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Jadomycin B, produced by the soil bacterium Streptomyces venezuelae ISP5230, induces cytotoxicity in human breast cancer cells in vitro and has antitumoral effects in animal models. In models of multidrugresistant, triple-negative breast cancer, jadomycin B has shown promise as it is not a substrate of ABCB1 and ABCG2 drug efflux transporters. The generation of reactive oxygen species and inhibition of topoisomerases are potential mechanisms of jadomycin B-mediated DNA damage and apoptosis. However, the mechanisms of jadomycin B's anticancer activity have not been fully elucidated. By gradually exposing MDA-MB-231 triple-negative human breast cancer cells to jadomycin B, we hypothesized that resistance could be selected to further understand jadomycin B's pharmacological mechanisms. A 3-fold increase in the jadomycin B IC50 was observed in MDA-MB-231 cells exposed to increasing jadomycin B concentrations (0-3 mu M) over 7 months, herein 231-JB cells. The 231-JB cells were cross-resistant to jadomycin F and S but not to the comparator drugs mitoxantrone, doxorubicin, and SN-38. The 231-JB cells did not have increased mRNA expression of topoisomerase-2 nor ABCB1 and ABCG2. Cyclooxygenase-2 (COX-2) increased by 25-fold, but expression of prostaglandin E2 receptor 4 did not significantly change. Cotreatment with celecoxib (15-45 mu M), a COX-2 inhibitor, resensitized the 231-JB cells to jadomycin B (IC50 1/4 1.41 +/- 0.24 to 0.75 +/- 0.31 mu M vs 2.28 +/- 0.54 with 0 mu M celecoxib). To our knowledge, this work represents the first report of the involvement of COX-2 in jadomycin B activity in vitro, proving to be an exciting new target for the exploration of jadomycin B anticancer activity. Significance Statement: Cyclooxygenase-2 (COX-2), the rate-limiting enzyme in prostaglandin production, is associated with procancer signaling. COX-2, ABCB1, and ABCG2 overexpression are typically correlated in cancer, contributing to chemotherapy resistance. We observed increased COX-2, but not ABCG2 or

来源平台：JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS