title: Anticancer activity of galactoxyloglucan polysaccharide-conjugated doxorubicin nanoparticles: Mechanistic insights and interactome analysis.
abstract: 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.
authors: Laboratory of Biopharmaceuticals and Nanomedicine, Division of Cancer Research, Regional Cancer Centre, Thiruvananthapuram, Kerala 695011, India.
authors: Manu M
authors: MM
authors: Joseph
authors: Laboratory of Biopharmaceuticals and Nanomedicine, Division of Cancer Research, Regional Cancer Centre, Thiruvananthapuram, Kerala 695011, India.
authors: S R
authors: SR
authors: Aravind
authors: Department of Hematopathology, UT MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors: Suraj K
authors: SK
authors: George
authors: Department of Pathology, Regional Cancer Centre, Thiruvananthapuram, Kerala 695011, India.
authors: K
authors: K
authors: Raveendran Pillai
authors: Department of Biochemistry, University of Kerala, Thiruvananthapuram, Kerala 695011, India.
authors: S
authors: S
authors: Mini
authors: Laboratory of Biopharmaceuticals and Nanomedicine, Division of Cancer Research, Regional Cancer Centre, Thiruvananthapuram, Kerala 695011, India. Electronic address: ttsreelekha@gmail.com.
authors: T T
authors: TT
authors: Sreelekha
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D030562:Databases, Protein; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D004337:Drug Carriers; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005936:Glucans / Q000737:chemistry*; D056945:Hep G2 Cells; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D050997:Nanomedicine; D053758:Nanoparticles; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010316:Particle Size; D011135:Polysaccharides, Bacterial / Q000737:chemistry*; D060066:Protein Interaction Maps; D040901:Proteomics / Q000379:methods; D013678:Technology, Pharmaceutical / Q000379:methods; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D005936:Glucans; C000601288:PST001; D011135:Polysaccharides, Bacterial; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin
keywords: Chemotherapy; Doxorubicin; Galactoxyloglucan nanoparticles; PST-Dox; Toxicity