Preclinical evaluation of exemestane as a novel chemotherapy for gastric cancer
Juan-Cheng Yang
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
Search for more papers by this authorNing Chang
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
Search for more papers by this authorDeng-Chyang Wu
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
Search for more papers by this authorWei-Chung Cheng
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
Search for more papers by this authorWei-Min Chung
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
Search for more papers by this authorWei-Chun Chang
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
Search for more papers by this authorFu-Ju Lei
Department of Gastroenterology, Chinese Medicine Research and Development Center, Sex Hormone Research Center, Research Center for Tumor Medicine, 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
Search for more papers by this authorChung-Jung Liu
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
Search for more papers by this authorI-Chen Wu
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
Search for more papers by this authorCorresponding Author
Hsueh-Chou Lai
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
Correspondence
Wen-Lung Ma and Hsueh-Chou Lai, Department of Gastroenterology, Chinese Medicine Research and Development Center, Sex Hormone Research Center, Research Center for Tumor Medicine, China Medical University Hospital, 91 Xueshi Rd., North District, Taichung 40403, Taiwan.
Emails: [email protected] and [email protected]
Search for more papers by this authorCorresponding Author
Wen-Lung Ma
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 Nursing, Asia University, Taichung, Taiwan
Correspondence
Wen-Lung Ma and Hsueh-Chou Lai, Department of Gastroenterology, Chinese Medicine Research and Development Center, Sex Hormone Research Center, Research Center for Tumor Medicine, China Medical University Hospital, 91 Xueshi Rd., North District, Taichung 40403, Taiwan.
Emails: [email protected] and [email protected]
Search for more papers by this authorJuan-Cheng Yang
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
Search for more papers by this authorNing Chang
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
Search for more papers by this authorDeng-Chyang Wu
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
Search for more papers by this authorWei-Chung Cheng
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
Search for more papers by this authorWei-Min Chung
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
Search for more papers by this authorWei-Chun Chang
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
Search for more papers by this authorFu-Ju Lei
Department of Gastroenterology, Chinese Medicine Research and Development Center, Sex Hormone Research Center, Research Center for Tumor Medicine, 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
Search for more papers by this authorChung-Jung Liu
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
Search for more papers by this authorI-Chen Wu
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
Search for more papers by this authorCorresponding Author
Hsueh-Chou Lai
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
Correspondence
Wen-Lung Ma and Hsueh-Chou Lai, Department of Gastroenterology, Chinese Medicine Research and Development Center, Sex Hormone Research Center, Research Center for Tumor Medicine, China Medical University Hospital, 91 Xueshi Rd., North District, Taichung 40403, Taiwan.
Emails: [email protected] and [email protected]
Search for more papers by this authorCorresponding Author
Wen-Lung Ma
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 Nursing, Asia University, Taichung, Taiwan
Correspondence
Wen-Lung Ma and Hsueh-Chou Lai, Department of Gastroenterology, Chinese Medicine Research and Development Center, Sex Hormone Research Center, Research Center for Tumor Medicine, China Medical University Hospital, 91 Xueshi Rd., North District, Taichung 40403, Taiwan.
Emails: [email protected] and [email protected]
Search for more papers by this authorFunding information
This study was supported in part by the Ministry of Science and Technology (MOST108-2320-B-039-017, MOST108-2314-B-039-052, MOST107-2320-B-039-017-MY3; MOST106-2221-E-039-011-MY3, and MOST108-2314-B-039-043-MY3); National Health Research Institute grant (NHRI-EX108-10705BI); and China Medical University/Hospital grant (DMR-100-096, CMU106-S-28, CMU107-N-05, CMU107-TC-02 and DMR-108-179); and Kaohsiung Medical University Hospital (KMUH104-4R48).
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.
CONFLICT OF INTERESTS
There is no conflict of interests in this work.
Open Research
DATA AVAILABILITY STATEMENT
All the data in the work can be provided upon reasonable request.
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