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

Preclinical evaluation of exemestane as a novel chemotherapy for gastric cancer.

Yang JC1,2, Chang N3,4, Wu DC5,6, Cheng WC1,2,3,4, Chung WM1,2,3,4, Chang WC1,2,3,4, Lei FJ1,3,4, Liu CJ5,6, Wu IC5,6, Lai HC1,2,3,4, Ma WL1,2,3,4,7.

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Department of Gastroenterology, Chinese Medicine Research and Development Center, Sex Hormone Research Center, Research Center for Tumor Medicine, China Medical University Hospital, Taichung, Taiwan.
Department of OBS & GYN, China Medical University Hospital, Taichung, Taiwan.
Graduate Institute of Chinese Medicine, Graduate Institute of BioMedical Sciences, School of Medicine, China Medical University, Taichung, Taiwan.
Department of Medicine, China Medical University, Taichung, Taiwan.
Department of Medicine, Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
Department of Nursing, Asia University, Taichung, Taiwan.


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.


aromatase; exemestane; gastric cancer

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