Antiproliferative effect of somatostatin analogs in gastroenteropancreatic neuroendocrine tumors

Somatostatin analogs were initially developed for the control of hormonal syndromes associated with neuro-endocrine tumors (NETs). In recent years, accumul ating data has supported their role as antiproliferative agents, capable of stabilizing tumor growth in patients with metastatic neuroendocrine malignancies, including carci-noid and pancreatic endocrine tumors. A phase Ⅲ, ran-domized, placebo-controlled trial has now demonstrated that octreotide long-acting repeatable (LAR) 30 mg can significantly prolong time to tumor progression among patients with metastatic midgut NETs regardless of functional status, chromogranin A level or age. In addition to signif icantly lengthening time to tumor pro-gression in the overall study population, subset analysis suggests that patients with low tumor burden are most likely to experience disease stabilization with octreotide LAR 30 mg, supporting the early use of octreotide LAR in patients with metastatic disease. Further research efforts are underway to evaluate the use of somatostatin analogs as antiproliferative agents in other types of gastroenteropancreatic-NETs. Ongoing studies are also evaluating novel somatostatin analogs and somatostatin analogs in combination with other anti-tumor therapies.

Antiproliferative and apoptosis-inducing potential of 3β-hydroxy-△5-steroidal congeners purified from the soft coral Dendronephthya putteri

The exploration and identification of antiproliferative phytochemicals have received increased attention in medicinal chemistry. In particular, research focused on the toxicology of marine natural products has increased in recent years. Terpenoids, among many secondary metabolites, have been demonstrated to act as effective anticancer agents. Soft corals, a group of marine invertebrates, produce a variety of terpenoids with biofunctional properties. The current study presents the extraction, purification, and identification of sterol congeners from the soft coral Dendronephthya putteri. The method involves 50% chloroform-methanol extraction, polar column fractionation, and analysis through GC-MSn. Dose-dependent antiproliferative activity was observed within the sterol-rich fraction (DPCMH 2-4), which consisted of 3β-hydroxy-Δ5-steroidal congeners. This fraction inhibited the growth of HL-60 and MCF-7 cells with IC50 values of 25.27±1.43 and 22.81±0.15 μg/mL, respectively. Apoptotic body formation, DNA damage, cell cycle arrest, and apoptotic cell signaling pathway activation were also observed, reinforcing the dose-dependent antiproliferative and apoptosis-inducing activity of 3β-hydroxy-Δ5-steroidal congeners. To our knowledge, this is the first report of anticancer agent identification from the soft coral D. putteri. Based on the observations, these steroidal congeners are promising candidates for the development of anticancer drugs.

Antiproliferative Properties of Vinyl Dipeptides: Synthesis and MCF-7 Cell Line Testing

Peptide mimics derived with close structure to peptide have vast utility because they are expected to interfere with biological targets while having superior drug-like properties if compared to peptides. In this work, novel vinyl dipeptides which are different in a double bond between the α-carbon of peptide and C1 of its side chain. Added to that, suitable substituents were selected to harness drug-like properties. The compounds were found to have moderate activities when tested against MCF-7 breast cancer cell line. For instance, the adamantyl analogue 2-(benzoylamino)-3-(2-furyl)-N-(1-adamantyl) propenamide (1c) and the heterocyclic analogue 2-(Benzoylamino)-3-(2-furyl)-N-[2-(5-cyanothia-zol-2-yl)] propenamide (1o) exhibited inhibition potency at 27.4 and 37.8 μM, respectively.

Gap junctions enhance the antiproliferative effect by transfer of microRNAs in glioma cells

