TY - JOUR
T1 - Anticancer activity of galactoxyloglucan polysaccharide-conjugated doxorubicin nanoparticles
T2 - Mechanistic insights and interactome analysis
AU - Joseph, Manu M.
AU - Aravind, S. R.
AU - George, Suraj K.
AU - Raveendran Pillai, K.
AU - Mini, S.
AU - Sreelekha, T. T.
N1 - Publisher Copyright:
© 2015 Elsevier B.V. All rights reserved.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - Toxicity associated with chemotherapeutic drugs such as doxorubicin (Dox), is one of the major obstacles that is currently affecting patients. PST-Dox (Galactoxyloglucan, PST001-conjugated Dox) nanoparticles were synthesized by encapsulating Dox with polysaccharide PST001, isolated from Tamarindus indica (Ti) by ionic gelation with tripolyphosphate (TPP). Herein, we demonstrate a detailed mechanistic and interactome network analysis that is specific to PST-Dox action in cancer cells and normal lymphocytes. Our results show that PST-Dox is superior to its parental counterparts, exhibiting a greater cytotoxicity by the induction of apoptosis against a wide variety of cancers by enhanced cellular uptake of Dox from the nanoparticle conjugates. Also, PST-Dox nanoparticles were non-toxic to normal lymphocytes with limited immunostimulatory effects up to certain doses. Elucidation of molecular mechanism by whole genome microarray in cancer cells and lymphocytes revealed that a large number of genes were dysregulated specifically in cancer cells. Specifically, a unique target gene EGR1, contextually determined translational activation of P53 in the cancerous and non-cancerous cells. Most of the key downregulated genes were tyrosine kinases, indicating the potential inhibitory action of PST-Dox on tyrosine kinase oncogenic pathways. Western blotting of proteins corresponding to the genes that were altered at the genomic level was very well correlated in the majority of them, except in a few that demonstrated post-transcriptional modifications. The important findings and highly disciplined approaches highlighted in the present study will speed up the therapeutic potential of this augmented nanoparticle formulation for more robust clinical studies and testing in several cancers.
AB - Toxicity associated with chemotherapeutic drugs such as doxorubicin (Dox), is one of the major obstacles that is currently affecting patients. PST-Dox (Galactoxyloglucan, PST001-conjugated Dox) nanoparticles were synthesized by encapsulating Dox with polysaccharide PST001, isolated from Tamarindus indica (Ti) by ionic gelation with tripolyphosphate (TPP). Herein, we demonstrate a detailed mechanistic and interactome network analysis that is specific to PST-Dox action in cancer cells and normal lymphocytes. Our results show that PST-Dox is superior to its parental counterparts, exhibiting a greater cytotoxicity by the induction of apoptosis against a wide variety of cancers by enhanced cellular uptake of Dox from the nanoparticle conjugates. Also, PST-Dox nanoparticles were non-toxic to normal lymphocytes with limited immunostimulatory effects up to certain doses. Elucidation of molecular mechanism by whole genome microarray in cancer cells and lymphocytes revealed that a large number of genes were dysregulated specifically in cancer cells. Specifically, a unique target gene EGR1, contextually determined translational activation of P53 in the cancerous and non-cancerous cells. Most of the key downregulated genes were tyrosine kinases, indicating the potential inhibitory action of PST-Dox on tyrosine kinase oncogenic pathways. Western blotting of proteins corresponding to the genes that were altered at the genomic level was very well correlated in the majority of them, except in a few that demonstrated post-transcriptional modifications. The important findings and highly disciplined approaches highlighted in the present study will speed up the therapeutic potential of this augmented nanoparticle formulation for more robust clinical studies and testing in several cancers.
KW - Chemotherapy
KW - Doxorubicin
KW - Galactoxyloglucan nanoparticles
KW - PST-Dox
KW - Toxicity
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U2 - 10.1016/j.ejpb.2015.04.001
DO - 10.1016/j.ejpb.2015.04.001
M3 - Article
C2 - 25864443
AN - SCOPUS:84928250531
SN - 0939-6411
VL - 93
SP - 183
EP - 195
JO - European Journal of Pharmaceutics and Biopharmaceutics
JF - European Journal of Pharmaceutics and Biopharmaceutics
ER -