Inhibition of aerobic glycolysis enhances the anti-tumor efficacy of Zoptarelin Doxorubicin in triple-negative breast cancer cells.

Abstract

AIM:

A characteristic of cancer cells including triple-negative breast cancers (TNBC) is an increased aerobic glycolysis for ATP production representing a selective therapeutic target. More than 70% of TNBC express gonadotropin-releasing hormone receptors (GnRH-R). These receptors can be used for targeted chemotherapy with cytotoxic GnRH agonists such as Zoptarelin Doxorubicin, in which doxorubicin is covalently linked to [D-Lys6 ]GnRH. In this study, we have analyzed whether inhibition of aerobic glycolysis can enhance the antitumor efficacy of GnRH-R-targeted chemotherapy using Zoptarelin Doxorubicin.

METHODS:

Triple-negative breast cancers cell lines MDA-MB-231 and HCC1806 were treated with Zoptarelin Doxorubicin, glycolysis inhibitor 2-deoxy-D-glucose (2DG) or the combination of both agents. Cell viability was measured using Alamar blue. Induction of apoptosis was quantified by measurement of loss of mitochondrial membrane potential. In vivo experiments were performed using nude mice bearing xenografted MDA-MB-231 tumors.

RESULTS:

Treatment of TNBC cells with Zoptarelin Doxorubicin or with 2DG resulted in a significant decrease of cell viability and a significant increase of apoptosis. Treatment with Zoptarelin Doxorubicin in combination with 2DG resulted in significantly reduced viability and enhanced apoptosis compared with single-agent treatments. Combinational index (CI) analysis revealed the co-treatment effect as a synergistic. The antitumor effects of Zoptarelin Doxorubicin or 2DG were confirmed in nude mice. The tumor reducing effects of Zoptarelin Doxorubicin were enhanced by combination with 2DG.

CONCLUSION:

The glycolytic phenotype of TNBC can be used to improve antitumor therapies. Co-treatment of Zoptarelin Doxorubicin with glycolysis inhibitor 2DG might be a suitable therapeutic option for GnRH receptor-positive TNBC.

• Authors: Carsten Gründker, Ulrike Wokoun, Martin Hellriegel, Günter Emons
• Journal: The journal of obstetrics and gynaecology research (J Obstet Gynaecol Res) Vol. 45 Issue 7 Pg. 1334-1342 (Jul 2019) ISSN: 1447-0756 [Electronic] Australia
• PMID: 31016845 (Publication Type: Journal Article)
• Copyright: © 2019 Japan Society of Obstetrics and Gynecology.

Chemical References

• Antineoplastic Agents
• Receptors, LHRH
• LHRH, lysine(6)-doxorubicin
• Gonadotropin-Releasing Hormone
• Doxorubicin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Doxorubicin (analogs & derivatives, pharmacology)
• Female
• Glycolysis (drug effects)
• Gonadotropin-Releasing Hormone (analogs & derivatives, pharmacology)
• Humans
• Mice
• Mice, Nude
• Receptors, LHRH (metabolism)
• Triple Negative Breast Neoplasms (drug therapy)