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J. Physiol. Pharmacol."],"published-print":{"date-parts":[[2025,1,1]]},"abstract":"<jats:p> Jadomycin B, a natural product isolated from Streptomyces venezuelae, exerts an anti-cancer effect on human triple negative breast cancer cells in vitro and has anti-tumoral effects in vivo in animal models of breast cancer. One proposed mechanism for this anti-cancer effect is through interaction with topoisomerase 2 (TOP2). Based on the previously described interactions between jadomycin B and TOP2 we hypothesized that jadomycin B will act additively with TOP2 poisons and produce a similar functional outcome in eliciting cell cycle arrest. Combined treatments of jadomycin B and the TOP2 poisons doxorubicin or mitoxantrone produced moderately synergistic to additive cytotoxicity (combination index values ranging from 0.72\u20130.94) in MDA-MB-231 cells. In comparison, combined mitoxantrone and doxorubicin produced additive cytotoxicity (combination index values 0.96\u20131.11). Jadomycin B combined with the proteosome inhibitor MG132 had additive cytotoxicity (combination index values 0.76\u20131.18). In contrast, mitoxantrone or doxorubicin cytotoxicity was antagonized by MG132 (combination index values 1.21\u20132.31). Jadomycin B treatment arrested cells in S-phase ( P\u00a0=\u00a00.0024) as opposed to mitoxantrone which caused G<jats:sub>2<\/jats:sub>\/M-phase arrest ( P\u00a0&lt;\u00a00.0001). In conclusion, jadomycin B interacts differently than known TOP2 poisons in combination, supporting a novel pharmacological mechanism(s) of action for jadomycin B cytotoxicity. <\/jats:p>","DOI":"10.1139\/cjpp-2024-0232","type":"journal-article","created":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T21:36:08Z","timestamp":1730410568000},"page":"36-45","update-policy":"https:\/\/doi.org\/10.1139\/csp-crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Pharmacological interactions of jadomycin B with topoisomerase poisons in MDA-MB-231 human breast cancer cells"],"prefix":"10.1139","volume":"103","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7336-0072","authenticated-orcid":false,"given":"Brendan T.","family":"McKeown","sequence":"first","affiliation":[{"name":"Dalhousie University","place":["Halifax, Canada"]},{"name":"Beatrice Hunter Cancer Research Institute","place":["Halifax, Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0040-5879","authenticated-orcid":false,"given":"Kerry B.","family":"Goralski","sequence":"additional","affiliation":[{"name":"Beatrice Hunter Cancer Research Institute","place":["Halifax, Canada"]},{"name":"Faculty of Medicine and College of Pharmacy, Faculty of Health, Dalhousie University","place":["Halifax, Canada"]},{"name":"Division of Pediatric Hematology and Oncology","place":["Halifax, Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"155","reference":[{"key":"refg1\/ref1","doi-asserted-by":"publisher","DOI":"10.5650\/jos.60.71"},{"key":"refg2\/ref2","doi-asserted-by":"publisher","DOI":"10.1016\/0040-4039(91)80152-V"},{"key":"refg3\/ref3","doi-asserted-by":"publisher","DOI":"10.1097\/CAD.0b013e3282ef4571"},{"key":"refg4\/ref4","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.22618"},{"key":"refg5\/ref5","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.886"},{"key":"refg6\/ref6","doi-asserted-by":"publisher","DOI":"10.1503\/cmaj.212097"},{"key":"refg7\/ref7","doi-asserted-by":"publisher","DOI":"10.1124\/pr.58.3.10"},{"key":"refg8\/ref8","doi-asserted-by":"publisher","DOI":"10.1016\/0165-6147(83)90490-X"},{"key":"refg9\/ref9","doi-asserted-by":"publisher","DOI":"10.1016\/0065-2571(84)90007-4"},{"key":"refg10\/ref10","doi-asserted-by":"publisher","DOI":"10.21873\/anticanres.12684"},{"key":"refg11\/ref11","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.Mct-08-0035"},{"key":"refg12\/ref12","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-2952(98)00307-4"},{"key":"refg13\/ref13","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2005.02.011"},{"key":"refg14\/ref14","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.110"},{"key":"refg15\/ref15","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.117.241125"},{"key":"refg16\/ref16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.114560"},{"key":"refg17\/ref17","doi-asserted-by":"publisher","DOI":"10.1097\/cad.0000000000000043"},{"key":"refg18\/ref18","doi-asserted-by":"publisher","DOI":"10.1007\/s10295-006-0113-4"},{"key":"refg19\/ref19","doi-asserted-by":"publisher","DOI":"10.1016\/s0006-2952(97)00116-0"},{"key":"refg20\/ref20","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20090119"},{"key":"refg21\/ref21","doi-asserted-by":"publisher","DOI":"10.1055\/s-2004-815537"},{"key":"refg22\/ref22","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2015.12.015"},{"key":"refg23\/ref23","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c00635"},{"key":"refg24\/ref24","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-016-4059-6"},{"key":"refg25\/ref25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0113832"},{"key":"refg26\/ref26","doi-asserted-by":"publisher","DOI":"10.1139\/cjc-2017-0573"},{"key":"refg27\/ref27","doi-asserted-by":"publisher","DOI":"10.1039\/C5OB01508A"},{"key":"refg28\/ref28","doi-asserted-by":"publisher","DOI":"10.1080\/01635581.2014.951736"},{"key":"refg29\/ref29","doi-asserted-by":"publisher","DOI":"10.1139\/cjpp-2022-0152"},{"key":"refg30\/ref30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0076676"},{"key":"refg31\/ref31","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-016-0433-9"},{"key":"refg32\/ref32","doi-asserted-by":"publisher","DOI":"10.1016\/j.colsurfb.2019.110741"},{"key":"refg33\/ref33","doi-asserted-by":"publisher","DOI":"10.1021\/jf404175t"},{"issue":"1","key":"refg34\/ref34","first-page":"97","volume":"6","author":"Zhang N.","year":"2016","journal-title":"Am. 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