Cytotoxicity of Elaoephorbia drupifera and other Cameroonian medicinal plants against drug sensitive and multidrug resistant cancer cells

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 IC(50) values below or around 30 μg/mL against the nine tested cancer cell lines. The lowest IC(50) value of 8.40 μg/mL was recorded with the extract of E. drupifera against MDA-MB231 breast cancer cell line. The IC(50) 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

Integrated genomics of ovarian xenograft tumor progression and chemotherapy response

<p>Abstract</p> <p>Background</p> <p>Ovarian cancer is the most deadly gynecological cancer with a very poor prognosis. Xenograft mouse models have proven to be one very useful tool in testing candidate therapeutic agents and gene function <it>in vivo</it>. In this study we identify genes and gene networks important for the efficacy of a pre-clinical anti-tumor therapeutic, MT19c.</p> <p>Methods</p> <p>In order to understand how ovarian xenograft tumors may be growing and responding to anti-tumor therapeutics, we used genome-wide mRNA expression and DNA copy number measurements to identify key genes and pathways that may be critical for SKOV-3 xenograft tumor progression. We compared SKOV-3 xenografts treated with the ergocalciferol derived, MT19c, to untreated tumors collected at multiple time points. Cell viability assays were used to test the function of the PPARγ agonist, Rosiglitazone, on SKOV-3 cell growth.</p> <p>Results</p> <p>These data indicate that a number of known survival and growth pathways including Notch signaling and general apoptosis factors are differentially expressed in treated vs. untreated xenografts. As tumors grow, cell cycle and DNA replication genes show increased expression, consistent with faster growth. The steroid nuclear receptor, PPARγ, was significantly up-regulated in MT19c treated xenografts. Surprisingly, stimulation of PPARγ with Rosiglitazone reduced the efficacy of MT19c and cisplatin suggesting that PPARγ is regulating a survival pathway in SKOV-3 cells. To identify which genes may be important for tumor growth and treatment response, we observed that MT19c down-regulates some high copy number genes and stimulates expression of some low copy number genes suggesting that these genes are particularly important for SKOV-3 xenograft growth and survival.</p> <p>Conclusions</p> <p>We have characterized the time dependent responses of ovarian xenograft tumors to the vitamin D analog, MT19c. Our results suggest that PPARγ promotes survival for some ovarian tumor cells. We propose that a combination of regulated expression and copy number can identify genes that are likely important for chemotherapy response. Our findings suggest a new approach to identify candidate genes that are critical for anti-tumor therapy.</p

Defending the genome from the enemy within:mechanisms of retrotransposon suppression in the mouse germline

The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline

Solvent-Induced Reversal of Activities between Two Closely Related Heterogeneous Catalysts in the Aldol Reaction

The relative rates of the aldol reaction catalyzed by supported primary and secondary amines can be inverted by 2 orders of magnitude, depending on the use of hexane or water as a solvent. Our analyses suggest that this dramatic shift in the catalytic behavior of the supported amines does not involve differences in reaction mechanism, but is caused by activation of imine to enamine equilibria and stabilization of iminium species. The effects of solvent polarity and acidity were found to be important to the performance of the catalytic reaction. This study highlights the critical role of solvent in multicomponent heterogeneous catalytic processes

Anticancer Activities of Six Selected Natural Compounds of Some Cameroonian Medicinal Plants

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 V(1) (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 V(1) 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 V(1) and 2-acetylfuro-1,4-naphthoquinone. IC(50) values around or below 4 µg/ml were obtained on 64.29% and 78.57% of the tested cancer cell lines for xanthone V(1) and 2-acetylfuro-1,4-naphthoquinone, respectively. The most sensitive cell lines (IC(50)<1 µg/ml) were breast MCF-7 (to xanthone V(1)), cervix HeLa and Caski (to xanthone V(1) 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 IC(50) 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 V(1). CONCLUSIONS/SIGNIFICANCE: The overall results of the present study provided evidence for the cytotoxicity of compounds xanthone V(1) and 2-acetylfuro-1,4-naphthoquinone, and bring supportive data for future investigations that will lead to their use in cancer therapy

Androgen-Regulated Transcriptional Control of Sialyltransferases in Prostate Cancer Cells

The expression of gangliosides is often associated with cancer progression. Sialyltransferases have received much attention in terms of their relationship with cancer because they modulate the expression of gangliosides. We previously demonstrated that GD1a production was high in castration-resistant prostate cancer cell lines, PC3 and DU145, mainly due to their high expression of β-galactoside α2,3-sialyltransferase (ST3Gal) II (not ST3Gal I), and the expression of both ST3Gals was regulated by NF-κB, mainly by RelB. We herein demonstrate that GD1a was produced in abundance in cancerous tissue samples from human patients with hormone-sensitive prostate cancers as well as castration-resistant prostate cancers. The expression of ST3Gal II was constitutively activated in castration-resistant prostate cancer cell lines, PC3 and DU145, because of the hypomethylation of CpG island in its promoter. However, in androgen-depleted LNCap cells, a hormone-sensitive prostate cancer cell line, the expression of ST3Gal II was silenced because of the hypermethylation of the promoter region. The expression of ST3Gal II in LNCap cells increased with testosterone treatment because of the demethylation of the CpG sites. This testosterone-dependent ST3Gal II expression was suppressed by RelB siRNA, indicating that RelB activated ST3Gal II transcription in the testosterone-induced demethylated promoter. Therefore, in hormone-sensitive prostate cancers, the production of GD1a may be regulated by androgen. This is the first report indicating that the expression of a sialyltransferase is transcriptionally regulated by androgen-dependent demethylation of the CpG sites in its gene promoter