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Abstract Background Malignant diseases are responsible of approximately 13% of all deaths each year in the world. Natural products represent a valuable source for the development of novel anticancer drugs. The present study was aimed at evaluating the cytotoxicity of a naphtyl butanone isolated from the leaves of Guiera senegalensis, guieranone A (GA). Results The results indicated that GA was active on 91.67% of the 12 tested cancer cell lines, the IC50 values below 4 μg/ml being recorded on 83.33% of them. In addition, the IC50 values obtained on human lymphoblastic leukemia CCRF-CEM (0.73 μg/ml) and its resistant subline CEM/ADR5000 (1.01 μg/ml) and on lung adenocarcinoma A549 (0.72 μg/ml) cell lines were closer or lower than that of doxorubicin. Interestingly, low cytotoxicity to normal hepatocyte, AML12 cell line was observed. GA showed anti-angiogenic activity with up to 51.9% inhibition of the growth of blood capillaries on the chorioallantoic membrane of quail embryo. Its also induced apotosis and cell cycle arrest. Ingenuity Pathway Analysis identified several pathways in CCRF-CEM cells and functional group of genes regulated upon GA treatment (P < 0.05), the Cell Cycle: G2/M DNA Damage Checkpoint Regulation and ATM Signaling pathways being amongst the four most involved functional groups. Conclusion The overall results of this work provide evidence of the cytotoxic potential of GA and supportive data for its possible use in cancer chemotherapy.

The frequent failure of standard cancer chemotherapy requires the development of novel drugs capable of killing otherwise drug-resistant tumors. Here, we have investigated a chloroform extract ofLaurus nobilisseeds. Fatty acids and 23 constituents of the volatile fraction were identified by gas chromotography/flame ionization detection (GC/FID) and gas chromatography/mass spectrometry (GC/MS), in good agreement with1H NMR (nuclear magnetic resonance) spectrum. Multidrug-resistant P-glycoprotein-expressing CEM/ADR5000 leukemia cells were hypersensitive (collaterally sensitive) toward this extract compared to drug-sensitive CCRF-CEM cells, whereas CEM/ADR5000 cells were 2586-fold resistant to doxorubicin as control drug. Collateral sensitivity was verified by measurement of apoptotic cells by flow cytometry. The log10IC50values of 3 compounds in the extract (limonene, eucalyptol, oleic acid) did not correlate with mRNA expression of the P-glycoprotein-codingABCB1/MDR1gene and accumulation of the P-glycoprotein substrate rhodamine in the NCI panel of tumor cell lines. A microarray-based profile of 20 genes predicted resistance to doxorubicin and 7 other anticancer drugs involved in the multidrug resistance phenotype but not to limonene, eucalyptol and oleic acid. In conclusion, our results show thatLaurus nobilisseed extract is suitable to kill multidrug-resistant P-glycoprotein expressing tumor cells. [ABSTRACT FROM AUTHOR]

Background: Multidrug resistance (MDR) is a major hurdle for cancer treatment worldwide and accounts for chemotherapy failure in over 90% of patients with metastatic cancer. Evidence of the cytotoxicity of Cameroonian plants against cancer cell lines including MDR phenotypes is been intensively and progressively provided. The present work was therefore designed to evaluate the cytotoxicity of the methanol extracts of twenty-two Cameroonian medicinal plants against sensitive and MDR cancer cell lines. Methods: The methanol maceration was used to obtain the crude plant extracts whilst the cytotoxicity of the studied extracts was determined using a resazurin reduction assay. Results: A preliminary assay on leukemia CCRF-CEM cells at 40 µg/mL shows that six of the twenty plant extract were able to enhance less than 50% of the growth proliferation of CCRF-CEM cells. These include Crinum zeylanicum (32.22%), Entada abyssinica (34.67%), Elaoephorbia drupifera (35.05%), Dioscorea bulbifera (45.88%), Eremomastax speciosa (46.07%) and Polistigma thonningii (45.11%). Among these six plants, E. drupifera showed the best activity with IC50 values below or around 30 µg/mL against the nine tested cancer cell lines. The lowest IC50 value of 8.40 µg/mL was recorded with the extract of E. drupifera against MDA-MB231 breast cancer cell line. The IC50 values below 10 µg/mL were recorded with the extracts of E. drupifera against MDA-MB231 breast cancer cells, C. zeylanicum against HCT116 p53+/+ and HCT116p53-/- colon cancer cells and E. abyssinica against HCT116 p53+/+ cells. Conclusion: The results of the present study provide evidence of the cytotoxic potential of some Cameroonian medicinal plants and a baseline information for the potential use of Elaoephorbia drupifera in the treatment of sensitive and drug-resistant cancer cell lines. [ABSTRACT FROM AUTHOR]

