Investigating the combined effects of jadomycin B and celecoxib against triple-negative breast cancer using zebrafish larval xenografts

Abstract

Breast cancer affects one in eight Canadian women over their lifetime. Triple-negative breast cancer (TNBC) represents 10%-20% of all advanced stage breast cancers, often developing multidrug resistance (MDR), commonly resulting in treatment failure. Jadomycin B (JB), a natural product of Streptomyces venezuelae, maintains cytotoxicity against MDR TNBCs, and its activity is enhanced when combined with selective cyclooxygenase-2 inhibitor, celecoxib (CXB) in vitro. Our objectives were to evaluate the toxicity and anticancer effects of JB combined with CXB using zebrafish larval xenografts as a model system. Fluorescent human TNBC MDA-MB-231 cells (231-enhanced green fluorescent protein (EGFP)) were generated and characterized for zebrafish larval xenografts. A maximum tolerated dose (MTD) in zebrafish larvae were determined for JB (20 µM) and CXB (5 µM). Zebrafish embryos were xenotransplanted with 50-100 231-EGFP cells and treated with the MTDs of JB and CXB alone or in combination. The combination of JB and CXB resulted in a 75% reduction in 231-EGFP fluorescence intensity, significantly higher than reductions caused by either drug alone (39% for JB, 15% for CXB) (p < 0.05). This study demonstrates that combining JB with CXB enhances anticancer activity in a zebrafish larval xenograft model of human TNBC, validating effects previously determined in vitro.

Keywords: breast cancer; chemotherapy; cyclooxygenase-2 (COX-2); jadomycin; zebrafish.