radical than other assays. In anti-inflammatory activity, albumin denaturation and human red blood cell membrane stabilization assay were performed by MSBE extract which result reported that the MSBE extract has good anti-inflammatory activity with more than 60% inhibition capacity on both assays. From this study, M. sericea bark extracts contain highly therapeutic phytocompounds which compounds possess good antioxidant and inflammatory activities.

Antiplasmodial and antileishmanial flavonoids from Mundulea sericea

Five known compounds (1–5) were isolated from the extract of Mundulea sericea leaves. Similar investigation of the roots of this plant afforded an additional three known compounds (6–8). The structures were elucidated using NMR spectroscopic and mass spectrometric analyses. The absolute configuration of 1 was established using ECD spectroscopy. In an antiplasmodial activity assay, compound 1 showed good activity with an IC50 of 2.0 μM against chloroquine-resistant W2, and 6.6 μM against the chloroquine-sensitive 3D7 strains of Plasmodium falciparum. Some of the compounds were also tested for antileishmanial activity. Dehydrolupinifolinol (2) and sericetin (5) were active against drug-sensitive Leishmania donovani (MHOM/IN/83/AG83) with IC50 values of 9.0 and 5.0 μM, respectively. In a cytotoxicity assay, lupinifolin (3) showed significant activity on BEAS-2B (IC50 4.9 μM) and HePG2 (IC50 10.8 μM) human cell lines. All the other compounds showed low cytotoxicity (IC50 > 30 μM) against human lung adenocarcinoma cells (A549), human liver cancer cells (HepG2), lung/bronchus cells (epithelial virus transformed) (BEAS-2B) and immortal human hepatocytes (LO2)

Deguelin inhibits HCV replication through suppressing cellular autophagy via down regulation of Beclin1 expression in human hepatoma cells

AimsDeguelin, a natural compound derived from Mundulea sericea (Leguminosae) and some other plants exhibits an activity to inhibit autophagy, a cellular machinery required for hepatitis C virus (HCV) replication. This study aimed to illuminate the impact of deguelin on HCV replication and mechanism(s) involved. MethodsHCV JFH-1-Huh7 infectious system was used for the investigation. Real time RT-PCR, Western blot, fluorescent microscopy assay were used to measure the expression levels of viral or cellular factors. Overexpression and silencing expression techniques were used to determine the role of key cellular factors. ResultsDeguelin treatment of Huh7 cells significantly inhibited HCV JFH-1 replication in a dose- and time-dependent manner. Deguelin treatment suppressed autophagy in Huh7 cells, evidenced by the decrease of LC3B-II levels, the conversion of LC3B–I to LC3B-II, and the formation of GFP-LC3 puncta as well as the increase of p62 level in deguelin-treated cells compared with control cells. HCV infection could induce autophagy which was also suppressed by deguelin treatment. Mechanism research reveals that deguelin inhibited expression of Beclin1, which is a key cellular factor for the initiation of the autophagosome formation in autophagy. Overexpression or silencing expression of Beclin1 in deguelin-treated Huh7 cells could weaken or enhance the inhibitory effect on autophagy by deguelin, respectively, and thus partially recover or further inhibit HCV replication correspondingly. Conclusions: Deguelin may serve as a novel anti-HCV compound via its inhibitory effect on autophagy, which warrants further investigation as a potential therapeutic agent for HCV infection.

Deguelin induces apoptosis in colorectal cancer cells by activating the p38 MAPK pathway.

ObjectivesDeguelin, a rotenoid extracted from Mundulea sericea (Leguminosae), exhibits antitumor effects on several types of human cancers. Due to the limited studies of deguelin on colorectal cancer (CRC), the present study was designed to investigate the antitumor effect of deguelin and to explore the underlying mechanism in CRC.Materials and methodsCell viability was assessed by the cell counting kit-8 (CCK-8) assay, and cell apoptosis was determined by the annexin v-propidium iodide staining using flow cytometry and Western blot in CRC cell lines after incubation with deguelin. The antitumor effect of deguelin was further evaluated in tumor xenograft models. Moreover, SB203580, a specific inhibitor of p38 MAPK, was used to confirm the involvement of p38 MAPK pathway in deguelin-induced apoptosis.ResultsDeguelin significantly inhibited cell proliferation and induced apoptosis in CRC cell lines (SW620 and RKO) in a time-dependent and dose-dependent manner. Western blot analysis also showed that the expression of proapoptotic proteins (cleaved caspase 3 and cleaved PARP) was upregulated, while that of antiapoptotic proteins (Bcl-2 and survivin) was downregulated after deguelin treatment in CRC cell lines. Moreover, oral administration of deguelin significantly suppressed tumor growth and induced apoptosis in subcutaneous xenograft mouse models without obvious toxicity. Additionally, Western blot revealed that deguelin-induced apoptosis might be regulated by the p38 MAPK pathway and inhibition of p38 MAPK could attenuate deguelin-induced proliferative inhibition and apoptosis in CRC cells.ConclusionCollectively, these results demonstrated that deguelin inhibited CRC cell growth by inducing apoptosis via activation of p38 MAPK pathway.

