Doxorubicin Conjugated to Immunomodulatory Anticancer Lactoferrin Displays Improved Cytotoxicity Overcoming Prostate Cancer Chemo resistance and Inhibits Tumour Development in TRAMP Mice
| Autor: | Jayanth Suryanarayanan Shankaranarayanan, Jagat R. Kanwar, Afrah Jalil Abd AL-Juhaishi, Rupinder K. Kanwar |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Iron Apoptosis Mice Transgenic Adenocarcinoma Pharmacology Article Interferon-gamma Mice 03 medical and health sciences 0302 clinical medicine DU145 Cell Line Tumor Spheroids Cellular polycyclic compounds Animals Topoisomerase II Inhibitors Medicine Doxorubicin Chemokine CCL4 Author Correction Cytotoxicity Drug Carriers Multidisciplinary biology Tumor Necrosis Factor-alpha business.industry Lactoferrin Prostatic Neoplasms Drug Synergism Neoplasm Proteins 3. Good health 030104 developmental biology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Drug delivery Cancer cell biology.protein Cattle Chemokine CCL17 Drug Screening Assays Antitumor business Drug carrier medicine.drug Tramp |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep32062 |
| Popis: | Advanced, metastatic, castration resistant and chemo-resistant prostate cancer has triggered change in the drug development landscape against prostate cancer. Bovine lactoferrin (bLf) is currently attracting attention in clinics for its anti-cancer properties and proven safety profile. bLf internalises into cancer cells via receptor mediated endocytosis, boosts immunity and complements chemotherapy. We employed bLf as an excellent functional carrier protein for delivering doxorubicin (Dox) into DU145 cells, CD44+/EpCAM+ double positive enriched DU145 3D prostaspheres and drug resistant ADR1000-DU145 cells, thus circumventing Dox efflux, to overcome chemo-resistance. Successful bLf-Dox conjugation with iron free or iron saturated bLf forms did not affect the integrity and functionality of bLf and Dox. bLf-Dox internalised into DU145 cells within 6 h, enhanced nuclear Dox retention up to 24 h and proved significantly effective (p 50 value of Dox from 5.3 μM to 1.3 μM (4 fold). Orally fed iron saturated bLf-Dox inhibited tumour development, prolonged survival, reduced Dox induced general toxicity, cardiotoxicity, neurotoxicity in TRAMP mice and upregulated serum levels of anti-cancer molecules TNF-α, IFN-γ, CCL4 and CCL17. The study identifies promising potential of a novel and safer bLf-Dox conjugate containing a conventional cytotoxic drug along with bLf protein to target drug resistance. |
| Databáze: | OpenAIRE |
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