Search

A number of erythropoiesis stimulants are entering the final stage of clinical trials due to recent scientific progress in hypoxia‐regulated erythropoiesis. Considering how erythropoiesis‐stimulating compounds enhance the capacity of the organism to transport oxygen, they pose a great risk of being misused as performance enhancers. In this paper, we report the metabolic fate of three popular hypoxia‐inducible factor‐prolyl hydroxylase Inhibitors (HIF‐PHI) compounds, namely, BAY 87‐2243, MK‐8617, and PT‐2385 in equine liver microsomes using Q‐Exactive high‐resolution mass spectrometry. This study found 22 metabolites for BAY 87‐2243 (19 phase I and three phase II), three metabolites for MK‐8617 (all phase I), and five metabolites for PT‐2385 (two phase I and three phase II). The major findings of the present study are as follows: (1) all three potential HIF‐PHI drug candidates, namely, BAY 87‐2243, MK‐8617, and PT‐2385 are susceptible to oxidation, producing their corresponding hydroxylated metabolites; (2) the ring dissociated metabolites were detected for BAY 87‐2243 and PT‐2385; (3) in the case of BAY 87‐2243 and PT‐2385, glucuronic acid conjugated metabolites were detected; and (4) none of the drugs produced sulfonic acid conjugated metabolites. [ABSTRACT FROM AUTHOR]

Inhibition of respiratory complex I (CI) is becoming a promising anti-cancer strategy, encouraging the design and the use of inhibitors, whose mechanism of action, efficacy and specificity remain elusive. As CI is a central player of cellular bioenergetics, a finely tuned dosing of targeting drugs is required to avoid side effects. We compared the specificity and mode of action of CI inhibitors metformin, BAY 87-2243 and EVP 4593 using cancer cell models devoid of CI. Here we show that both BAY 87-2243 and EVP 4593 were selective, while the antiproliferative effects of metformin were considerably independent from CI inhibition. Molecular docking predictions indicated that the high efficiency of BAY 87-2243 and EVP 4593 may derive from the tight network of bonds in the quinone binding pocket, although in different sites. Most of the amino acids involved in such interactions are conserved across species and only rarely found mutated in human. Our data make a case for caution when referring to metformin as a CI-targeting compound, and highlight the need for dosage optimization and careful evaluation of molecular interactions between inhibitors and the holoenzyme.

Tumor metastasis is directly correlated to poor prognosis and high mortality. Circulating tumor cells (CTCs) play a pivotal role in metastatic cascades, of which CTC clusters is highly metastatic compared to single CTCs. Although platelets and neutrophils within the bloodstream could further exacerbate the pro-metastatic effect of single CTCs, the influence of platelets and neutrophils on CTC clusters mediated metastasis remains unclear. In this study, a pro-metastatic complex composed of CTC clusters, platelets and neutrophils, namely circulating tumor microemboli (CTM), was identified in vivo among different metastatic tumor, which was demonstrated with highly upregulation of hypoxia-inducible factor-1α (HIF-1α). While knock-out of HIF-1α or therapeutically downregulating of HIF-1α via HIF-1α inhibitor (BAY87–2243)-loaded neutrophil cyto-pharmaceuticals (PNEs) could efficiently restrain CTM mediated lung metastasis. The underlying mechanism of metastasis inhibition was attributed to the downregulation of HIF-1α-associated PD-L1, which would enhance immune response for inhibiting metastatic cells. Thus, our work here illustrates that hypoxia was an essential factor in promoting CTM colonization in lung. More importantly, we provide a promising strategy by targeted downregulation of HIF-1α in CTM via neutrophil cyto-pharmaceuticals for treatment of CTM mediated metastasis. Targeted downregulation of hypoxia-inducible factor-1α via neutrophil cyto-pharmaceuticals for restraining circulating tumor microemboli mediated metastasis [Display omitted] • CTC clusters, platelets and neutrophils constitute the pro-metastatic complex. • Circulating tumor microemboli was verified with upregulation of HIF-1α and PD-L1. • Neutrophil cyto-pharmaceuticals efficiently restrain CTM mediated lung metastasis. [ABSTRACT FROM AUTHOR]

Inhibition of respiratory complex I (CI) is becoming a promising anti-cancer strategy, encouraging the design and the use of inhibitors, whose mechanism of action, efficacy and specificity remain elusive. As CI is a central player of cellular bioenergetics, a finely tuned dosing of targeting drugs is required to avoid side effects. We compared the specificity and mode of action of CI inhibitors metformin, BAY 87-2243 and EVP 4593 using cancer cell models devoid of CI. Here we show that both BAY 87-2243 and EVP 4593 were selective, while the antiproliferative effects of metformin were considerably independent from CI inhibition. Molecular docking predictions indicated that the high efficiency of BAY 87-2243 and EVP 4593 may derive from the tight network of bonds in the quinone binding pocket, although in different sites. Most of the amino acids involved in such interactions are conserved across species and only rarely found mutated in human. Our data make a case for caution when referring to metformin as a CI-targeting compound, and highlight the need for dosage optimization and careful evaluation of molecular interactions between inhibitors and the holoenzyme.