OBJECTIVE To investigate the permeability of gap junction composed of connexin 43(Cx43)for micro RNAs(mi RNAs)and the impact of gap junction-mediated transfer of mi RNAs in glioma U87 cells.METHODS Co-culture assay demonstrated the transmission of miR NAs through gap junction channel into adjacent cells.U87 cells were labeled with green fluorescein protein(GFP)as receivers and cells were transfected mi RNAs as donors.Receiver cells and donor cells were mixed together in a ratio of 1∶1.After 12 h co-culture,cells were separated using a BD influx flow cytometer based on the GFP labeled.Quantitative real-time polymerase chain reaction(q RT-PCR)was applied detect to the expressions of miR NAs and Cx43 mR NA.Western blotting was performed to detect the protein expressions of Cx43 and GFP in U87 cells.CCK-8 assay is used to detect cell growth.RESULTS Co-culture assays demonstrated mi R-34a could transfer between U87 cells.The role of the contact independent could also transfer of miR-34a.Gap junctions inhibitor(CBX and 18-α-GA)showed lower miR-34a expression than co-culture group,whereas gap junctions enhancer(RA and Galanglin)enhanced miR-34a expression.Knockdown of Cx43 could significantly decrease the transferring of miR-34a between U87 cells.Different length of miR NAs(miR-1827,miR-144,miR-203a and miR-1183)were similar to the expression of miR-34a between U87 cells.Additionally,we demonstrated that gap junctions mediate the effect of antiproliferation mediated by mi R-34a in U87 cells.The functional inhibition of gap junctions using either si RNA or inhibition eliminated the miR-34a mediated antiproliferation,whereas the enhancement of gap junctions treatment augmented this mi R34a-mediated antiproliferation.CONCLUSION Our study demonstrates that gap junction composed of Cx43-mediated transfer mi RNAs in different length of nucleotides and gap junction-mediated transfer of mi R-34a enhance the antiproliferative effect in glioma U87 cells.

Antiproliferative effect of extracts of Sida rhombifolia L.(Malvaceae)on the Allium cepa cell cycle

Field collected roots of four populations of Sida rhombifolia were used for preparing aqueous de-coctions at two concentrations:4g/L;and 16g/L.Afterwards,we used three groups of six onion(Allium cepa)bulbs for testing each population.Slides were made with all bulbs through the smashing technique.Cells in all phases of the cell cycle of A.cepa were analyzed.The mitotic index(%of cells in mitosis)was calculated,and the statistical analysis through theχ2 test was carried out at 5%probability.The results showed that the aqueous extracts of S.rhombifolia have antiproliferative activity at high concentrations.Practically no chromosomal ab-errations were induced by treatments.

Antiproliferative Triterpenoid Saponins from Leptaulus citroides Baill. from the Madagascar Rain Forest

Bioassay-guided fractionation of EtOH extracts obtained from the roots and wood of the Madagascan plant Leptaulus citroides Baill.(Cardiopteridaceae)led to the isolation of ethyl esters of three new triterpenoid saponins(1–3)and the known sesquiterpenoid cinnamosmolide(4).The structures of 1–3 were elucidated by extensive 1D and 2D NMR experiments and mass spectrometry.Compounds 1,2,and 4 showed moderate cytotoxicity against the A2780 human ovarian cancer cell line with IC50 values of 2.8,10.2 and 2.0 lM,respectively.

Antiproliferative Activity of “<i>Lycopersicon esculentum</i>” Leaves (Var. Paul Robenson): Preliminary Study

Among plants, the Lycopersicon esculentum (Solanaceae) is the most important for its beneficial effects on health. Several epidemiological studies have shown the benefits of tomato consumption in the cancer and cardiovascular disease prevention. Tomato products constitute the major source of lycopene, the most potent antioxidant among carotenoids in vitro. In tomatoes leaves are also present many secondary metabolites including phenolic compounds, phytoalexins, protease inhibitors and glycoalkaloids who protect against adverse effects of hosts including fungi, bacteria, viruses, and insects and are involved in host-plant resistance. In this work we evaluated the antiproliferative activity of tomato leaves extract (var. Paul Robenson) in vitro.

Comparative Antiproliferative Action of Two Extracts from <i>Tilia x viridis</i>on Normal and Tumoral Lymphocytes: Rela-tionship with Antioxidant Activity