Ethnomedicinal plants used by traditional healers in the management of HIV/AIDS opportunistic diseases in Lusaka, Zambia

Despite the use of ethnobotanical remedies to manage human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), there is paucity of empirical data on the specific plant species used by traditional healers to manage HIV/AIDS opportunistic infections in Zambia. Therefore, this study documented putative plant species used to manage HIV and AIDS-related opportunistic diseases in Lusaka, Zambia. Exploratory, semi-structured interviews and detailed descriptive studies of 40 traditional healers were conducted. The following ethnobotanical data were recorded: plant species, parts used, modes of preparation, administration, and diseases treated. Data were analyzed by calculating percentage frequencies, familiarity index (Fi), and informant consensus factor (FIC). A total of 84 plant species from 38 families, mostly the Fabaceae, were used as ethnomedicines. Roots, leaves and stem bark were mostly harvested for the treatment of STIs including HIV, skin infections, diarrhea, malaria, tuberculosis, persistent cough, erectile dysfunction, oral infections, cancer and weight loss. Thirteen plants were used to manage three different diseases: Abrus precatorius, Albizia anthelmintica, Carica papaya, Cassia abbreviata, Combretum elaeagnoides, Flueggea virosa, Mimosa pigra, Mundulea sericea, Musa acuminata, Piliostigma thonningii, Ricinus communis, Securidaca longepedunculata, and Syzygium guineense. Garcinia livingstonei, Kigelia africana, Peltophorum africanum and Ziziphus mucronata were individually used to manage four different disease conditions. Only Plumbago zeylanica was used to manage five different disease conditions. These multi-use plants may have broad antimicrobial activities but risk over-exploitation. The results of this study urge a fundamental rethink of how patients and public health authorities view traditional plant medicines for HIV/AIDS management in Lusaka, Zambia.

Antibacterial and Anticancer Activity of Ethnomedicinal Plants Used in the Jongilanga Community, Mpumalanga

Seventy-four ethanolic extracts were prepared from traditionally used medicinal plants in the Jongilanga community in Mpumalanga South Africa. The aim was to determine the biological activity of the selected plants against cancer, mycobacteria species and acne. From the results, it was evident that Mundulea sericea was able to inhibit the proliferation of human melanoma cells (A375) with a fifty percent inhibitory concentration (IC50) ranging between 50 and 100 µg/ml as well as the ability to inhibit Mycobacterium tuberculosis, Mycobacterium smegmatis and Propionibacterium acnes with minimum inhibitory concentrations (MIC) of 125, 31.25 and 7.9 µg/ml respectively. This further led to the investigation of the antioxidant and anti-inflammatory activity as well as the influence of the extract on mycothiol disulphide reductase (Mtr) and glutathione reductase enzymes (Gtr) as potential targets against the above-mentioned diseases. M. sericea inhibited the COX-2 enzyme, responsible for inflammation, with an IC50 value of 10.70 ± 1.14 µg/ml, furthermore compounds previously isolated from M. sericea showed potential inhibition of COX-2 in molecular docking studies. Low radical scavenging capacity against the DPPH free radical with an IC50 value of 60.52 ± 2.40 µg/ml was obtained, however, M. sericea showed a higher affinity towards Mtr as compared to Gtr, which makes it an ideal plant for use as an antimycobacterial agent.