Background: The flora of Saudi Arabia is one of the richest biodiversity areas in the Arabian Peninsula and comprises very important genetic resources of crop and medicinal plants. The present study was designed to investigate the cytotoxicity and the antibacterial activities of the organic extracts from twenty six Saudi Arabian medicinal plants. The study was also extended to the investigation of the effects of the extracts from the four best plants, Ononis serrata (SY160), Haplophyllum tuberculatum (SY177), Pulicaria crispa (SY179), and Achillea beiberstenii (SY-200) on cell cycle distribution, apoptosis, caspases activities and mitochondrial function in leukemia CCRF-CEM cell line. Methods: A resazurin assay was used to assess the cytotoxicity of the extracts on a panel of human cancer cell lines whilst the microbroth dilution was used to determine the minimal inhibitory concentration (MIC) of the samples against twelve bacterial strains belonging to four species, Escherichia coli, Enterobacter aerogenes, Klebsiella pneumoniae and Pseudomonas aeruginosa. Results: The best activity on leukemia cell lines were recorded with SY177 (IC50 of 9.94 μg/mL ) and SY179 (IC50 of 1.81 μg/mL ) against CCRF-CEM as well as Ach-b (IC50 of 9.30 μg/mL ) and SY160 (IC50 of 5.06 μg/mL ) against HL60 cells. The extracts from SY177 and SY179 were also toxic against the seven solid cancer cell lines studied with the highest IC50 values of 31.64 μg/mL (SY177 against Hep-G2 cells). SY177 and Ach-b induced cell cycle arrest in G0/G1 and S phases whilst SY160 and SY179 induced arrest in G0/G1 phase. All the four plant extracts induced apoptosis in CCRF-CEM cells with the alteration of the mitochondrial membrane potential. In the antibacterial assays, only Ach-b displayed moderate antibacterial activities against E. coli and E. aerogenes ATCC strains (MIC of 256 μg/mL ), AG100ATeT and K. pneumoniae ATCC strains (MIC of 128 μg/mL ). Conclusions: Finally, the results of the present investigation provided supportive data for the possible use of some Saudi Arabian plants investigated herein, and mostly Haplophyllum tuberculatum, Pulicaria crispa, Ononis serrata and Achillea beiberstenii in the control of cancer diseases. [ABSTRACT FROM AUTHOR]

Chemotherapy is a mainstay of cancer treatment. Due to increased drug resistance and the severe side effects of currently used therapeutics, new candidate compounds are required for improvement of therapy success. Shikonin, a natural naphthoquinone, was used in traditional Chinese medicine for the treatment of different inflammatory diseases and recent studies revealed the anticancer activities of shikonin. We found that shikonin has strong cytotoxic effects on 15 cancer cell lines, including multidrugresistant cell lines. Transcriptome-wide mRNA expression studies showed that shikonin induced genetic pathways regulating cell cycle, mitochondrial function, levels of reactive oxygen species, and cytoskeletal formation. Taking advantage of the inherent fluorescence of shikonin, we analyzed its uptake and distribution in live cells with high spatial and temporal resolution using flow cytometry and confocal microscopy. Shikonin was specifically accumulated in the mitochondria, and this accumulation was associated with a shikonin-dependent deregulation of cellular Ca2+ and ROS levels. This deregulation led to a breakdown of the mitochondrialmembrane potential, dysfunction of microtubules, cell-cycle arrest, and ultimately induction of apoptosis. Seeing as both the metabolism and the structure of mitochondria show marked differences between cancer cells and normal