Armel Herve Nwabo Kamdje

Notch-3 and Notch-4 signaling rescue from apoptosis human B-ALL cells in contact with human bone marrow―derived mesenchymal stromal cells

Although many literature data are available on the role of Notch signaling in T-cell acute lymphoblastic leukemia (ALL) biology, the importance of this molecular pathway in the development of B-lineage ALL (B-ALL) cells in the BM microenvironment is unknown so far. In this study, we used anti-Notch molecules neutralizing Abs and γ-secretase inhibitor (GSI) XII to investigate the role of the Notch signaling pathway in the promotion of human B-ALL cell survival in presence of stromal cell support. The treatment with combinations of anti-Notch molecule neutralizing Abs resulted in the decrease of B-ALL cell survival, either cultured alone or cocultured in presence of stromal cells from normal donors and B-ALL patients. Interestingly, the inhibition of Notch-3 and -4 or Jagged-1/-2 and DLL-1 resulted in a dramatic increase of apoptotic B-ALL cells by 3 days, similar to what is obtained by blocking all Notch signaling with the GSI XII. Our data suggest that the stromal cell-mediated antiapoptotic effect on B- ALL cells is mediated by Notch-3 and -4 or Jagged-1/-2 and DLL-1 in a synergistic manner.

Signaling pathways in breast cancer: Therapeutic targeting of the microenvironment

Breast cancer is the most common cancer in women worldwide. Understanding the biology of this malignant disease is a prerequisite for selecting an appropriate treatment. Cell cycle alterations are seen in many cancers, including breast cancer. Newly popular targeted agents in breast cancer include cyclin dependent kinase inhibitors (CDKIs) which are agents inhibiting the function of cyclin dependent kinases (CDKs) and agents targeting proto-oncogenic signaling pathways like Notch, Wnt, and SHH (Sonic hedgehog). CDKIs are categorized as selective and non-selective inhibitors of CDK. CDKIs have been tried as monotherapy and combination therapy. The CDKI Palbocyclib is now a promising therapeutic in breast cancer. This drug recently entered phase III trial for estrogen receptor (ER) positive breast cancer after showing encouraging results in progression free survival in a phase II trials. The tumor microenvironment is now recognized as a significant factor in cancer treatment response. The tumor microenvironment is increasingly considered as a target for combination therapy of breast cancer. Recent findings in the signaling pathways in breast cancer are herein summarized and discussed. Furthermore, the therapeutic targeting of the microenvironment in breast cancer is also considered.

Anticancer and antioxidant activities of methanol extracts and fractions of some Cameroonian medicinal plants.

OBJECTIVEnTo obtain a scientific basis of the use of plant-derived preparations by many rural people in Cameroon, for their primary health care needs in the treatment of diseases such as cancer.nnnMETHODSnThe antiproliferative effect of 11 plants methanol crude extracts on four cancer cells using sulforhodamine-B assay and their antioxidant activities using 1-diphenyl-2-picrylhydrazyl radical and nitric oxide radical scavenging ability were investigated. The Ekebergia senegalensis (E. senegalensis) and Protea elliotii (P. elliotii) extracts were selected based on their antioxidant and anticancer activities, and partition in hexane, dichloromethane, ethyl acetate, butanol and methanol was done. Each fraction was submitted to antioxidant and anticancer activities, and the effect of the dichloromethane fraction (the most antiproliferative fraction) on NCI-H460 cell cycle was determined by flow cytometry.nnnRESULTSnThe most antiproliferative substances were found for the extracts from E. senegalensis, P. elliotii, Terminalia macroptera and Vitellaria paradoxa. Whereas the most antioxidant substances were found for the extracts from Cissus populnea, E. senegalensis, P. elliotii, Terminalia macroptera, Vitellaria paradoxa, and Gardenia aqualla. Dichloromethane fraction of P. elliotii was found to be highly antiproliferative to NCI-H460 cancer cells and showed S phase arrest cell cycle progression. Ethyl acetate n-butanol and methanol fractions showed quite strong antioxidant activity for both E. senegalensis and P. elliotii, as compared to that of gallic acid.nnnCONCLUSIONSnOverall, the antiproliferative and antioxidant activities of some of the extracts lend some support to their use in the traditional medicine of Adamawa Region, Cameroon to treat cancer.

Notch signalling drives bone marrow stromal cell-mediated chemoresistance in acute myeloid leukemia

Both preclinical and clinical investigations suggest that Notch signalling is critical for the development of many cancers and for their response to chemotherapy. We previously showed that Notch inhibition abrogates stromal-induced chemoresistance in lymphoid neoplasms. However, the role of Notch in acute myeloid leukemia (AML) and its contribution to the crosstalk between leukemia cells and bone marrow stromal cells remain controversial. Thus, we evaluated the role of the Notch pathway in the proliferation, survival and chemoresistance of AML cells in co-culture with bone marrow mesenchymal stromal cells expanded from both healthy donors (hBM-MSCs) and AML patients (hBM-MSCs*). As compared to hBM-MSCs, hBM-MSCs* showed higher level of Notch1, Jagged1 as well as the main Notch target gene HES1. Notably, hBM-MSCs* induced expression and activation of Notch signalling in AML cells, supporting AML proliferation and being more efficientin inducing AML chemoresistance than hBM-MSCs*. Pharmacological inhibition of Notch using combinations of Notch receptor-blocking antibodies or gamma-secretase inhibitors (GSIs), in presence of chemotherapeutic agents, significant lowered the supportive effect of hBM-MSCs and hBM-MSCs* towards AML cells, by activating apoptotic cascade and reducing protein level of STAT3, AKT and NF-κB. These results suggest that Notch signalling inhibition, by overcoming the stromal-mediated promotion of chemoresistance,may represent a potential therapeutic targetnot only for lymphoid neoplasms, but also for AML.

