Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells
Open Access
- 9 April 2020
- Vol. 12 (4), 928
- https://doi.org/10.3390/cancers12040928
Abstract
Mitotane is the only drug approved for the treatment of adrenocortical carcinoma (ACC). The regimen to be added to mitotane is a chemotherapy including etoposide, doxorubicin, and cisplatin. This pharmacological approach, however, has a limited efficacy and significant toxicity. Evidence indicates that ACC seems to be sensitive to alkylating agents. Trabectedin is an anti-tumor drug that acts as an alkylating agent with a complex mechanism of action. Here, we investigated whether trabectedin could exert a cytotoxic activity in in vitro cell models of ACC. Cell viability was evaluated by MTT assay on ACC cell lines and primary cell cultures. The gene expression was evaluated by q-RT-PCR, while protein expression and localization were studied by Western blot and immunocytochemistry. Combination experiments were performed to evaluate their interaction on ACC cell line viability. Trabectedin demonstrated high cytotoxicity at sub-nanomolar concentrations in ACC cell lines and patient-derived primary cell cultures. The drug was able to reduce /β catenin nuclear localization, although it is unclear whether this effect is involved in the observed cytotoxicity. Trabectedin/mitotane combination exerted a synergic cytotoxic effect in NCI-H295R cells. Trabectedin has antineoplastic activity in ACC cells. The synergistic cytotoxic activity of trabectedin with mitotane provides the rationale for testing this combination in a clinical study.Funding Information
- PharmaMar (NA)
This publication has 48 references indexed in Scilit:
- Human adrenocortical carcinoma cell linesMolecular and Cellular Endocrinology, 2012
- Wnt/β-Catenin Signaling: Components, Mechanisms, and DiseasesDevelopmental Cell, 2009
- Sox17, the canonical Wnt antagonist, is epigenetically inactivated by promoter methylation in human breast cancerBreast Cancer Research and Treatment, 2009
- Development of an Adrenocorticotropin-Responsive Human Adrenocortical Carcinoma Cell LineJournal of Clinical Endocrinology & Metabolism, 2008
- EWS/FLI Mediates Transcriptional Repression via NKX2.2 during Oncogenic Transformation in Ewing's SarcomaPLOS ONE, 2008
- Epigenetic Inactivation of the Canonical Wnt Antagonist SRY-Box Containing Gene 17 in Colorectal CancerCancer Research, 2008
- Gene expression profile of prostate cancer cell lines: Effect of nerve growth factor treatmentMolecular and Cellular Endocrinology, 2008
- Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination StudiesPharmacological Reviews, 2006
- Human Dkk-1, a gene encoding a Wnt antagonist, responds to DNA damage and its overexpression sensitizes brain tumor cells to apoptosis following alkylation damage of DNAOncogene, 2002
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001