Antitumor activity of efrapeptins, alone or in combination with 2-deoxyglucose, in breast cancer in vitro and in vivo

Abstract

Efrapeptins (EF), a family of fungal peptides, inhibit proteasomal enzymatic activities and the in vitro and in vivo growth of HT-29 cells. They are also known inhibitors of F 1 F 0 -ATPase, a mitochondrial enzyme that functions as an Hsp90 co-chaperone. We have previously shown that treatment of cancer cells with EF results in disruption of the Hsp90:F 1 F 0 -ATPase complex and inhibition of Hsp90 chaperone activity. The present study examines the effect of EF on breast cancer growth in vitro and in vivo. As a monotherapy, EF inhibited cell proliferation in vitro with an IC 50 value ranging from 6 nM to 3.4 μM. Inhibition of Hsp90 chaperone function appeared to be the dominant mechanism of action and the factor determining cellular sensitivity to EF. In vitro inhibition of proteasome became prominent in the absence of adequate levels of Hsp90 and F 1 F 0 -ATPase as in the case of the relatively EF-resistant MDA-MB-231 cell line. In vivo, EF inhibited MCF-7 and MDA-MB-231 xenograft growth with a maximal inhibition of 60% after administration of 0.15 and 0.3 mg/kg EF, respectively. 2-Deoxyglucose (2DG), a known inhibitor of glycolysis, acted synergistically with EF in vitro and antagonistically in vivo. In vitro, the synergistic effect was attributed to a prolonged endoplasmic reticulum (ER) stress. In vivo, the antagonistic effect was ascribed to the downregulation of tumoral and/or stromal F 1 F 0 -ATPase by 2DG.

2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy

“…Interestingly, Aft et al found that 2DG treatment of breast cancer cells resulted in the up-regulation of GLUT-1 and the accelerated uptake of glucose and 2DG. This indiscriminate uptake is detrimental to the cells [86].…”

Diversity of Linear Non-Ribosomal Peptide in Biocontrol Fungi

“…The analogs of efrapeptins contain alpha-azide carboxylic acid ( Figure 4, Table 2). Efrapeptins have antifungal, antimalarial, insecticidal and antitumor activities [20,23]. In particular, they can inhibit the ATPase and, disturb the interaction between ATPase and heat shock protein 90 (Hsp90) [24][25][26].…”

Alternative Approaches to Hsp90 Modulation for the Treatment of Cancer

“…F 1 F 0 ATP synthase was proposed to possess co-chaperone function by interacting with Hsp90 in several different cancer cell lines [28,43]. Furthermore, inhibition of F 1 F 0 ATP synthase directly affected client protein maturation.…”

“…Hsp90 requires ATP for chaperone activity and inhibition of ATP synthase with pan ATP synthase inhibitors such as oligomycin A, 2-deoxy-D-glucose, antimycin A and efrapeptins prevent Hsp90-dependent client maturation, which destabilizes the client–Hsp90 complex, leading to client degradation via the proteosome (Figure 3) [43,48,49]. ATP synthase inhibitors do not induce the HSR, as oligomycin A and efrapeptins manifested little to no increase in Hsp90, Hsp70 and Hsp27 levels.…”