title: Rhodacyanine derivative selectively targets cancer cells and overcomes tamoxifen resistance.
abstract: MKT-077, a rhodacyanine dye, was shown to produce cancer specific cell death. However, complications prevented the use of this compound beyond clinical trials. Here we describe YM-1, a derivative of MKT-077. We found that YM-1 was more cytotoxic and localized differently than MKT-077. YM-1 demonstrated this cytotoxicity across multiple cancer cell lines. This toxicity was limited to cancer cell lines; immortalized cell models were unaffected. Brief applications of YM-1 were found to be non-toxic. Brief treatment with YM-1 restored tamoxifen sensitivity to a refractory tamoxifen-resistant MCF7 cell model. This effect is potentially due to altered estrogen receptor alpha phosphorylation, an outcome precipitated by selective reductions in Akt levels (Akt/PKB). Thus, modifications to the rhodocyanine scaffold could potentially be made to improve efficacy and pharmacokinetic properties. Moreover, the impact on tamoxifen sensitivity could be a new utility for this compound family.
authors.affiliation: Department of Molecular Medicine, USF Health Byrd Alzheimer's Institute, College of Medicine, University of South Florida, Tampa, Florida, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Koren
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Miyata
authors.forename: Janine
authors.initials: J
authors.lastname: Kiray
authors.forename: John C
authors.initials: JC
authors.lastname: O'Leary
authors.forename: Lana
authors.initials: L
authors.lastname: Nguyen
authors.forename: Jianping
authors.initials: J
authors.lastname: Guo
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Blair
authors.forename: Xiaokai
authors.initials: X
authors.lastname: Li
authors.forename: Xiokai
authors.initials: X
authors.lastname: Li
authors.forename: Umesh K
authors.initials: UK
authors.lastname: Jinwal
authors.forename: Jin Q
authors.initials: JQ
authors.lastname: Cheng
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
authors.forename: Chad A
authors.initials: CA
authors.lastname: Dickey
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000737:chemistry / Q000633:toxicity; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011726:Pyridinium Compounds / Q000737:chemistry* / Q000633:toxicity; D013629:Tamoxifen / Q000494:pharmacology*; D013844:Thiazoles / Q000737:chemistry* / Q000633:toxicity
chemical_list: D047628:Estrogen Receptor alpha; D011726:Pyridinium Compounds; D013844:Thiazoles; C481079:rhodacyanine; D013629:Tamoxifen; C079109:N-(3-pyridylmethyl)adriamycin; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt