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Rottlerin as a novel chemotherapy agent for adrenocortical carcinoma
Yi Zhu1,2, Minjie Wang3, Xu Zhao2,4
1Third Military Medical University, Chongqing, P.R. China.
Abstract:
Adrenocortical carcinoma (ACC) is a rare, but aggressive endocrine malignancy with a generally poor clinical outcome. There is no effective therapy for advanced and metastatic ACC. In our study, we found that an existing drug (rottlerin) exerted its tumour-suppressive function in ACC. Specifically, rottlerin inhibited cellular proliferation of ACC cell lines (NCI-H295R and SW-13) in a dose- and time-dependent manner. We also found that rottlerin induced cell apoptosis and promoted G0/G1 cell cycle arrest in ACC cell lines. The cellular migration and invasion of ACC cell lines were decreased after treatment with rottlerin. Further, the molecular expression of lipoprotein receptor related protein 6 (LRP6) and β-catenin were down-regulated in rottlerin-treated ACC cells, which indicated that Wnt/β-catenin signaling was involved in the tumour-suppressive function of rottlerin. To further confirm the anti-tumour function of rottlerin, a nude mouse ACC xenograft model was used. The xenograft growth curves and TUNEL assays demonstrated that rottlerin inhibited proliferation and induced apoptosis in the ACC xenograft model. Furthmore, we verified that rottlerin down-regulated the expression of LRP6 and β-catenin in vivo. The ACC cell line and xenograft mouse model data indicated that rottlerin significantly inhibited proliferation and induced apoptosis of ACC cells, likely via suppression of the Wnt/β-catenin signaling pathway. Our study indicated the potential therapeutic utility of rottlerin as a novel and potential chemotherapeutic agent for ACC.
Insights
Rottlerin, an existing drug, shows promise in treating aggressive adrenocortical carcinoma (ACC). It inhibits cancer cell growth, promotes apoptosis, and reduces migration, potentially by suppressing the Wnt/β-catenin pathway.
Area of Science:
- Endocrinology
- Oncology
- Pharmacology
Background:
- Adrenocortical carcinoma (ACC) is an aggressive endocrine malignancy with limited treatment options for advanced stages.
- Current therapies for metastatic ACC are largely ineffective, highlighting the need for novel therapeutic strategies.
Purpose of the Study:
- To investigate the potential anti-cancer effects of rottlerin on adrenocortical carcinoma.
- To elucidate the underlying molecular mechanisms of rottlerin's tumor-suppressive function in ACC.
Main Methods:
- In vitro studies using ACC cell lines (NCI-H295R, SW-13) to assess proliferation, apoptosis, cell cycle, migration, and invasion.
- In vivo studies using a nude mouse ACC xenograft model to evaluate tumor growth inhibition and apoptosis induction.
- Molecular analysis of Wnt/β-catenin signaling pathway components (LRP6, β-catenin) in response to rottlerin treatment.
Main Results:
- Rottlerin significantly inhibited ACC cell proliferation, induced apoptosis, and promoted G0/G1 cell cycle arrest in vitro.
- Rottlerin decreased cellular migration and invasion of ACC cell lines.
- In vivo studies confirmed rottlerin's ability to inhibit tumor growth and induce apoptosis in an ACC xenograft model.
- Rottlerin treatment led to the downregulation of LRP6 and β-catenin expression in both cell lines and xenografts, indicating Wnt/β-catenin pathway suppression.
Conclusions:
- Rottlerin exhibits significant tumor-suppressive effects in adrenocortical carcinoma models.
- The anti-cancer activity of rottlerin is likely mediated through the inhibition of the Wnt/β-catenin signaling pathway.
- Rottlerin represents a potential novel chemotherapeutic agent for adrenocortical carcinoma.