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.

<p>Dihydroartemisinin Inhibits the Proliferation of Leukemia Cells K562 by Suppressing PKM2 and GLUT1 Mediated Aerobic Glycolysis</p>

“…Many studies have reported that as a glucose analogue, 2DG could inhibit glycolysis through inhibiting hexokinase and play a direct or auxiliary role in antitumor. 10,28,42 Confusingly, the combination of 2DG and DHA had neither synergy nor antagonism on the expression of PKM2 and GLUT1 in our study ( Figure 5). The potential mechanisms of DHA and 2DG on glycolysis might be different.…”

LINC01605 promotes aerobic glycolysis through lactate dehydrogenase A in triple‐negative breast cancer

“…Furthermore, a wide range of factors that might serve as therapeutic targets suppressed breast cancer by regulating aerobic glycolysis, including betulinic acid, 31 miRNA‐186‐3p, 32 tumor‐derived macrophages, 33 and zoptarelin doxorubicin. 34 Our current study showed that LINC01605 promoted breast cancer by targeting LDHA, which is also a crucial enzyme in aerobic glycolysis. Although this is the first report of the role of LINC01605 in breast cancer by regulating aerobic glycolysis, noncoding RNAs have been extensively explored and proven as key mediators of aerobic glycolysis in breast cancer for a long time.…”

Insights into the Role of Estrogen Receptor β in Triple-Negative Breast Cancer

“…For example, it was shown that exposure of TNBC cells to high glucose concentrations induces proliferation and abrogates the apoptotic effects induced by the drug metformin [150]. Other studies demonstrated that combined treatments, inducing the metabolic switch from glycolysis to OXPHOS, increases the sensitivity of TNBC cells to mitochondrial respiratory complex I inhibitors [151]; whereas inhibition of aerobic glycolysis enhances antitumor efficacy of Zoptarelin Doxorubicin, a cytotoxic agonist of gonadotropin-releasing hormone receptor (GnRH-R), expressed in more than 70% of TNBC tumors [152]. Altogether, these studies indicate that combinational treatment, including energy metabolism-targeting agents, may represent a therapeutic strategy for aggressive TNBC treatment.…”