cells, shikonin is a promising candidate for the next generation of chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Natural products are well recognized as sources of drugs in several human ailments. In the present work, we carried out a preliminary screening of six natural compounds, xanthone V1 (1); 2-acetylfuro-1,4-naphthoquinone (2); physcion (3); bisvismiaquinone (4); vismiaquinone (5); 1,8-dihydroxy-3-geranyloxy-6-methylanthraquinone (6) against MiaPaCa-2 pancreatic and CCRF-CEM leukemia cells and their multidrug-resistant subline, CEM/ADR5000. Compounds 1 and 2 were then tested in several other cancer cells and their possible mode of action were investigated Methodology/Findings: The tested compounds were previously isolated from the Cameroonian medicinal plants Vismia laurentii (1, 3, 4, 5 and 6) and Newbouldia laevis (2). The preliminary cytotoxicity results allowed the selection of xanthone V1 and 2-acetylfuro-1,4-naphthoquinone, which were then tested on a panel of cancer cell lines. The study was also extended to the analysis of cell cycle distribution, apoptosis induction, caspase 3/7 activation and the anti-angiogenic properties of xanthone V1 and 2-acetylfuro-1,4-naphthoquinone. IC50 values around or below 4 μg/ml were obtained on 64.29% and 78.57% of the tested cancer cell lines for xanthone V1 and 2-acetylfuro-1,4-naphthoquinone, respectively. The most sensitive cell lines (IC50,1 μg/ml) were breast MCF-7 (to xanthone V1), cervix HeLa and Caski (to xanthone V1 and 2-acetylfuro-1,4- naphthoquinone), leukemia PF-382 and melanoma colo-38 (to 2-acetylfuro-1,4-naphthoquinone). The two compounds showed respectively, 65.8% and 59.6% inhibition of the growth of blood capillaries on the chorioallantoic membrane of quail eggs in the anti-angiogenic assay. Upon treatment with two fold IC50 and after 72 h, the two compounds induced cell cycle arrest in S-phase, and also significant apoptosis in CCRF-CEM leukemia cells. Caspase 3/7 was activated by xanthone V1 Conclusions/Significance: The overall results of the present study provided evidence for the cytotoxicity of compounds xanthone V1 and 2-acetylfuro-1,4-naphthoquinone, and bring supportive data for future investigations that will lead to their use in cancer therapy. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance.: Echinops giganteus, Imperata cylindrica, Piper capense and Xylopia aethiopica are four medicinal spices used in Cameroon to treat cancers. Aim of the study: The above plants previously displayed cytotoxicty against leukemia CCRF-CEM and CEM/ADR5000 cell lines as well as human pancreatic MiaPaCa-2 cells. The present study aims at emphasizing the study of the cytotoxicity and the modes of action of the above plants on a panel of ten cancer cell lines including various sensitive and drug-resistant phenotypes. The study has been extended to the isolation of the bioactive constituents from Echinops giganteus. Materials and methods: The cytotoxicity of the extracts was determined using a resazurin reduction assay, whereas the caspase-Glo assay was used to detect the activation of caspases 3/7, caspase 8 and caspase 9 in cells treated with the four extracts. Flow cytometry was used for cell cycle analysis and detection of apoptotic cells, analysis of mitochondrial membrane potential (MMP) as well as measurement of reactive oxygen species (ROS). Results: The four tested extracts inhibited the proliferation of all tested cancer cell lines including sensitive and drug-resistant phenotypes. Collateral sensitivity of cancer cells to the extract of Echinops giganteus was generally better than to doxorubicin. The recorded IC50 ranges were 3.29µg/mL [against human knockout clones HCT116 (p53 −/− ) colon cancer cells] to 14.32µg/mL (against human liver hepatocellular carcinoma HepG2 cells) for the crude extract from Echinops giganteus, 4.17µg/mL (against breast cancer cells transduced with control vector MDA-MB231 cells) to 19.45µg/mL (against MDA-MB-231 BCRP cells) for that of Piper capense, 4.11µg/mL (against leukemia CCRF-CEM cells) to 30.60µg/mL (against leukemia HL60AR cells) for Xylopia aethiopica, 3.28µg/mL [against HCT116 (p53 −/− ) cells] to 33.43µg/mL (against HepG2 cells) for Imperata cylindica and 0.11µg/mL (against CCRF-CEM cells) to 132.47µg/mL (against HL60AR cells) for doxorubicin. The four tested extracts induced apoptosis in CCRF-CEM cells via the alteration loss of MMP whilst that of Piper capense also enhanced the production of ROS. Conclusion: The studied plants are potential cytotoxic drugs that deserve more detailed exploration in the future, to develop novel anticancer drugs against sensitive and otherwise drug-resistant phenotypes. [Copyright &y& Elsevier]