Deguelin Potentiates Apoptotic Activity of an EGFR Tyrosine Kinase Inhibitor (AG1478) in PIK3CA-Mutated Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is known to be intrinsically resistant to inhibitors for epidermal growth factor receptor (EGFR). Until now, clinical outcomes for HNSCC using EGFR inhibitors as single agents have yielded disappointing results. Here, we aimed to study whether combinatorial treatment using AG1478 (EGFR tyrosine kinase inhibitor) and deguelin, which is a rotenoid isolated from the African plant Mundulea sericea, could enhance the anti-tumor effects of AG1478 in HNSCC. For Ca9-22 cells with EGFR, KRAS, and PIK3CA wild types, AG1478 alone suppressed both phosphorylated levels of ERK and AKT and induced apoptosis. On the contrary, for HSC-4 cells with EGFR and KRAS wild types, and a PIK3CA mutant, AG1478 alone did not suppress the phosphorylated level of AKT nor induce apoptosis, while it suppressed ERK phosphorylation. Forced expression of constitutively active PIK3CA (G1633A mutation) significantly reduced the apoptotic effect of AG1478 on the PIK3CA wild-type Ca9-22 cells. When HSC-4 cells with the PIK3CA G1633A mutation were treated with a combination of AG1478 and deguelin, combination effects on apoptosis induction were observed through the inhibition of the AKT pathway. These results suggest that the combination of EGFR tyrosine kinase inhibitor with deguelin is a potential therapeutic approach to treat PIK3CA-mutated HNSCC.

The Akt Pathway Inhibitor Degeulin Prevents Staphylococcal Enterotoxin B Induced Splenocyte Proliferation and Inflammation

Staphylococcal Enterotoxin B (SEB) is considered a potential biological weapon. It is toxic by both inhalation and ingestion. Effects of ingestion include fever, vomiting and diarrhoea, while inhalation may additionally result in chest pain, dyspnoea, pulmonary oedema and respiratory failure. Severe exposure may be fatal and treatment relies on symptomatic support. At a cellular level, SEB up-regulates T-cell proliferation leading to a pathological inflammatory response. Deguelin, a rotenoid isolated from the African plant Mundulea sericea (Leguminosae), has been shown to reduce cellular proliferation by inhibiting the phosphoinositide 3-kinase/Akt (PI3K/Akt) signalling pathway. Using isolated murine splenocytes, we have demonstrated that treatment with deguelin reduces SEB inducing T cell proliferation by 60%. Deguelin treatment also decreased IL-2 and CCL2 secretion by splenocytes exposed to SEB. We demonstrate that targeting cellular proliferation can significantly reduce inflammation after SEB exposure and suggest that anti-proliferatives may have a role as potential generic medical counter measures if superantigens are used as biological weapons.

Deguelin induces apoptosis by targeting both EGFR-Akt and IGF1R-Akt pathways in head and neck squamous cell cancer cell lines.

Deguelin, a rotenoid compound from the African plant Mundulea sericea (Leguminosae), has been shown to possess antitumor activities but the exact role for the growth factor receptor mediated signaling pathway in head and neck squamous cell carcinoma (HNSCC) is currently still unclear. In the present study, we investigated the effect of deguelin on epidermal growth factor receptor (EGFR) and insulin-like growth factor-1 receptor (IGF1R) pathways in HNSCC cell lines. Flowcytometric analysis revealed accumulation of annexin V positivity in deguelin-treated cells, showing that deguelin induced apoptosis. The deguelin-induced apoptosis was accompanied by the reduction of constitutive phosphorylated levels of IGF1R, Akt, and extracellular signal-regulated kinase1/2 (ERK1/2). LY294002-mediated inhibition of phosphatidylinositol-3 kinase, which is an upstream effector for Akt activation, increased cleavage of poly(ADP-ribosyl) polymerase (PARP) but ERK inhibition by U0126 did not. Deguelin inhibited both IGF-1- and EGF-induced Akt activation. These results showed that deguelin possessed antitumor effect by targeting Akt in dual axis such as EGFR and IGF1R signaling pathways and suggested that it provides an applicable therapeutic strategy for HNSCC patients.

