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Evaluation of cytotoxic and chemotherapeutic properties of boldine in breast cancer using in vitro and in vivo models

Authors Paydar M, Kamalidehghan B, Wong YL, Wong WF, Looi CY, Mustafa MR

Received 24 November 2013

Accepted for publication 27 February 2014

Published 6 June 2014 Volume 2014:8 Pages 719—733

DOI https://doi.org/10.2147/DDDT.S58178

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 4

Mohammadjavad Paydar,1 Behnam Kamalidehghan,2 Yi Li Wong,1 Won Fen Wong,3 Chung Yeng Looi,1 Mohd Rais Mustafa1

1Department of Pharmacology, 2Department of Pharmacy, 3Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

Abstract: To date, plants have been the major source of anticancer drugs. Boldine is a natural alkaloid commonly found in the leaves and bark of Peumus boldus. In this study, we found that boldine potently inhibited the viability of the human invasive breast cancer cell lines, MDA-MB-231 (48-hour IC50 46.5±3.1 µg/mL) and MDA-MB-468 (48-hour IC50 50.8±2.7 µg/mL). Boldine had a cytotoxic effect and induced apoptosis in breast cancer cells as indicated by a higher amount of lactate dehydrogenase released, membrane permeability, and DNA fragmentation. In addition, we demonstrated that boldine induced cell cycle arrest at G2/M phase. The anticancer mechanism is associated with disruption of the mitochondrial membrane potential and release of cytochrome c in MDA-MB-231. Boldine selectively induced activation of caspase-9 and caspase-3/7, but not caspase-8. We also found that boldine could inhibit nuclear factor kappa B activation, a key molecule in tumor progression and metastasis. In addition, protein array and Western blotting analysis showed that treatment with boldine resulted in downregulation of Bcl-2 and heat shock protein 70 and upregulation of Bax in the MDA-MB-231 cell line. An acute toxicity study in rats revealed that boldine at a dose of 100 mg/kg body weight was well tolerated. Moreover, intraperitoneal injection of boldine (50 or 100 mg/kg) significantly reduced tumor size in an animal model of breast cancer. Our results suggest that boldine is a potentially useful agent for the treatment of breast cancer.

Keywords: boldine, breast cancer, caspase cascade, Bcl-2/Bax, heat shock protein 70, nuclear factor kappa B

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