Doxazosin and erlotinib have anticancer effects in the endometrial cancer cell and important roles in ER alpha and Wnt/beta-catenin signaling pathways

Karaca B., Bakır E., Yerer M. B., Cumaoğlu A., Hamurcu Z., Eken A.

JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, cilt.35, sa.11, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 35 Sayı: 11
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1002/jbt.22905
  • Dergi Adı: JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Applied Science & Technology Source, BIOSIS, Biotechnology Research Abstracts, Chemical Abstracts Core, EMBASE, Environment Index, Food Science & Technology Abstracts, MEDLINE
  • Anahtar Kelimeler: apoptosis, cytotoxicity, doxazosin, erlotinib, Wnt/beta-catenin, ESTROGEN-RECEPTOR, BETA-CATENIN, OXIDATIVE STRESS, IN-VITRO, C-MYC, APOPTOSIS, TAMOXIFEN, QUINAZOLINE, EGFR, 4-HYDROXYTAMOXIFEN
  • Erciyes Üniversitesi Adresli: Evet

Özet

ER alpha and Wnt/beta-catenin pathways are critical for the progression of most endometrial cancers. We aimed to investigate the cytotoxic and apoptotic effects of tamoxifen and quinazoline derivative drugs of doxazosin and erlotinib, and their roles in ER alpha and Wnt/beta-catenin signaling pathways in human endometrial cancer RL 95-2 cell. 3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide assay and xCELLigence systems were performed to evaluate cytotoxicity. Furthermore, apoptotic induction was tested by Annexin V analysis. Caspase-3 and -9 activity and changes in the mitochondrial membrane potential were evaluated. The level of reactive oxygen species was measured by incubating with dichlorofluorescein diacetate. Protein ratios of p-ER alpha/ER alpha, GSK3 beta/p-GSK3 beta, and p-beta-catenin/beta-catenin and expression levels of ESR1, EGFR, c-Myc genes were evaluated to elucidate mechanisms in signaling pathways. We found that the tested drugs showed cytotoxic and apoptotic effects in the cells. Doxazosin significantly reduced ESR1 expression, slightly reduced the p-beta-catenin/beta-catenin ratio and c-Myc expression. Erlotinib significantly increased c-Myc expression while significantly decreasing the p-beta-catenin/beta-catenin and p-ER alpha/ER alpha ratio, and ESR1 expression. However, we observed that the cells develop resistance to erlotinib over a certain concentration, suggesting that ER alpha, ESR1, EGFR, and c-Myc may be a new target for overcoming drug resistance in the treatment of endometrial cancer. We also observed that erlotinib and doxazosin play an important role in the ER alpha signaling pathway and can act as potent inhibitors of PKA and/or tyrosine kinase in the Wnt/beta-catenin signaling pathway in RL 95-2 cell. In conclusion, doxazosin and erlotinib may have a possible therapeutic potential in human endometrial cancer.