PMID- 23251606
OWN - NLM
STAT- MEDLINE
DCOM- 20130603
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 12
DP  - 2012
TI  - Cellular and molecular mechanisms underlie the anti-tumor activities exerted by 
      Walterinnesia aegyptia venom combined with silica nanoparticles against multiple 
      myeloma cancer cell types.
PG  - e51661
LID - 10.1371/journal.pone.0051661 [doi]
LID - e51661
AB  - 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, 
      NFkappaB 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.
FAU - Badr, Gamal
AU  - Badr G
AD  - Princess Johara Alibrahim Center for Cancer Research, Prostate Cancer Research 
      Chair, College of Medicine, King Saud University, Riyadh, Saudi Arabia. 
      badr73@yahoo.com
FAU - Al-Sadoon, Mohamed K
AU  - Al-Sadoon MK
FAU - Abdel-Maksoud, Mostafa A
AU  - Abdel-Maksoud MA
FAU - Rabah, Danny M
AU  - Rabah DM
FAU - El-Toni, Ahmed M
AU  - El-Toni AM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121210
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Elapid Venoms)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Receptors, CXCR4)
RN  - 126547-89-5 (Intercellular Adhesion Molecule-1)
RN  - 7631-86-9 (Silicon Dioxide)
SB  - IM
MH  - Actin Cytoskeleton/drug effects
MH  - Animals
MH  - Antineoplastic Agents/pharmacology/*therapeutic use
MH  - Apoptosis/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Chemokine CXCL12/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Down-Regulation/drug effects
MH  - Drug Screening Assays, Antitumor
MH  - Elapid Venoms/pharmacology/*therapeutic use
MH  - Elapidae/*metabolism
MH  - Enzyme Activation/drug effects
MH  - Humans
MH  - Intercellular Adhesion Molecule-1/metabolism
MH  - Membrane Potential, Mitochondrial/drug effects
MH  - Multiple Myeloma/*drug therapy/enzymology/*pathology
MH  - Nanoparticles/*therapeutic use
MH  - Polymerization/drug effects
MH  - Proto-Oncogene Proteins c-bcl-2/metabolism
MH  - Receptors, CXCR4/metabolism
MH  - Silicon Dioxide/*chemistry
MH  - Time Factors
PMC - PMC3518476
COIS- Competing Interests: All authors have read and agreed the contents of the 
      manuscript and approved the submission. The authors declare no conflicts of 
      interest, state that the manuscript has not been published or submitted 
      elsewhere.
EDAT- 2012/12/20 06:00
MHDA- 2013/06/05 06:00
PMCR- 2012/12/10
CRDT- 2012/12/20 06:00
PHST- 2012/08/18 00:00 [received]
PHST- 2012/11/06 00:00 [accepted]
PHST- 2012/12/20 06:00 [entrez]
PHST- 2012/12/20 06:00 [pubmed]
PHST- 2013/06/05 06:00 [medline]
PHST- 2012/12/10 00:00 [pmc-release]
AID - PONE-D-12-24932 [pii]
AID - 10.1371/journal.pone.0051661 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(12):e51661. doi: 10.1371/journal.pone.0051661. Epub 2012 Dec 10.