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- Title
Pharmacological interactions of jadomycin B with topoisomerase poisons in MDA-MB-231 human breast cancer cells.
- Authors
McKeown, Brendan T.; Goralski, Kerry B.
- Abstract
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 0.72–0.94) in MDA-MB-231 cells. In comparison, combined mitoxantrone and doxorubicin produced additive cytotoxicity (combination index values 0.96–1.11). Jadomycin B combined with the proteosome inhibitor MG132 had additive cytotoxicity (combination index values 0.76–1.18). In contrast, mitoxantrone or doxorubicin cytotoxicity was antagonized by MG132 (combination index values 1.21–2.31). Jadomycin B treatment arrested cells in S-phase (P = 0.0024) as opposed to mitoxantrone which caused G2/M-phase arrest (P < 0.0001). In conclusion, jadomycin B interacts differently than known TOP2 poisons in combination, supporting a novel pharmacological mechanism(s) of action for jadomycin B cytotoxicity.
- Subjects
TRIPLE-negative breast cancer; CYTOTOXINS; BREAST cancer; CELL cycle; DNA topoisomerase II
- Publication
Canadian Journal of Physiology & Pharmacology, 2025, Vol 103, Issue 1, p36
- ISSN
0008-4212
- Publication type
Academic Journal
- DOI
10.1139/cjpp-2024-0232