Preclinical evaluation of exemestane as a novel chemotherapy for gastric cancer

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.

Targeting lipid droplet lysophosphatidylcholine for cisplatin chemotherapy

“…16 Targeting the steroidogenic enzyme cytochrome CYP450 19A1 (aromatase) with exemestane can be effective for patients with GCa. 17 Study shows that differential levels of LDLR expression in EOC cells determine the platinum sensitivity in an LDLR-dependent manner. 10 LDLR expression reprogrammes cellular transcriptome associated with lipid metabolism (Lands cycle in LD) to be the mechanism underlying cisplatin sensitivity.…”

Inflammation-Related Genes Serve as Prognostic Biomarkers and Involve in Immunosuppressive Microenvironment to Promote Gastric Cancer Progression

“…Wang et al showed that CYP1A1 was a possible new molecular target for GC therapy ( 34 ). Yang et al found that CYP19A1 was a prognostic biomarker of GC ( 35 ). Ma et al showed that high CYP1A1 expression may be a favorable factor for patients with GC ( 36 ).…”

Ursolic acid silences CYP19A1/aromatase to suppress gastric cancer growth

“…Threshold value (Ct) dynamics were used (2 −ΔΔCt ) for the quantitation of gene expression. The qRT‐PCR primer sequences used were as follows 20 : CYP19A1 forward 5′‐ACC CTT CTG CGT CGT GTC A‐3′, reverse 5′‐TCT GTG GAA ATC CTG CGT CTT‐3′.…”

“…The WST-1 assay was used for assessing cell growth. 24 Briefly, 2.5 × 10 3 cells/well were seeded in 96-well plates with RPMI/10% fetal bovine serum (FBS) and were incubated for 24 h. The drugs were then added following previous work, 20 and the cells were further incubated (single treatment: UA [20,40,60, 80, and 100 μM] and 5-FU [10 μM]). After 48 h of incubation, 1:10/v:v of WST-1 (Roche) solution was added for a further 60-min incubation period, after which the cell viability was measured through colorimetric detection with an ELISA plate reader (BECKMAN COULTER PARADIGM TM Detection Platform) at an absorbance of 450 nm to generate an optical density proportional to the relative abundance of live cells in the given wells.…”