Jadomycin B Acts Synergistically with NSAIDs to Produce Cytotoxic Effects in Human Breast Cancer Cells in vitro

BACKGROUND: Breast cancer is the most prevalent cancer in North American women. Jadomycin B is a novel compound that is effective in killing triple negative human breast cancer cells that have become resistant to anthracycline and taxane chemotherapies. The mechanism through which jadomycin B exerts its cytotoxic effect remains to be fully characterized. A quantitative PCR (qPCR) array of cancer drug targets identified cyclooxygenase-2 (COX-2) as a gene of interest in jadomycin B resistant breast cancer cells. OBJECTIVE: To explore the effects of COX-2 signalling on jadomycin B cytotoxicity in MDA-MB-231 cells as a model of invasive triple-negative, human breast cancer requiring more effective treatments. METHODS AND RESULTS: Control MDA-MB-231 (231-CON) cells exposed to increasing concentrations of jadomycin B (0-2.2 µM) over 7 months developed a 3-fold resistance to jadomycin B as determined using methyl-tetrazolium (MTT) cell viability assays. By qPCR, there was a significant increase in COX-2 (40 fold, p < 0.05) but not cyclooxygenase-1 (COX-1) (0.17 fold, p < 0.05), mRNA expression in jadomycin resistant (231-JB) versus 231-CON cells. A similar increase in COX-2 was not observed in mitoxantrone resistant MDA-MB-231 cells (231-MITX). We therefore hypothesized that inhibition of COX-2 signalling would increase the susceptibility of breast cancer cells to jadomycin B. The 231-CON and 231-JB cells were treated with jadomycin B with or without the COX-2 selective inhibitor celecoxib (CXB), or COX-1/2 inhibitors ibuprofen (IBU) or Naproxen (NAP). The SynergyFinder 2.0 web application was used to analyze the cytotoxicity (MTT assays) of these combinations and calculate synergy scores using the Bliss model. IBU and NAP were found to act synergistically with jadomycin B in both control and jadomycin resistant cells, while CXB acted additively (Table 1). CONCLUSIONS: Jadomycin B acts additively or synergistically with inhibitors of COX-2 in vitro, resulting in increased cytotoxic effect. These results justify further investigation into the COX-2 signaling pathway as a means to elucidate the mechanism of action of jadomycin B. Additionally, our research has the potential to contribute to an improved understanding of breast cancer relevant COX-2 signalling, facilitating the use of COX-2 inhibitors as chemosensitizers. © FASEB.