4.7 Article

FLTX2: A Novel Tamoxifen Derivative Endowed with Antiestrogenic, Fluorescent, and Photosensitizer Properties

期刊

出版社

MDPI
DOI: 10.3390/ijms22105339

关键词

tamoxifen; estrogen receptors; SERM; fluorescence; FRET; reactive oxygen species; superoxide anions; photosensitization; FLTX1; breast cancer; laser dye; molecular dynamics

资金

  1. MINECO (Spain) [SAF2014-61644-EXP]
  2. (MINECO-MCIU)-European Social Funds (ESF) [SAF-2013-48399-R]
  3. Agencia Estatal de Investigacion (AEI-MICINN)
  4. Agencia Estatal de Investigacion (Spain) [MAT2016-79866-R]
  5. EU-FEDER [PID2019-110430GB-C21, PID2019-107335RA-I00]
  6. Gobierno de Canarias (Spain) [2020010067]
  7. MICIU (Spain) [RTI2018-094356B-C21]
  8. Universidad de la Laguna-Cabildo de Tenerife
  9. MEDI Fund
  10. FDCAN Fund

向作者/读者索取更多资源

Tamoxifen is a widely used selective estrogen receptor modulator for breast cancer treatment, but it has undesirable effects on uterine tissues. FLTX2, a derivative of tamoxifen, shows promising antiestrogen properties and induces apoptotic cell death in MCF7 cells through photosensitization.
Tamoxifen is the most widely used selective modulator of estrogen receptors (SERM) and the first strategy as coadjuvant therapy for the treatment of estrogen-receptor (ER) positive breast cancer worldwide. In spite of such success, tamoxifen is not devoid of undesirable effects, the most life-threatening reported so far affecting uterine tissues. Indeed, tamoxifen treatment is discouraged in women under risk of uterine cancers. Recent molecular design efforts have endeavoured the development of tamoxifen derivatives with antiestrogen properties but lacking agonistic uterine tropism. One of this is FLTX2, formed by the covalent binding of tamoxifen as ER binding core, 7-nitrobenzofurazan (NBD) as the florescent dye, and Rose Bengal (RB) as source for reactive oxygen species. Our analyses demonstrate (1) FLTX2 is endowed with similar antiestrogen potency as tamoxifen and its predecessor FLTX1, (2) shows a strong absorption in the blue spectral range, associated to the NBD moiety, which efficiently transfers the excitation energy to RB through intramolecular FRET mechanism, (3) generates superoxide anions in a concentration- and irradiation time-dependent process, and (4) Induces concentration- and time-dependent MCF7 apoptotic cell death. These properties make FLTX2 a very promising candidate to lead a novel generation of SERMs with the endogenous capacity to promote breast tumour cell death in situ by photosensitization.

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