Starving tumors: inhibition of glycolysis reduces viability of human endometrial and ovarian cancer cells and enhances antitumor efficacy of GnRH receptor-targeted therapies.

Abstract

OBJECTIVE:

Increased glycolysis for energy production is necessary for survival of tumor cells and thus represents a selective therapeutic target. We have analyzed in vitro whether inhibition of glycolysis can reduce the viability of human endometrial and ovarian cancer cells and whether it can enhance the antitumor efficacy of GnRH receptor-targeted therapies.

MATERIALS AND METHODS:

Cell viability of ovarian and endometrial cancer cells treated without or with glycolysis inhibitor 2-Deoxy-D-Glucose (2DG) alone or in combination with GnRH-II antagonist [Ac-D2Nal(1), D-4Cpa(2), D-3Pal(3,6)(8),Leu, D-Ala(10)]GnRH-II or with cytotoxic GnRH-I agonist AEZS-108 (AN-152) was measured using alamar blue assay. Induction of apoptosis was analyzed using TUNEL assay and quantified by measurement of loss of mitochondrial membrane potential. Apoptotic signaling was measured by quantification of activated caspase-3 by using the Western blot technique.

RESULTS:

Treatment of endometrial and ovarian cancer cells with glycolysis inhibitor 2DG resulted in a significant decrease of cell viability and a significant increase of apoptosis. Treatment with 2DG in combination with the GnRH-II antagonist or with AEZS-108 resulted in a significant reduced viability compared with single-agent treatments. The observed reduction in viability was due to induction of apoptosis. Also for apoptosis induction, a significant stronger effect in the case of cotreatments compared with single-agent treatments could be observed. These additive effects could be correlated to increased activation of caspase-3.

CONCLUSIONS:

The glycolytic phenotype of human endometrial and ovarian cancer cells can be targeted for therapeutic intervention. In addition, cotreatment of a glycolysis inhibitor with GnRH receptor-targeted therapies might be a suitable therapy for GnRH receptor-positive human endometrial and ovarian cancers.

• Authors: Madita Reutter, Günter Emons, Carsten Gründker
• Journal: International journal of gynecological cancer : official journal of the International Gynecological Cancer Society (Int J Gynecol Cancer) Vol. 23 Issue 1 Pg. 34-40 (Jan 2013) ISSN: 1525-1438 [Electronic] England
• PMID: 23154267 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Antineoplastic Agents, Hormonal
• Receptors, LHRH
• Deoxyglucose

Topics

• Antimetabolites, Antineoplastic (administration & dosage, pharmacology)
• Antineoplastic Agents, Hormonal (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Carcinoma, Endometrioid (drug therapy, metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Deoxyglucose (administration & dosage, pharmacology)
• Drug Evaluation, Preclinical
• Drug Synergism
• Endometrial Neoplasms (drug therapy, metabolism)
• Female
• Glycolysis (drug effects)
• Humans
• Molecular Targeted Therapy (methods)
• Ovarian Neoplasms (drug therapy, metabolism)
• Receptors, LHRH (antagonists & inhibitors)
• Starvation (chemically induced, pathology)
• Treatment Outcome