Enhanced effect of geldanamycin nanocomposite against breast cancer cells growing in vitro and as xenograft with vanquished normal cell toxicity

Prabhu, Suma and Ananthanarayanan, Preeta and Sajida, Kannangar Aziz and Rai, Sharada and Mutalik, Srinivas and Rao, Satish BS (2017) Enhanced effect of geldanamycin nanocomposite against breast cancer cells growing in vitro and as xenograft with vanquished normal cell toxicity. Toxicology and Applied Pharmacology, 320. pp. 60-72. ISSN 0041-008X

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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 Geldanamycin (GDM), a potent inhibitor of Hsp90 was withdrawn from clinical trials due to its undesirable hepatotoxicity.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.

Item Type: Article
Uncontrolled Keywords: Breast cancer; Geldanamycin; Hepatocellular toxicity; Hsp90; Nanocomposite; SPION.
Subjects: Life Sciences > MLSC Manipal
Medicine > KMC Manipal > Pathology
Pharmacy > MCOPS Manipal > Pharmaceutics
Depositing User: KMC Library
Date Deposited: 22 May 2017 03:38
Last Modified: 22 May 2017 03:38
URI: http://eprints.manipal.edu/id/eprint/148926

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