Deguelin Action Involves c-Met and EGFR Signaling Pathways in Triple Negative Breast Cancer Cells

BackgroundTreatment of breast cancer patients with antiestrogens and aromatase inhibitor(s) or Herceptin have shown significant success in steroid receptor positive or Her-2+ breast cancers respectively. However, choice of treatments for breast cancer patients with negative status for estrogen, progesterone receptors and HER2/neu is limited. As a result, search for appropriate therapy regimen for these triple negative breast cancers (TNBC) has become a major focus of investigations for many laboratories. Recently, Deguelin, a natural product isolated from African plant Mundulea sericea (Leguminossae) has shown both antiproliferative actions in various cancers including breast as well as chemoprenventive activity against carcinogen induced experimental cancers. In this report we evaluated efficacy and mechanism of action of Deguelin in triple negative breast cancer cell lines.Methods/FindingsIn vitro, Deguelin in a dose and time dependent manner inhibited the growth of MDA-MB-231, MDA-MB-468, BT-549 and BT-20 cells. Deguelin (2 or 4 mg/kg body weight), when injected intraperitoneally, reduced the in vivo tumor growth of MDA-MB-231 cells transplanted subcutaneously in athymic mice. Moreover it was nontoxic as evident from daily observations on mobility, food and water consumption and comparison of bodyweight and other visceral organ weights with those in control animals at the termination of the study. The western blot analyses and immunostaining studies indicated that the deguelin effects may be mediated through EGFR-PAKT/c-Met p-ERK and NF-κB by down regulating their downstream targets such as p-STAT3, c-Myc, Survivin.Conclusion/SignificanceThese results suggest that Deguelin may have a significant therapeutic value for the treatment of TNBC patients.

The Dynamics of Buprestidae (Coleoptera) in Rocky Highveld Grasslands of Ezemvelo Nature Reserve, Gauteng, South Africa

Buprestidae is a large family of woodboring beetles with nearly 15,000 valid species. The family is well represented in South Africa; however, the distribution and hosts of most species are unknown. The abundance of many species is generally correlated with well-wooded areas since most species' larvae inhabit dead or dying wood. Ezemvelo Nature Reserve, being predominantly grassland, has rocky ridges dominated by Acacia caffra (Thunb.) Willd., Protea caffra Meisner, and Mundulea sericea (Willd.) Chev. The majority of the larger species of buprestids were found in these areas. The smaller species, belonging to the genera Acmaeodera Eschscholtz, Anthaxia Eschscholtz, Agrilus Curtis and often very difficult to differentiate in the field, likely utilize woody forbs. The objective of this study was to compare species richness and relative abundance of buprestid in three habitats over a period of a year in Ezemvelo Nature Reserve. Results indicate that there are overlaps among species occurring in different habitats; however, certain species are host-plant specific.

Deguelin, a novel anti-tumorigenic agent targeting apoptosis, cell cycle arrest and anti-angiogenesis for cancer chemoprevention

Deguelin is a natural compound of the flavonoid family products isolated from Derris trifoliata Lour. or Mundulea sericea (Leguminosae). It exhibited significant anti-tumorigenesis and anti-proliferative activity in various types of cancer both in vitro and in vivo. Deguelin induced cell apoptosis by blocking anti-apoptotic pathways, such as PI3K-Akt, IKK-IκBα-NF-κB and AMPK-mTOR-survivin, while inhibiting tumor cell propagation and malignant transformation through p27-cyclinE-pRb-E2F1 cell cycle control and HIF-1α-VEGF anti-angiogenic pathways. In pre-clinical trials, deguelin markedly decreased the tumor incidence. These biological findings identified deguelin as a novel anti-tumorigenic agent targeting apoptosis, cell cycle arrest and anti-angiogenesis for cancer chemoprevention and chemotherapy.

Abstract 573: Deguelin inhibits the expression of estrogen receptor alpha in human breast cancer cells

Abstract The estrogen receptor alpha (ERα), a nuclear receptor and transcription factor governs the action of estrogen. This hormone is the major contributor to normal breast development and breast carcinogenesis. Thus, antiestrogens are widely utilized to treat and circumvent the progression of hormone receptor positive breast cancer. However, resistance to these agents develops after sustained use and major risk factors such as enhanced susceptibility to endometrial cancer have been associated with this type of treatment. In an effort to develop natural therapeutic compounds against ERα positive breast cancer, the effect of deguelin, a rotenoid isolated from an African plant; Mundulea sericea on ERα positive human breast cancer cells was investigated. Here we report that deguelin treatment downregulated the expression of ERα protein in a dose dependent manner in MCF-7 and T47D human breast cancer cell lines as determined by immunoblotting. Quantitative RT-PCR analysis revealed that the mRNA expression of ERα target genes Cathepsin D (CTSD), Trefoil factor 1 (TFF1) and the Progesterone receptor (PGR) was also downregulated by 50% in the presence of deguelin in MCF-7 cells. Furthermore, deguelin treatment significantly inhibited the proliferation of these two cell lines. Importantly, estrogen mediated stimulation of cell growth was reduced by 30% in MCF-7 cells after deguelin treatment. Together these findings suggest that deguelin suppresses ERα signaling, paving the way for the development of a novel natural therapeutic agent against endocrine receptor positive breast cancer. Future studies are aimed at deciphering the molecular mechanisms by which deguelin adversely affects ERα function. (This work was supported by NCI CA140321). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 573. doi:1538-7445.AM2012-573