Tilia species have been used in Asia, Europe and in America to treat anxiety and also for the treatment of colds and inflammation. The oxygen reactive species (ROS) (hydrogen peroxide (H2O2) and the superoxide anion (O2) are involve in the balance cell proliferation/death in lymphocytes. It was reported the presence of flavonoids in Tilia species which possess antioxidant properties. The aim of this study was to determine comparatively the effect of an aqueous (AE) and ethanol (E) extract from Tilia x viridis, on the proliferation of tumoral and normal concanavalin A stimulated murine lymphocytes in relation to antioxidant activities such as peroxidase (Px), catalase (CAT) and superoxide dismutase (SOD) activities involves in H2O2 modulation. Also a phytochemical pattern of the two extracts in relation to flavonoids content was determined. Both extracts presented antiproliferative action on both type of lymphocytes but E was more selective on the tumoral lymphocytes inhibition (EC50 (μg/ml, Mean ±SEM) (tumoral): 50 ± 4;EC50;(normal lymphocytes): 323 ± 20);this action was related to a high polyphenols content (150 ± 10 mg/g extract) and high “per se” SOD and low Px activities. In conclusion, the extracts could be a source of antioxidant compounds which contribute to a selective antiproliferative action on tumoral cells, acting through the modulation of H2O2 levels.

Total synthesis of cajanine and its antiproliferative activity against human hepatoma cells

Cajanine,a constituent of Cajanaus cajan L.,used in traditional Chinese medicine,is a promising drug candidate because of its broad range of bioactivities.However,the total synthesis of cajanine and its derivatives has never been reported.Herein,we report the total synthesis of cajanine in nine steps with an overall yield of 10%together with its analog,longistyline A,in 8%yield.The antiproliferative activity of the two compounds against a human hepatoma cell line is also reported.

Apocynaceae species with antiproliferative and/or antiplasmodial properties: a review of ten genera

Apocynaceae is a large family of tropical trees, shrubs and vines with most species producing white latex. Major metabolites of species are triterpenoids, iridoids, alkaloids and cardenolides, which are known for a wide range of biological and pharmacological activities such as cardioprotective, hepatoprotective, neuroprotective, anti-inflammatory, anticancer and antimalarial properties. Prompted by their anticancer and antimalarial properties, the current knowledge on ten genera(Allamanda, Alstonia, Calotropis, Catharanthus, Cerbera, Dyera, Kopsia, Nerium, Plumeria and Vallaris) is updated. Major classes of metabolites are described using some species as examples. Species with antiproliferative(APF) and/or antiplasmodial(APM) properties have been identified. With the exception of the genus Dyera, nine genera of 22 species possess APF activity. Seven genera(Alstonia, Calotropis, Catharanthus, Dyera, Kopsia, Plumeria and Vallaris) of 13 species have APM properties. Among these species, Alstonia angustiloba, Alstonia macrophylla, Calotropis gigantea, Calotropis procera, Catharanthus roseus, Plumeria alba and Vallaris glabra displayed both APF and APM properties. The chemical constituents of these seven species are compiled for assessment and further research.

Antiproliferative piperidine alkaloids from giant taro(Alocasia macrorrhiza)

The rhizome of giant taro(Alocasia macrorrhiza(L.)Schott),which is a highly adaptable wild plant,is a traditional Chinese herbal medicine.In the current study,the antiproliferative constituents of giant taro were investigated and six new(1−6)and four known piperidine alkaloids(7−10)were isolated from its rhizomes.Their chemical structures and absolute configurations were elucidated using various spectroscopic methods and the Mosher ester method.The isolated alkaloids were screened for the antiproliferative activity through MTT assay.The results indicated that piperidine alkaloids exerted potential antiproliferative activity against HepG2,AGS and MCF-7 tumor cells.Further researches showed that compounds 3−5 dose-dependently decreased the colony formation rate and induced the apoptosis of AGS cells,while compound 4 induced AGS cell death via the proapoptotic pathway.This study demonstrates that the piperidine alkaloids isolated from giant taro exhibit significant antitumor activity,which provides phytochemical evidence for further development and utilization.

Simultaneous Screening and Analysis of Anti-inflammatory and Antiproliferative Compounds from Euphorbia maculata Combining Bio-affinity Ultrafiltration with Multiple Drug Targets

