TOP2A is overexpressed and is a therapeutic target for adrenocortical carcinoma.

Therapeutic Approaches
Rare Disease
Drug Repurposing

Abstract

Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with no effective therapy for patients with unresectable disease. The aim of the current study was i) to evaluate TOP2A expression and function in human adrenocortical neoplasm and ACC cells and ii) to determine the anticancer activity of agents that target TOP2A. TOP2A mRNA and protein expression levels were evaluated in 112 adrenocortical tissue samples (21 normal adrenal cortex, 80 benign adrenocortical tumors, and 11 ACCs). In vitro siRNA knockdown of TOP2A in ACC cell lines (NCI-H295R and SW13) was used to determine its effect on cellular proliferation, cell cycle, anchorage-independent growth, and cellular invasion. We screened 14 TOP2A inhibitors for their anticancer activity in ACC cells. TOP2A mRNA and protein expression was significantly higher in ACC than in benign and normal adrenocortical tissue samples (P<0.05). Knockdown of TOP2A gene expression in ACC cell lines significantly decreased cell proliferation, anchorage-independent growth, and invasion (P<0.05). A screening assay in NCI-H295R cells showed that 11 of 14 TOP2A inhibitors had antiproliferative activity, 5 of the 14 TOP2A inhibitors had a higher antiproliferative activity than mitotane, and aclarubicin was the agent with the highest activity. Aclarubicin was validated to significantly decrease proliferation and tumor spheroid size in both NCI-H295R and SW13 ACC cell lines (P<0.05). Our results suggest that TOP2A is overexpressed in ACC, regulates cellular proliferation and invasion in ACC cells, and is an attractive target for ACC therapy. Of the TOP2A inhibitors screened, aclarubicin is a good candidate agent to test in future clinical trials for patients with locally advanced and metastatic ACC.

Authors

Jain, Meenu; Zhang, Lisa; He, Mei; Zhang, Ya-Qin; Shen, Min; Kebebew, Electron;

Keywords

  • Aclarubicin/ pharmacology
  • Adrenal Cortex Neoplasms/ metabolism
  • Adrenocortical Carcinoma/ metabolism
  • Antigens, Neoplasm/ genetics
  • Antigens, Neoplasm/ metabolism
  • Antineoplastic Agents/ pharmacology
  • Apoptosis/ drug effects
  • Cell Line, Tumor
  • Cell Proliferation/ drug effects
  • DNA Topoisomerases, Type II/ genetics
  • DNA Topoisomerases, Type II/ metabolism
  • DNA-Binding Proteins/ antagonists & inhibitors
  • DNA-Binding Proteins/ genetics
  • DNA-Binding Proteins/ metabolism
  • Gene Knockdown Techniques
  • Humans
  • RNA, Messenger/ metabolism
  • RNA, Small Interfering/ genetics
  • Topoisomerase II Inhibitors/ pharmacology

External Links