title: Enhanced anticancer efficacy of snake venom combined with silica nanoparticles in a murine model of human multiple myeloma: molecular targets for cell cycle arrest and apoptosis induction.
abstract: Multiple myeloma (MM) is a clonal disease of plasma cells that reside in the bone marrow (BM). MM is an incurable disease; thus, screening for novel anti-myeloma drugs remains critically important. We recently described a silica nanoparticle-based snake venom delivery model that targets cancer cells, but not normal cells. Using this model, we demonstrated a strong enhancement of the antitumor activity of snake venom extracted from Walterinnesia aegyptia (WEV) in two breast carcinoma cell lines when the venom was combined with silica nanoparticles (WEV+NP). In the present study, we aimed to delineate the in vivo therapeutic efficacy of WEV+NP in an MM-bearing experimental nude mouse model. We found that treatment with WEV+NP or WEV alone significantly inhibited tumor growth compared to treatment with NP or vehicle. WEV+NP- and WEV-treated cancer cells exhibited marked elevations in oxidative stress and robust reductions in the levels of interleukin-6 (IL-6) and B cell-activating factor (BAFF). WEV+NP also decreased the surface expression of the chemokine receptors CXCR3, CXCR4 and CXCR6 to a greater extent than WEV alone, and WEV+NP subsequently reduced migration in response to the cognate ligands CXCL10, CXCL12 and CXCL16. Furthermore, we found that WEV+NP strongly inhibited insulin-like growth factor 1 (EGF-1)- and IL-6-mediated MM cell proliferation, altered the cell cycle and enhanced the induction of apoptosis of MM cells. In addition, the results of treatment with WEV+NP or WEV alone revealed that the combination of WEV with NP robustly decreased the expression of cyclin D1, Bcl-2 and the phosphorylation of AKT; increased the expression of cyclin B1; altered the mitochondrial membrane potential; increased the activity of caspase-3, -8 and -9; and sensitized MM cells to growth arrest and apoptosis. Our data reveal the therapeutic potential of the nanoparticle-sustained delivery of snake venom to fight cancer cells.
authors: Zoology Department, College of Science, King Saud University, Riyadh, Saudi Arabia.
authors: Mohamed K
authors: MK
authors: Al-Sadoon
authors: Danny M
authors: DM
authors: Rabah
authors: Gamal
authors: G
authors: Badr
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D053264:B-Cell Activating Factor / Q000276:immunology; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004546:Elapid Venoms / Q000494:pharmacology*; D017815:Elapidae; D005434:Flow Cytometry; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D053758:Nanoparticles / Q000627:therapeutic use*; D011897:Random Allocation; D013047:Specific Pathogen-Free Organisms; D023041:Xenograft Model Antitumor Assays
chemical_list: D053264:B-Cell Activating Factor; D004546:Elapid Venoms; D015850:Interleukin-6; C505720:Tnfsf13b protein, mouse
keywords: Apoptosis; B-cell lymphoma 2; Bcl-2; CK; CKRs; IL-6; MM; Myeloma; NP; Nanoparticles; Proliferation; ROS; Snake venom; WEV; WEV+NP; Walterinnesia aegyptia venom; Walterinnesia aegyptia venom combined with nanoparticles; chemokine; chemokine receptors; interleukin-6; multiple myeloma; nanoparticles; reactive oxygen species