title: Enhanced effect of geldanamycin nanocomposite against breast cancer cells growing in vitro and as xenograft with vanquished normal cell toxicity.
abstract: Despite enormous advances in remedies developed for breast cancer, an effective therapeutic strategy by targeting malignant cells with the least normal tissue toxicity is yet to be developed. Hsp90 is considered to be an important therapeutic target to inhibit cell proliferation. Geldanamycin (GDM), a potent inhibitor of Hsp90 was withdrawn from clinical trials due to its undesirable hepatotoxicity. We report a superparamagnetic iron oxide (SPION) based polymeric nanocomposite of GDM augmenting anticancer competence with decreased hepatic toxicity. The particle size of nanocomposite was ascertained to be 76±10nm with acceptable stability. A comparative dose dependent in vitro validation of cytotoxicity showed an enhanced cellular damage and necrosis in breast cancer (MCF-7) cell line at a low dose of 5.49nM (in GDM nanocomposite) in contrast to 20nM of pure GDM, while normal breast epithelial cells (MCF-10A) were least affected. Besides, in vivo study (in breast cancer xenografts) substantiated 2.7 fold delay in tumor progression mediated by redundancy in the downstream functions of p-Akt and MAPK-Erk leading to apoptosis with negligible hepatotoxicity. Pure GDM disrupted the function and morphology of liver with lesser therapeutic efficacy than the GDM nanocomposite. These findings deduce that GDM based polymeric magnetite nanocomposite play a vital role in efficacious therapy while vanquishing normal cells and hepatic toxicity and thereby promising it to be reinstated in clinics.
authors.affiliation: Department of Radiation Biology and Toxicology, School of Life Sciences, Manipal University, Manipal 576 104, Karnataka, India.
authors.forename: Suma
authors.initials: S
authors.lastname: Prabhu
authors.affiliation: Department of Biotechnology, School of Life Sciences, Manipal University, Manipal 576 104, Karnataka, India.
authors.forename: Preeta
authors.initials: P
authors.lastname: Ananthanarayanan
authors.affiliation: Department of Biotechnology, School of Life Sciences, Manipal University, Manipal 576 104, Karnataka, India.
authors.forename: Sajida Kannangar
authors.initials: SK
authors.lastname: Aziz
authors.affiliation: Department of Pathology, Kasturba Medical College, Mangalore Campus, Manipal University, Mangalore 575 001, Karnataka, India.
authors.forename: Sharada
authors.initials: S
authors.lastname: Rai
authors.affiliation: Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576 104, Karnataka, India.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Mutalik
authors.affiliation: Department of Radiation Biology and Toxicology, School of Life Sciences, Manipal University, Manipal 576 104, Karnataka, India. Electronic address: rao.satish@manipal.edu.
authors.forename: Satish Rao Bola
authors.initials: SR
authors.lastname: Sadashiva
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D016227:Benzoquinones / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage*; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053761:Nanocomposites / Q000008:administration & dosage*; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects / Q000502:physiology; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; C001277:geldanamycin
keywords: Breast cancer; Geldanamycin; Hepatocellular toxicity; Hsp90; Nanocomposite; SPION