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DDTC Suppresses Ovarian Cancer Development via the PI3K/AKT/mTOR Signaling Pathway
Meng Li1, Wenqi Zhang2, Yihan Wang1
1Department of Pharmacology, College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050200 Hebei Province, China.
Abstract:
In prior research, 6,12-diphenyl-3,9-diazatetraasterane-1, 5, 7, 11-tetracarboxylate (DDTC) has been shown to be an effective inhibitor of the growth of the SKOV3 and A2780 ovarian cancer (OC) cell lines. Flow cytometry analyses indicated that DDTC was able to suppress P-CNA expression at the protein level within OC cells, while RNA-seq indicated that DDTC treatment was associated with marked changes in gene expression profiles within A2780 cells. Molecular docking analyses suggested that DDTC has the potential to readily dock with key signaling proteins including PI3K, AKT, and mTOR. In line with these findings, DDTC treatment inhibited the growth of xenograft tumors in a mouse model system. Such treatment was also associated with reduced p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, and CyclinD1 (CCND1) expressions and with the increased expression of PTEN in vitro and in vivo. Together, these results suggest that DDTC is capable of readily inhibiting OC development at least in part via targeting and modulating signaling via the PI3K/AKT/mTOR axis.
Insights
6,12-diphenyl-3,9-diazatetraasterane-1,5,7,11-tetracarboxylate (DDTC) effectively inhibits ovarian cancer (OC) cell growth and xenograft tumors by modulating the PI3K/AKT/mTOR pathway.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Ovarian cancer (OC) remains a significant health challenge with limited effective treatments.
- 6,12-diphenyl-3,9-diazatetraasterane-1,5,7,11-tetracarboxylate (DDTC) has demonstrated preliminary efficacy against OC cell lines.
Purpose of the Study:
- To investigate the anti-cancer mechanisms of DDTC in ovarian cancer.
- To evaluate DDTC's efficacy in preclinical models and identify its molecular targets.
Main Methods:
- Cell viability assays, flow cytometry, and RNA-sequencing (RNA-seq) were used to assess DDTC's effects on OC cell lines (SKOV3, A2780).
- Molecular docking was employed to predict DDTC's interactions with key signaling proteins.
- Xenograft mouse models were utilized to evaluate DDTC's in vivo efficacy and mechanism of action.
Main Results:
- DDTC suppressed P-CNA expression and altered gene expression profiles in OC cells.
- Molecular docking suggested DDTC targets PI3K, AKT, and mTOR.
- DDTC inhibited xenograft tumor growth, reduced p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, and CyclinD1 expression, and increased PTEN expression.
Conclusions:
- DDTC demonstrates significant potential as an anti-ovarian cancer therapeutic.
- DDTC exerts its anti-cancer effects by inhibiting the PI3K/AKT/mTOR signaling pathway.
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