Euphorbia maculata has long been used for managing different impairments in Asian countries.However,its antioxidant,anti-inflammatory and antiproliferative potentialities,along with its potential bioactive compounds remain unexplored.In this context,a bio-a ffinity ultrafiltration strategy was developed to fish out ligand candidates against Cycloxygenase-2(COX-2),Topoisomerase I(Topo I),and TopoisomeraseⅡ(TopoⅡ).Thereafter,lead compounds activities were assessed in silico and in vitro for ascertaining the screening results and forecasting its corresponding activities.As a result,the E.maculata ethyl acetate(EMEA)fraction showed interesting COX-2 inhibition activity with an IC 50 value of 0.67±0.09μg/mL,as well as good growth inhibitions for three malignant cell lines.EMEA chemical fingerprinting was also conducted to enable a tentative identification of 17 compounds,among which,11 were assessed as ligand candidates to COX-2,8 compounds to Topo I,and 10 compounds to TopoⅡ.Dihydromyricetin and quercetin-3-O-arabinoside were revealed to be multipotent compounds which exerted good a ffinity to the three targeted enzymes,and also supported with their molecular docking simulations and in vitro assay validations.The interrelationship between E.maculata’s associated activities(antioxidant,anti-inflammatory and antiproliferative)was revealed with the corresponding multipotent phytochemical active components from this work.It also provided a useful direction for its empirical traditional use and further explorations in the near future.

NEW ANTIPROLIFERATIVE WITHANOLIDES FROM THE SEEDS OF DATURA METEL

Three new with anolides,daturaselines A-C(1-3),and three new with anolides glycosides,daturasesides A-C(4-6),were isolated and identified from ethyl acetate-soluble fraction of ethanol extract of Datura metel seeds.The structures of new compounds were established according to the 1D and 2D NMR spectra,combined with high resolution

Indole phytoalexin derivatives induce mitochondrialmediated apoptosis in human colorectal carcinoma cells

AIM To investigate the mechanism of the antiproliferative effect of synthetic indole phytoalexin derivatives on human colorectal cancer cell lines.METHODS Changes in cell proliferation and the cytotoxic effect of the tested compounds on human colorectal cancer cell lines and human fibroblasts were evaluated using MTS and Brd U assay,allowing us to choose the most potent substance.Cell cycle alterations were analyzed using flow cytometric analysis.The apoptosis-inducing effect of compound K-453 on the HCT116 cell line was examined with annexin V/PI double staining using flow cytometry,as well as acridine orange/propidium iodide(AO/PI)staining.The flow cytometry method also allowed us to measure changes in levels or activation states of other factors associated with apoptosis,such as poly(ADP-ribose)polymerase(PARP),caspase-3 and-9,cytochrome c,Bcl-2 family proteins,and also the integrity of the mitochondrial membrane.To evaluate activity of the transcription factors and proteins involved in signaling pathways we used Western blot analysis together with flow cytometry.RESULTS Among the ten tested compounds,compound K-453{(±)-trans-1,2-dimethoxy-2’-(3,5-bis-trifluoromethylphenylamino)spiro{indoline-3,5’[4’,5’]dihydrothiazol}exhibited the most potent activity with IC50=32.22±1.14μmol/L in human colorectal HCT116 cells and was thus selected for further studies.Flow cytometric analysis revealed a K-453-induced increase in the population of cells with sub-G1 DNA content,which is considered as a marker of apoptotic cell death.The apoptosis-inducing effect of compound K453 was also confirmed by annexin V/PI double staining and AO/PI staining.The apoptosis was associated with the loss of mitochondrial membrane potential,PARP cleavage,caspase-3 and caspase-9 activation,release of cytochrome c,as well as changes in the levels of Bcl-2family members.Moreover,flow cytometry showed that compound K-453 stimulates phosphorylation of p38MAPK but decreases phosphorylation of Akt and Erk1/2.Activation of p38 MAPK was also confirmed using Western blot analysis.This analysis also revealed downregulation of NF-κB1(p50)and Rel A(p65)proteins and the loss of their anti-apoptotic activity.CONCLUSION In our study compound K-453 exhibited an antiproliferative effect by induction of intrinsic apoptosis as well as modulation of several signaling pathways.

