Abstract
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 IC50 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, BclXL 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.
Highlights
Hematologic malignancies are one of the most prevalent types of human cancers worldwide and cause high mortality rates
We focused special attention on the cellular and molecular mechanisms underlying the anti-tumor activities exerted on the migration, invasion, proliferation and apoptosis of primary MM cells isolated from MM patients as well as 2 human MM cell lines (U266 and RPMI 8226)
Preparation of Walterinnesia Aegyptia Venom Walterinnesia aegyptia snakes were collected from the central region of Saudi Arabia (No specific permits were required for the described field studies as well as no specific permissions were required for these locations/activities because the location is not privately-owned or protected in any way and the field studies did not involve endangered or protected species)
Summary
Hematologic malignancies are one of the most prevalent types of human cancers worldwide and cause high mortality rates. The Bcl-2 family of proteins consists of prominent regulators of apoptosis signaling that are often misappropriated in many cancers, including lung carcinoma, lymphoma, breast carcinoma and MM [16]. Members of this protein family can be divided into death antagonists, such as Bcl-2, and death agonists, such as Bak and Bax [17]. Bcl-2 overexpression has been implicated in cancer chemoresistance, while high levels of pro-apoptotic proteins, such as Bax, promote apoptosis and sensitize tumor cells to various anti-cancer therapies
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