Introduction. The present study aims at evaluating the cytotoxicity of twelve parts from six Cameroonian medicinal plants on sensitive and drug-resistant cancer cell lines. We also studied the mode of action of the most active plants, Gladiolus quartinianus, Vepris soyauxii, and Anonidium mannii. Methods. The cytotoxicity of the extracts was determined using a resazurin assay. Flow cytometry was used for cell-cycle analysis and detection of apoptosis, analysis of mitochondrial membrane potential (MMP), and measurement of reactive oxygen species (ROS). Results. At 40g/mL, three extracts showed a growth of CCRF-CEM leukemia cells by less than 50%. This includes the extracts from G. quartinianus (GQW; 25.69%), Vepris soyauxii leaves (VSL; 29.82%), and Anonidium mannii leaves (AML; 31.58%). The lowest IC50 values below 30 Μg/mL were obtained with GQW, AML and VSL against 7/9, 8/9, and 9/9 tested cancer cell lines, respectively. The lowest IC50 values for each plant were 4.09 Μg/mL, and 9.14 Μg/mL (against U87MG.ΔEGFR cells), respectively, for VSL and AML and 10.57 Μg/mL (against CCRF-CEM cells) for GQW. GQW induced cell cycle arrest between G0/G1 and S phases, whilst VSL and AML induced arrest in G0/G1. All three extracts induced apoptosis in CCRF-CEM cells by loss of MMR whilst AML also enhanced production of ROS. Conclusion. The three active plants may be a source for the development of new anticancer drugs. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Beilschmiedia acuta Kosterm, Clausena anisata (Willd) Hook, Fagara tessmannii Engl., Newbouldia laevis Seem., and Polyscias fulva (Hiern) Harms. are medicinal plants used in Cameroonian traditional medicine in the treatment of various types of cancers. The present study aims at investigating 11 methanolic extracts from the above Cameroonian medicinal plants on a panel of human cancer cell lines, including various drug-resistant phenotypes. Possible modes of action were analyzed for two extracts from Beilschmiedia acuta and Polyscia fulva and alpha-hederin, the representative constituent of Polyscia fulva. Materials and methods: Cytotoxicity was determined using a resazurin assay. Cell cycle, apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) were measured by flow cytometry. Cellular response to alpha-hederin was investigated by a mRNA microarray approach. Results: Prescreening of extracts (40µg/mL) showed that three of eleven plant extracts inhibited proliferation of CCRF-CEM cells by more than 50%, i.e. BAL (73.65%), the bark extract of Beilschmiedia acuta (78.67%) and PFR (68.72%). Subsequent investigations revealed IC50 values below or around 30µg/mL of BAL and PFR in 10 cell lines, including drug-resistant models, i.e. P-glycoprotein-overexpressing CEM/ADR5000, breast cancer resistance protein-transfected MDA-MB-231-BCRP, TP53 knockout cells (HCT116 p53−/−), and mutation-activated epidermal growth factor receptor-transfected U87MG.ΔEGFR cells. IC50 values below 5µg/mL of BAL were obtained for HCT116 (p53−/−) cells. IC50 values below 10µM of alpha-hederin were found for sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 cells. The BAL and PFR extracts induced cell cycle arrest between G0/G1 and S phases. PFR-induced apoptosis was associated with increased ROS generation and MMP breakdown. Microarray-based cluster analysis revealed a gene expression profile that predicted cellular response to alpha-hederin. Conclusion: BAL, PFL and alpha-hederin, an exemplarily taken constituent of Beilschmiedia acuta and Polyscia fulva extracts revealed cytotoxicity towards cancer cell lines. Hence, Beilschmiedia acuta and Polyscia fulva may be valuable to develop drugs against otherwise drug-resistant cancer cells. [Copyright &y& Elsevier]