In vitro cytotoxicity of Indonesian stingless bee products against human cancer cell lines

Objective:To screen crude extracts of propolis,bee pollen and honey from four stingless bee species[Trigona incisa(T.incisa)],Timia apicalis,Trigona fuso-baltata and Trigona filscibasis)native to East Kalimantan.Indonesia for cytotoxic activity against five human cancer cell lines(HepG2,SW620,ChaGo-1,KATO-Ⅲand BT474).Methods:All samples were extracted with methanol,and then subpartitioned with n-hexane and ethyl acetate.Each crude extract was screened at 20μg/mL for in vitro cytotoxicity against the cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.Tn addition,four previously shown bioactive components from propolis(apigenin,cafieic acid phenyl ester,kaempferol and naringenin)and two chemotherapeutic drugs(doxorubicin and 5-fluorouracil)were used to evaluate the sensitivity of the cell lines.Results:Overall,crude extracts from propolis and honey had higher cytotoxic activities than bee pollen,but the activity was dependent upon the extraction solvent,bee species and cell line.Propolis extracts from T.incisa and Tarda apicalis showed the highest and lowest cytotoxic activity,respectively.Only the HepG2 cell line was broadly sensitive to the honey extracts.For pure compounds,doxorubicin was the most cytotoxic,the four propolis compounds the least,but the ChaGo-I cell line was sensitive to kaempferol at 10μg/mL and KATO-Ⅲwas sensitive to kaempferol and apigenin at 10μg/mL,.All pure compounds were effective against the BT474 cell line.Conclusions:Propolis from f,incisa and Trigona fusco-balteata contain an in vitro cytotoxic activity against human cancer cell lines.Further study is required,including the isolation and characterization of the active antiproliferative agent(s).

Bee pollen extract of Malaysian stingless bee enhances the effect of cisplatin on breast cancer cell lines

Objective: To evaluate the antioxidant and antiproliferative effect of methanolic bee pollen extract(BPE) of Malaysian stingless bee [Lepidotrigona terminata(L. terminata)]and its synergistic effect with cisplatin(a chemotherapeutic drug) on MCF-7 cancer cell line.Methods: The antioxidant activity of BPE from L. terminata was measured by using1,1-diphenyl-2-picrylhydrazyl radical(DPPH) assay. Antiproliferative activity at different concentrations of BPE and cisplatin was determined through using MTT assay on MCF-7 and L929 cell lines. An interaction effect(synergistic, additive and antagonistic) between BPE and cisplatin was determined by Compu Syn software based on MTT assay data.Results: The EC50(50% decrement of DPPH inhibition) of BPE was 0.5 mg/m L.L. terminata BPE exhibited antiproliferative activity on both cancer and normal cell lines.The IC50(concentration of drug that was required for 50% of cell inhibition in vitro) of BPE on MCF-7 was 15 mg/m L whereas in normal cell line L929 was 26 mg/m L. The IC50 for cisplatin on MCF-7 was 20 mmol/L. The combination effect of BPE and cisplatin on MCF-7 cells showed that BPE at 15 mg/m L was able to potentiate the inhibitory effect of cisplatin at all different concentrations(2.5–20.0 mg/m L). The average of cancer cells inhibition which was potentiated by BPE was around 50%. A combination index values of less than 1 reported in the Compu Syn software further proved the synergistic effect between BPE and cisplatin, suggesting that BPE was working synergistically with cisplatin.Conclusions: Our study therefore suggested that BPE of Malaysian stingless bee,L. terminata is a potential chemopreventive agent and can be used as a supplementary treatment for chemotherapy drugs. BPE might be able to be used to potentiate the effect of chemotherapy drugs with the possibility to reduce the required dose of the drugs. The molecular mechanisms of how the BPE exerts antiproliferative activity will be a much interesting area to look for in future studies.

A critical review on Nepal Dock(Rumex nepalensis):A tropical herb with immense medicinal importance

Rumex nepalensis Spreng.(Polygonaceae) commonly known as Nepal Dock has wide-spectrum therapeutic potencies and is extensively used for centuries in traditional medicine systems. The leaves of this plant are edible and a rich source of natural antioxidants. They act as a possible food supplement and are largely used in pharmaceutical industry. Extracts and metabolites from this plant exhibits pharmacological activities including anti-inflammatory, antioxidant, antibacterial, antifungal, antiviral, insecticidal, purgative, analgesic, antipyretic, anti-algal, central nervous system depressant, genotoxic, wound healing and skeletal muscle relaxant activity. Due to its remarkable biological activities, it has the potential to act as a rich source of drug against life threatening diseases. However, more studies are needed to scientifically validate the traditional uses of this plant, beside isolating and identifying their active principles and characterizing the mechanisms of action. We present herein a critical account of its botany, ecology, traditional uses, phytoconstituent profile and major pharmacological activities reported in recent years and therefore will provide a source of information on this plant for further studies.