Abstract 3829: Inhibition of breast cancer metastasis by deguelin in an experimental model

Abstract Breast cancer is a second leading cause of cancer related deaths in women. Cancer related deaths in breast cancer patients are due to metastasis of disease. Thus new drugs which could successfully inhibit metastatic disease spread are highly desired. However till date there are only a few experimental models available to study metastatic progression of breast cancer. Murine 4T1 mammary breast cancer cells when transplanted s.c./or into mammary gland metastasizes to lungs, liver and bone similar to that observed in women with stage IV metastatic disease. Thus this model is highly appropriate for studies related to breast cancer metastasis. Previously we have shown that Deguelin, originally isolated from an African plant Mundulea sericea significantly inhibits the growth of triple negative breast cancer and that the Deguelin effect is mediated through inhibition of WNT signaling pathway. However their therapeutic effect in vivo is still unexplored. We evaluated the effects of Deguelin on growth (in vitro and in vivo) and lung metastasis of 4T1 cells. In vitro, Deguelin inhibited growth of 4T1 cells in time and concentration depended manner; optimum growth inhibition was obtained at 250nM Deguelin concentration after 72 hr. treatment. Toxicity study performed in 4-6 weeks old female BALB/c mice suggested that Deguelin administered as a suspension (saline/gum Arabic/Deguelin) daily for two weeks by intraperitoneal (i.p.) injection was well tolerated up to 16mg/kg body weight, and no toxicity (loss of appetite, body weight loss, mobility, morbidity, death) was observed in Deguelin treated animals. In vivo, as compared to vehicle treated animals, Deguelin (2 or 6mg/kg body weight) administered daily for 21 days i.p significantly (P<0.05) inhibited growth of 4T1 cells (0.5 million cells/mouse) transplanted s.c. in to 4-6 weeks old female BALB/c mice. Similarly Deguelin also reduced (27-33%, P< 0.02) the number of metastatic lesions in the lungs subsequent to i.v. injection of 7500 to 10,000 4T1 cells in syngeneic mice as compared to vehicle treated control group. Immunohistochemical analysis of control/Deguelin treated 4T1 cells, and lung metastatic lesions suggest that Deguelin inhibited Ki67 expression suggesting its antiproliferative action in this model. In addition, phospho AKT, cyclin D1, Cox-2 and Hif-1α protein expressions were down regulated. Our results suggest that Deguelin effect on the growth and metastasis may be mediated by targeting signaling molecules involved in pAKT, HIF-1, Cox-2 pathway. These results provide a promising lead for a potential therapeutic agent to treat metastatic breast cancer. This work was supported in part by the National Cancer Institute grant CA140321. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3829. doi:1538-7445.AM2012-3829

A flavanone and antimicrobial activities of the constituents of extracts from Mundulea sericea

In this study, 12 compounds, which include a new flavanone 5-methoxy mundulin (1), were isolated from the leaves, stem bark and twigs of Mundulea sericea (Willd.) A. Chev. (Fabaceae; Papilionoideae). The structures of the compounds were identified based on spectral data analyses. The constituents of M. sericea also showed antimicrobial activities (MIQ = 0.01–100 µg) against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and Candida albicans.

Anticancer efficacy of deguelin in human prostate cancer cells targeting glycogen synthase kinase‐3 β/β‐catenin pathway

