Preclinical evaluation of exemestane as a novel chemotherapy for gastric cancer

J Cell Mol Med. 2019 Nov;23(11):7417-7426. doi: 10.1111/jcmm.14605. Epub 2019 Sep 26.


CYP19A1/aromatase (Ar) is a prognostic biomarker of gastric cancer (GCa). Ar is a critical enzyme for converting androstenedione to oestradiol in the steroidogenesis cascade. For decades, Ar has been targeted with Ar inhibitors (ARIs) in gynaecologic malignancies; however, it is unexplored in GCa. A single-cohort tissue microarray examination was conducted to study the association between Ar expression and disease outcome in Asian patients with GCa. The results revealed that Ar was a prognostic promoter. Bioinformatics analyses conducted on a Caucasian-based cDNA microarray databank showed Ar to be positively associated with GCa prognosis for multiple clinical modalities, including surgery, 5-Fluorouracil (5-FU) for adjuvant chemotherapy, or HER2 positivity. These findings imply that targeting Ar expression exhibits a potential for fulfilling unmet medical needs. Hence, Ar-targeting compounds were tested, and the results showed that exemestane exhibited superior cancer-suppressing efficacy to other ARIs. In addition, exemestane down-regulated Ar expression. Ablating Ar abundance with short hairpin (sh)Ar could also suppress GCa cell growth, and adding 5-FU could facilitate this effect. Notably, adding oestradiol could not prevent exemestane or shAr effects, implicating a nonenzymatic mechanism of Ar in cancer growth. Regarding translational research, treatment with exemestane alone exhibited tumour suppression efficacy in a dose-dependent manner. Combining subminimal doses of 5-FU and exemestane exerted an excellent tumour suppression effect without influencing bodyweight. This study validated the therapeutic potentials of exemestane in GCa. Combination of metronomic 5-FU and exemestane for GCa therapy is recommended.

Keywords: aromatase; exemestane; gastric cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / therapeutic use*
  • Antineoplastic Agents / therapeutic use*
  • Aromatase Inhibitors / therapeutic use*
  • Cell Proliferation / drug effects
  • Down-Regulation / drug effects
  • Drug Evaluation, Preclinical
  • Female
  • Fluorouracil / therapeutic use
  • Humans
  • Male
  • Middle Aged
  • Prognosis
  • Receptors, Estrogen / metabolism
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / metabolism


  • Androstadienes
  • Antineoplastic Agents
  • Aromatase Inhibitors
  • Receptors, Estrogen
  • exemestane
  • Fluorouracil