title: A Novel Strategy to Co-target Estrogen Receptor and Nuclear Factor κB Pathways with Hybrid Drugs for Breast Cancer Therapy.
abstract: Nearly 75% of breast tumors express estrogen receptor (ER), and will be treated with endocrine therapy, such as selective estrogen receptor modulator (SERM), tamoxifen, or aromatase inhibitors. Despite their proven success, as many as 40-50% of ER+ tumors fail to respond to endocrine therapy and eventually recur as aggressive, metastatic cancers. Therefore, preventing and/or overcoming endocrine resistance in ER+ tumors remains a major clinical challenge. Deregulation or activation of the nuclear factor κB (NFκB) pathway has been implicated in endocrine resistance and poor patient outcome in ER+ tumors. As a consequence, one option to improve on existing anti-cancer treatment regimens may be to introduce additional anti-NFκB activity to endocrine therapy drugs. Our approach was to design and test SERM-fumarate co-targeting hybrid drugs capable of simultaneously inhibiting both ER, via the SERM, raloxifene, and the NFκB pathway, via fumarate, in breast cancer cells. We find that the hybrid drugs display improved anti-NFκB pathway inhibition compared to either raloxifene or fumarate. Despite some loss in potency against the ER pathway, these hybrid drugs maintain anti-proliferative activity in ER+ breast cancer cells. Furthermore, these drugs prevent clonogenic growth and mammosphere formation of ER+ breast cancer cells. As a proof-of-principle, the simultaneous inhibition of ER and NFκB via a single bifunctional hybrid drug may represent a viable approach to improve the anti-inflammatory activity and prevent therapy resistance of ER-targeted anti-cancer drugs.
authors.affiliation: Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, 835 S. Wolcott, E202 MSB, MC90, Chicago, IL, 60612, USA. ikastr2@uic.edu.
authors.forename: Irida
authors.initials: I
authors.lastname: Kastrati
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60612, USA.
authors.forename: Marton I
authors.initials: MI
authors.lastname: Siklos
authors.affiliation: Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, 835 S. Wolcott, E202 MSB, MC90, Chicago, IL, 60612, USA.
authors.forename: Svitlana D
authors.initials: SD
authors.lastname: Brovkovych
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60612, USA.
authors.forename: Gregory R J
authors.initials: GRJ
authors.lastname: Thatcher
authors.affiliation: Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, 835 S. Wolcott, E202 MSB, MC90, Chicago, IL, 60612, USA. jfrasor@uic.edu.
authors.forename: Jonna
authors.initials: J
authors.lastname: Frasor
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D005650:Fumarates / Q000008:administration & dosage; D006801:Humans; D061986:MCF-7 Cells; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics*; D020849:Raloxifene Hydrochloride / Q000008:administration & dosage; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics*; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000008:administration & dosage
chemical_list: D018931:Antineoplastic Agents, Hormonal; D005650:Fumarates; D016328:NF-kappa B; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride
keywords: Breast cancer; Co-targeting drugs; Estrogen receptor; NFκB pathway