title: Noscapine chemosensitization enhances docetaxel anticancer activity and nanocarrier uptake in triple negative breast cancer.
abstract: Chemosensitization and enhanced delivery to solid tumor are widely explored strategies to augment the anticancer efficacy of existing chemotherapeutics agents. The aim of current research was to investigate the role of low dose Noscapine (Nos) in potentiating docetaxel cytotoxicity and enhancing tumor penetration of nanocarriers. The objectives are; (1) To evaluate the chemo-sensitizing effect of Nos in combination with docetaxel (DTX), and to elucidate the possible mechanism (2) To investigate the effect of low dose Nos on tumor stroma and enhancing nanocarrier uptake in triple negative breast cancer (TNBC) bearing nude mice. Cytotoxicity and flow cytometry analysis of DTX in Nos (4µM) pre-treated MDA-MB-231 cells showed 3.0-fold increase in cell killing and 30% increase in number of late apoptotic cells, respectively. Stress transducer p38 phosphorylation was significantly upregulated with Nos exposure. DTX showed remarkable downregulation in expression of bcl-2, survivin and pAKT in Nos pre-treated MDA-MB-231 cells. Nos pre-sensitization significantly (p<0.02) enhanced the anti-migration effect of DTX. In vivo studies in orthotopic TNBC tumor bearing mice showed marked reduction in tumor collagen-I levels and significantly (p<0.03) higher intra-tumoral uptake of coumarin-6 loaded PEGylated liposomes (7-fold) in Nos treated group. Chemo-sensitization and anti-fibrotic effect of Nos could be a promising approach to increase anticancer efficacy of DTX which can be used for other nanomedicinal products.
authors.affiliation: College of Pharmacy and Pharmaceuical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Doddapaneni
authors.affiliation: College of Pharmacy and Pharmaceuical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
authors.forename: Ketan
authors.initials: K
authors.lastname: Patel
authors.affiliation: College of Pharmacy and Pharmaceuical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
authors.forename: Nusrat
authors.initials: N
authors.lastname: Chowdhury
authors.affiliation: College of Pharmacy and Pharmaceuical Sciences, Florida A&M University, Tallahassee, FL 32307, USA. Electronic address: mandip.sachdeva@famu.edu.
authors.forename: Mandip
authors.initials: M
authors.lastname: Singh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D054443:Cell Migration Assays; D002465:Cell Movement / Q000187:drug effects; D003374:Coumarins / Q000378:metabolism; D000077143:Docetaxel; D004337:Drug Carriers / Q000737:chemistry*; D004789:Enzyme Activation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008081:Liposomes; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D009665:Noscapine / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D058105:Polymerization / Q000187:drug effects; D013194:Staining and Labeling; D043823:Taxoids / Q000494:pharmacology*; D013844:Thiazoles / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000473:pathology*; D014404:Tubulin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; D004337:Drug Carriers; D008081:Liposomes; D043823:Taxoids; D013844:Thiazoles; D014404:Tubulin; C517282:coumarin 6; D000077143:Docetaxel; D009665:Noscapine; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Chemosensitization; Docetaxel; Noscapine; Triple negative breast cancer; Tumor stroma