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: John Koren 3rd, Yoshinari Miyata, Janine Kiray, John C O'Leary 3rd, Lana Nguyen, Jianping Guo, Laura J Blair, Xiaokai Li, Xiokai Li, Umesh K Jinwal, Jin Q Cheng, Jason E Gestwicki, Chad A Dickey
• Journal: PloS one (PLoS One) Vol. 7 Issue 4 Pg. e35566 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22563386 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Estrogen Receptor alpha
• Pyridinium Compounds
• Thiazoles
• rhodacyanine
• Tamoxifen
• N-(3-pyridylmethyl)adriamycin
• Doxorubicin
• Proto-Oncogene Proteins c-akt

Topics

• Cell Line, Tumor
• Cell Survival (drug effects)
• Doxorubicin (analogs & derivatives, chemistry, toxicity)
• Drug Resistance, Neoplasm (drug effects)
• Estrogen Receptor alpha (metabolism)
• HEK293 Cells
• HeLa Cells
• Humans
• Neoplasms (metabolism, pathology)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyridinium Compounds (chemistry, toxicity)
• Tamoxifen (pharmacology)
• Thiazoles (chemistry, toxicity)