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 (4 µM) 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.

Reversal of drug-resistance by noscapine chemo-sensitization in docetaxel resistant triple negative breast cancer

“…In our recently published study, we have evidently showed that Nos treatment lead to the activation of early stress markers such as phospho p38 and phospho JNK (family of MAP kinases) in a time and dose dependent manner, thus may sensitize TNBC cells to DTX to induce apoptosis significantly. In the same study, we published that Nos could act as an anti-fibrotic agent and enhance the tumor penetration of coumarin-6 loaded PEGylated liposomes in triple negative breast cancer xenografts 32 .…”

Chemosensitizing Effect of Cernumidine Extracted from Solanum cernuum on Bladder Cancer Cells in Vitro

“…[27] A low dose of the benzylisoquinoline alkaloid noscapine acted as a chemosensitizer for docetaxel on triple negative breast cancer cells. [9] These results showed the promising use of natural compounds associated with chemotherapeutic agents already clinically used to overcome chemoresistance and to enhance the drug sensitivity.…”

“…Such efforts are motivated by their chemosensitizing or synergetic/additive effects against malignant tumors . In this context, bioactive compounds from natural products have been explored to act as potent chemosensitizer in combination with conventional chemotherapeutic drugs . This strategy can offer several benefits such as overcoming limitations with existing chemotherapeutic regimes by reducing the dosage required and consequently, the side effects of the chemosensitizing agent used.…”

Liposomes co-Loaded with 6-Phosphofructo-2-Kinase/Fructose-2, 6-Biphosphatase 3 (PFKFB3) shRNA Plasmid and Docetaxel for the Treatment of non-small Cell Lung Cancer

“…In order to identify and confirm various markers involved in the cytotoxicity by the co-delivery, we carried out the western blotting for apoptotic markers in A549 and H460 cells (40). Protein markers of cell survival and apoptosis were evaluated.…”