Cellular and molecular mechanisms underlie the anti-tumor activities exerted by Walterinnesia aegyptia venom combined with silica nanoparticles against multiple myeloma cancer cell types

• Published in: PloS one 2012-12, Vol.7 (12), p.e51661
• Main Authors: Badr, Gamal, Al-Sadoon, Mohamed K, Abdel-Maksoud, Mostafa A, Rabah, Danny M, El-Toni, Ahmed M
• Format: Article
• Language: English
• Subjects: Actin; Actin Cytoskeleton - drug effects; AKT protein; Analysis; Angiogenesis; Animals; Annexin V; Anticancer properties; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor agents; Apoptosis; Apoptosis - drug effects; Bax protein; Bcl-2 protein; BIM protein; Biological effects; Biology; Breast cancer; Cancer; Cancer therapies; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Cellular signal transduction; Chemokine CXCL12 - pharmacology; Chemokines; Chemotaxis; CXC chemokines; CXCL12 protein; CXCR4 protein; Cytometry; Cytoskeleton; Development and progression; Dose-Response Relationship, Drug; Down-Regulation - drug effects; Drug delivery systems; Drug Screening Assays, Antitumor; Effectors; Elapid Venoms - pharmacology; Elapid Venoms - therapeutic use; Elapidae - metabolism; Enzyme Activation - drug effects; Extracellular signal-regulated kinase; Flow cytometry; Health aspects; Humans; Intercellular Adhesion Molecule-1 - metabolism; Kinases; Leukocytes (mononuclear); Ligands; Lymphocytes B; Lymphoma; Lymphomas; Mcl-1 protein; Medical prognosis; Medical research; Medicine; Membrane potential; Membrane Potential, Mitochondrial - drug effects; Mitochondria; Molecular modelling; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - enzymology; Multiple Myeloma - pathology; Nanoparticles; Nanoparticles - therapeutic use; Nanotechnology; NF-κB protein; Pathogenesis; Polymerization - drug effects; Prostate cancer; Proteins; Proto-Oncogene Proteins c-bcl-2 - metabolism; R&D; Receptors, CXCR4 - metabolism; Research & development; Silica; Silicon dioxide; Silicon Dioxide - chemistry; Snakes; Time Factors; Venom; Venoms; Walterinnesia aegyptia; Zoology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0051661

Multiple myeloma (MM) is a clonal disease of plasma cells that remains incurable despite the advent of several novel therapeutics. In this study, we aimed to delineate the impact of snake venom extracted from Walterinnesia aegyptia (WEV) alone or in combination with silica nanoparticles (WEV+NP) on primary MM cells isolated from patients diagnosed with MM as well as on two MM cell lines, U266 and RPMI 8226. The IC(50) values of WEV and WEV+NP that significantly decreased MM cell viability without affecting the viability of normal peripheral mononuclear cells (PBMCs) were determined to be 25 ng/ml and 10 ng/ml, respectively. Although both WEV (25 ng/ml) and WEV+NP (10 ng/ml) decreased the CD54 surface expression without affecting the expression of CXCR4 (CXCL12 receptor) on MM cells, they significantly reduced the ability of CXC chemokine ligand 12 (CXCL12) to induce actin cytoskeleton rearrangement and the subsequent reduction in chemotaxis. It has been established that the binding of CXCL12 to its receptor CXCR4 activates multiple intracellular signal transduction pathways that regulate MM cell chemotaxis, adhesion, and proliferation. We found that WEV and WEV+NP clearly decreased the CXCL12/CXCR4-mediated activation of AKT, ERK, NFκB and Rho-A using western blot analysis; abrogated the CXCL12-mediated proliferation of MM cells using the CFSE assay; and induced apoptosis in MM cell as determined by PI/annexin V double staining followed by flow cytometry analysis. Monitoring the expression of B-cell CCL/Lymphoma 2 (Bcl-2) family members and their role in apoptosis induction after treatment with WEV or WEV+NP revealed that the combination of WEV with NP robustly decreased the expression of the anti-apoptotic effectors Bcl-2, Bcl(XL) and Mcl-1; conversely increased the expression of the pro-apoptotic effectors Bak, Bax and Bim; and altered the mitochondrial membrane potential in MM cells. Taken together, our data reveal the biological effects of WEV and WEV+NP and the underlying mechanisms against myeloma cancer cells.