Anticancer activity of Salvia officinalis essential oil and its principal constituents against hormone-dependent tumour cells

Objective: To investigate the in vitro antiproliferative action of essential oil from Salvia officinalis L.(S. officinalis) grown in Sicily(Italy), and its main components on hormone-dependent cancer cell lines. Methods: S. officinalis essential oil was prepared by hydrodistillation. The actions of the S. officinalis essential oil and its three principal components(毩-thujone, 1,8-cineole and camphor) were evaluated in LNCaP cells(prostate carcinoma), MCF7 cells(breast carcinoma) and He La cells(cervical carcinoma) at various dosages and diverse time points. Cell viability and proliferation were estimated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results: S. officinalis essential oil at doses of 100 μg/m L and 200 μg/m L induced a significant reduction of cell viability in MCF7, LNCa P and He La cell lines after a 48-hour incubation. The same cell lines also showed decreased cell viability when they were treated with a mixture of three major components of the essential oil, at doses of 100 μg/mL and 200 μg/mL, after a 48-hour incubation. Conclusions: These preliminary results could shed light on the formulation of new therapeutic agents with antiproliferative activity. Thus supplementary investigations are fundamental to examine the molecular mechanisms of the anticancer effects of this species of Salvia in cancer cells and to achieve confirmation of its in vivo anticancer activity.

Antioxidant and antitumor potential of wild and IMT-Acultivated Osmundea pinnatifida

Osmundea pinnatifida is a red edible seaweed known as pepper dulse.O.pinnatifida was cultivated in the farm of ALGAplus(ílhavo,Portugal).This farm is integrated with a seabream and seabass commercial aquaculture and uses the nutrient-enriched water resultant from the fish production as its cultivation medium in the integrated multi-trophic aquaculture(IMTA)manner.Wild and IMTA-cultivated samples of O.pinnatifi da were screened for antioxidant and antitumor activities.The antioxidant capacity of solvent extracts from wild and IMTA cultivated samples was assessed in two methods(2,2-diphenyl-1-picrylhydrazyl(DPPH)and oxygen radical absorbance capacity(ORAC)),and their total phenolic contents(TPC)were estimated.Antitumor activity was evaluated in three different tumor cell lines(HepG-2,MCF-7,and SH-SY5Y)through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay.Among the solvents used for extraction,dichloromethane was the most eff ective to extract phenolic compounds and presented higher ORAC.A significant correlation was found between TPC and ORAC,which was also sustained by the principal components analysis(PCA).Dichloromethane extracts induced a cytostatic eff ect on MCF-7 cells and showed weak cytotoxicity to SH-SY5Y cells and weak impact on cell proliferation.Overall,there were no statistically signifi cant differences in the biological activities shown by the wild and IMTA-cultivated samples.Hence,O.pinnatifida can be obtained in an economical and environmentally sustainable way through IMTA,maintaining bioactive properties in a high potential for further nutraceutical purposes.

Bioactivity‑Guided Isolation of Totarane‑Derived Diterpenes from Podocarpus neriifolius and Structure Revision of 3‑Deoxy‑2α‑hydroxynagilactone E

Bioactivity-guided phytochemical investigation of Podocarpus neriifolius D.Don.(Podocarpaceae)has led to the isolation of one new(2)and three known(1,3,and 4)B-type podolactones,along with three totarane-type diterpenes(5-7).Their structures were determined by interpretation of High Resolution ElectroSpray Ionization Mass Spectrometry(HRESIMS)and 1D and 2D NMR data,and comparison with the values reported in the literature.The structure of compound 1,previously identifed as 3-deoxy-2α-hydroxynagilactone E(8),was revised as its 2β-epimer,which has been reported recently as a new compound.All of the isolates were evaluated for their antiproliferative activity against a panel of four human cancer cell lines,namely,ovarian(OVCAR3),breast(MDA-MB-231),colon(HT-29),and melanoma(MDA-MB-435),and compounds 1 and 3 were found to be cytotoxic with IC_(50) values in the low micromolar range for most of the cell lines used.The major compound,inumakilactone A(3),was further tested in vivo using the HT-29,MDA-MB-435,and OVCAR3 cells in a murine hollow fber model,for the frst time.