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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.

Author information

1
Department of Gastroenterology, Chinese Medicine Research and Development Center, Sex Hormone Research Center, Research Center for Tumor Medicine, China Medical University Hospital, Taichung, Taiwan.
2
Department of OBS & GYN, China Medical University Hospital, Taichung, Taiwan.
3
Graduate Institute of Chinese Medicine, Graduate Institute of BioMedical Sciences, School of Medicine, China Medical University, Taichung, Taiwan.
4
Department of Medicine, China Medical University, Taichung, Taiwan.
5
Department of Medicine, Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
6
Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
7
Department of Nursing, Asia University, Taichung, Taiwan.

Abstract

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

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