Developmental pathways associated with cancer metastasis: Notch, Wnt, and Hedgehog

Master developmental pathways, such as Notch, Wnt, and Hedgehog, are signaling systems that control proliferation, cell death, motility, migration, and stemness. These systems are not only commonly activated in many solid tumors, where they drive or contribute to cancer initiation, but also in primary and metastatic tumor development. The reactivation of developmental pathways in cancer stroma favors the development of cancer stem cells and allows their maintenance, indicating these signaling pathways as particularly attractive targets for efficient anticancer therapies, especially in advanced primary tumors and metastatic cancers. Metastasis is the worst feature of cancer development. This feature results from a cascade of events emerging from the hijacking of epithelial-mesenchymal transition, angiogenesis, migration, and invasion by transforming cells and is associated with poor survival, drug resistance, and tumor relapse. In the present review, we summarize and discuss experimental data suggesting pivotal roles for developmental pathways in cancer development and metastasis, considering the therapeutic potential. Emerging targeted antimetastatic therapies based on Notch, Wnt, and Hedgehog pathways are also discussed.

Signaling pathways bridging fate determination of neural crest cells to glial lineages in the developing peripheral nervous system

Fate determination of neural crest cells is an essential step for the development of different crest cell derivatives. Peripheral glia development is marked by the choice of the neural crest cells to differentiate along glial lineages. The molecular mechanism underlying fate acquisition is poorly understood. However, recent advances have identified different transcription factors and genes required for the complex instructive signaling process that comprise both local environmental and cell intrinsic cues. Among others, at least the roles of Sox10, Notch, and neuregulin 1 have been documented in both in vivo and in vitro models. Cooperative interactions of such factors appear to be necessary for the switch from multipotent neural crest cells to glial lineage precursors in the peripheral nervous system. This review summarizes recent advances in the understanding of fate determination of neural crest cells into different glia subtypes, together with the potential implications in regenerative medicine.

Mesenchymal stromal cells’ role in tumor microenvironment: involvement of signaling pathways

Mesenchymal stromal cells (MSCs) are adult multipotent stem cells residing as pericytes in various tissues and organs where they can differentiate into specialized cells to replace dying cells and damaged tissues. These cells are commonly found at injury sites and in tumors that are known to behave like wounds that do not heal.” In this article, we discuss the mechanisms of MSCs in migrating, homing, and repairing injured tissues. We also review a number of reports showing that tumor microenvironment triggers plasticity mechanisms in MSCs to induce malignant neoplastic tissue formation, maintenance, and chemoresistance, as well as tumor growth. The antitumor properties and therapeutic potential of MSCs are also discussed.

Newtonoate as an active principle of Newtonia griffoniana for anxiolytic activity in Swiss mice.

Abstract Background: Newtonia griffoniana (Mimosaceae) is a Central African rain forest tree, whose bark extracts are used in Cameroonian folk medicine for the treatment of anxiety and sleep disorders. Methods: We evaluated the anxiolytic effects of N. griffoniana stem bark methanol extract and its major isolated constituent 2,3,4-trihydroxybutylpentatriacontanoate (newtonoate) on the elevated plus maze. Results: Significant increases in the percentage of entries into open arms were induced by both N. griffoniana extract (100 and 150 mg/kg BW; p<0.01) and newtonoate (doses of 3 and 15 mg/kg BW; p<0.05). Conversely, decreases in the percentage of entries into closed arms were observed at the same doses. In addition, N. griffoniana methanol extract (100 mg/kg) and the isolated newtonoate (30 mg/kg) induced significant (p<0.01 and p<0.05, respectively) increases in the time spent in the open arms, while inducing a decrease in the time spent in the closed arms. Newtonoate treatment also decreased head dipping number at doses of 3 and 15 mg/kg, while N. griffoniana methanol extract induced the same effect at 200 mg/kg. Conclusions: These results suggest that N. griffoniana bark extract has anxiolytic properties, which justify its use in folk medicine. Such effects are at least partly mediated by newtonoate.

Stromal control of chronic lymphocytic leukemia cells

License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Research and Reports in Biology 2013:4 23–32 Research and Reports in Biology Dovepress

Interests in the use of Rapid Prostate Antigen Screening Test in the North-Cameroon

Introduction : The number of prostate cancer detected late because of the lack of means of investigation allowing a proximity screening, the poverty which characterize north are the two main elements which led us to lead this study which had for objective to shown the value of using rapid PSA screening tests. Method : We conducted a cross-sectional analytical study in the city of Ngaoundere and Garoua for a period of 5 months. Results : A total of 220 PSA level assays were performed over the 5-month period of our study with variations between the two selected centers. Of 30 samples used to study the sensitivity of rapid PSA screening tests, 22 were positive and 8 negative. The concordance rate for the positive values of the rapid test strip test versus the assay was 100%. The concordance of negative values was 87.5%. In addition, in a sample of 41 patients, PSA tests were performed in 30 patients, or 73.17%, and diagnosed prostate cancer in 69.23% of diagnosed cancer cases. Conclusion : Rapid PSA screening tests are good tools for diagnosing prostate cancer when combined with other tools such as digital rectal examination and ultrasound.