borrelidin and Breast-Neoplasms

Borrelidin is an inhibitor of threonyl-tRNA synthetase with both anticancer and antiangiogenic activities. Although borrelidin could be a potent drug that can treat metastatic cancer through synergistic therapeutic effects, its severe liver toxicity has limited the use for cancer therapeutics. In this study, we developed a liposomal formulation of borrelidin to treat metastatic breast cancer effectively through its combined anticancer and antiangiogenic effects while reducing the potential liver toxicity. The liposomal formulation was optimized to maximize loading stability and efficiency of lipophilic borrelidin in the liposomal membrane and its delivery efficiency to primary tumor in a mouse model of metastatic breast cancer. Liposomal borrelidin showed significant in vitro therapeutic effects on proliferation and migration of tumor cells and angiogenesis of endothelial cells. Furthermore, liposomal borrelidin exhibited superior inhibitory effects on primary tumor growth and lung metastasis in vivo compared to free borrelidin. More importantly, liposomal borrelidin did not induce any significant systemic toxicity in the mouse model after multiple injections.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Stability; Fatty Alcohols; Female; Human Umbilical Vein Endothelial Cells; Humans; Liposomes; Lung Neoplasms; Mice; Xenograft Model Antitumor Assays

Clinically effective anti-cancer drugs have to tread a narrow line between selective cytotoxicity on tumor cells and tolerable adverse effects against healthy tissues. This causes the failure of many potential cancer drugs in advanced clinical trials, hence signifying the importance of a comprehensive initial estimate of the cytotoxicity of prospective anti-cancer drugs in preclinical studies. In this study, the cytotoxicity of borrelidin, a macrolide antibiotic with a high cytotoxic selectivity for proliferating endothelial cells and leukemia cells, was tested on malignant and non-malignant breast cells. Highly metastatic breast cancer cell lines (MDA-MB-231 and MDA-MB-435) showed promising results and exhibited good sensitivity to borrelidin at low nanomolar concentrations, but borrelidin was cytotoxic to a non-malignant breast epithelial cell line (MCF10A) as well. Furthermore, although a high sensitivity of endothelial cells (human umbilical vein endothelial cells; HUVEC) and individual leukemia cell lines (Jurkat and IM9) to borrelidin was confirmed in this study, another leukemia cell line (HL60) and an immortalized endothelial cell line (EA.hy926) displayed a significantly decreased sensitivity. Reduced sensitivity to borrelidin was associated with elevated bcl-2 expression in these cell lines. In conclusion, the results presented show that borrelidin displays high and selective cytotoxicity against subgroups of cancer cells and endothelial cells, but, owing to its non-specific toxicity to non-malignant cells, its clinical application might be restricted because of likely adverse effects and limited efficacy in bcl2-overexpressing cancer cells.

Topics: Adenosine Triphosphate; Antibiotics, Antineoplastic; Blotting, Western; Breast; Breast Neoplasms; Cell Line, Tumor; Epithelial Cells; Fatty Alcohols; Female; Genes, bcl-2; Human Umbilical Vein Endothelial Cells; Humans; Leukemia; Tetrazolium Salts; Thiazoles