Activation of survival pathways has been associated with chemoresistance and progression of androgen independence which places a major obstacle to successful treatment of metastatic prostate cancer. Deguelin, a rotenoid isolated from Mundulea sericea, has an anticancer effect against several types of cancers; however, the mechanism of its antitumor effects on prostate cancer is not well understood. The aim of our study was to elucidate the effect of deguelin on the growth of prostate cancer cells and its putative mechanism of action. Deguelin decreased the viability of both androgen-dependent and -independent prostate cancer cells but not normal prostate epithelial cells. Downregulation of phosphorylated Akt and GSK-3β by deguelin promoted proteosomal degradation of β-catenin that resulted in decreased nuclear accumulation and inhibited transactivation of β-catenin-responsive genes. Deguelin-induced downregulation of proliferative (cyclin D1 and c-myc) and antiapoptotic proteins (Mcl-1, Bcl-xL and survivin) in prostate cancer cells culminated in the induction of apoptosis, inhibition of DNA synthesis and cell growth, altered membrane integrity, marked reduction of invasiveness, inhibition of anchorage-dependent and -independent colony formation. Our data demonstrated for the first time that deguelin inhibits the growth and survival of human androgen-independent prostate cancer cells, and its anticancer and antimetastatic activity occurs, at least in part through downregulating GSK-3β/β-catenin signaling pathway and antiapoptotic survival proteins. Taken together our study indicates that deguelin may have translational potential as therapeutic agent for advanced or metastatic prostate cancer.

PI3K/AKT Pathway as a Potential Therapeutic Target In Myelodysplastic Syndrome

AbstractAbstract 1871 Introduction:PI3K/AKT pathway is involved in cell growth, proliferation and apoptosis. A key downstream effector is the phosphorylated serine-threonine Akt (p-AKT). Constitutive activation of PI3K/AKT has been observed in solid tumours and leukemic cells. Inhibition of PI3K/AKT activity, results in apoptosis in cell lines (CL) after treatment with different compounds, e.g. deguelin, a natural product from the leguminous Mundulea sericea, with antitumour effects. Aims: To evaluate PI3K/AKT activation in MDS patients and its therapeutic potential in MDS. Methods:PI3K/AKT activation was evaluated by flow cytometry (FC) using an alexa-fluor 488-antibody Ser 473 p-AKT (Cell Signalling Technology). A triple immunostaining procedure using CD45-PerCP and CD34-PE was used for p-AKT expression in CD34+ primary samples. The p-AKT activity was determined using Kolmogorov-Smirnov test (D). CD34+ cells from healthy donors and Jurkat cells were used as negative and positive controls respectively. Apoptosis (determined by Annexin V and PI/7AAD) and cell cycle arrest (using RNAse and PI) were determined following treatments with LY294002 (50uM), and deguelin (100-500nM) in P-39 myeloid leukemia cell line, with constitutive PI3K/AKT activation. Apoptosis was determined in bone marrow mononuclear cells and CD34+ cells from MDS patients with the same treatments. To evaluate in vivo activity of deguelin, we used a xenotransplant model. Briefly, NODSCID mice were injected intrafemurally with P-39 CL and 12 days post transplant a three week-course of treatment, every other day, was started (deguelin 4mg/Kg, n=3 vs vehicle, n=3). Results:P-39 CL showed constitutive PI3K/AKT activation with levels significantly higher than in CD34+cells from controls (median±SD= 0.73. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Low Dose Deguelin Suppresses In‐situ Oral Cancer Meatstasis through Down Regulation of Akt‐independent NF‐kB Signaling

Deguelin, a rotenoid from Mundulea sericea, has a diversity of antitumor activities. Previous studies have shown deguelin inhibited tumor cell proliferation by inducing apoptosis through the inhibition of Akt signaling. However, the anti‐metastatic effects of deguelin have not been explored. In this study, we evaluated low dose deguelin (IC10) effects on oral cancer cells invasion/migration potentials in vitro and on in‐situ oral cancer animal model. Our results showed deguelin significantly inhibited the invasion and migration ability of oral cancer cells at low dose with no cytotoxic effects as evaluated by cell viability, proliferation and cell cycle distribution analyses. Western blot analysis showed low dose deguelin did not alter the phosphorylation level of AKT in SAS and CA922 cell lines. However, low dose deguelin suppressed the activation of IκB kinase and led to the sequential inhibition of IκB phosphorylation. Low dose deguelin also suppressed the NF‐κB reporter activity in a dose‐dependent and time‐dependent manner. Furthermore, in vivo study showed that low dose deguelin treatment significantly inhibited the orthotopic xenograft tumor growth and tumor invasion with no systemic toxicity and body weight loss. In conclusions, our data showed low dose deguelin inhibited the invasion/migration of oral cancer in vitro and in‐situ by Akt‐independent downregulation of NF‐κB signaling. These findings may have clinical implications in utilizing deguelin to treat metastatic oral cancers.