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Author: Andreas Koeberle3
Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males.

Abstract (Expand)

Proinflammatory leukotrienes (LTs) are produced by 5-lipoxygenase (5-LO) aided by 5-LO-activating protein (FLAP). LT biosynthesis inhibitors are currently under clinical investigation as treatments for … respiratory and cardiovascular diseases. Here, we have revealed a sex bias in the efficiency of clinically relevant LT biosynthesis inhibitors, showing that their effects are superior in females. We found that androgens cause these sex differences by impeding the LT-biosynthetic 5-LO/FLAP complex assembly. Lower doses of the FLAP inhibitor MK886 were required to reduce LTB4 levels in exudates of female versus male mice and rats. Following platelet-activating factor-induced shock, MK886 increased survival exclusively in female mice, and this effect was abolished by testosterone administration. FLAP inhibitors and the novel-type 5-LO inhibitors licofelone and sulindac sulfide exhibited higher potencies in human blood from females, and bioactive 5-LO/FLAP complexes were formed in female, but not male, human and murine leukocytes. Supplementation of female blood or leukocytes with 5alpha-dihydrotestosterone abolished the observed sex differences. Our data suggest that females may benefit from anti-LT therapy to a greater extent than males, prompting consideration of sex issues in LT modifier development.

Authors: S. Pace, C. Pergola, F. Dehm, A. Rossi, J. Gerstmeier, F. Troisi, H. Pein, A. M. Schaible, C. Weinigel, S. Rummler, H. Northoff, S. Laufer, T. J. Maier, O. Radmark, B. Samuelsson, A. Koeberle, L. Sautebin, O. Werz

Date Published: 25th Jul 2017

Publication Type: Not specified

Modulation of actin dynamics as potential macrophage subtype-targeting anti-tumour strategy

Abstract (Expand)

Tumour-associated macrophages mainly comprise immunosuppressive M2 phenotypes that promote tumour progression besides anti-tumoural M1 subsets. Selective depletion or reprogramming of M2 may represent … an innovative anti-cancer strategy. The actin cytoskeleton is central for cellular homeostasis and is targeted for anti-cancer chemotherapy. Here, we show that targeting G-actin nucleation using chondramide A (ChA) predominantly depletes human M2 while promoting the tumour-suppressive M1 phenotype. ChA reduced the viability of M2, with minor effects on M1, but increased tumour necrosis factor (TNF)alpha release from M1. Interestingly, ChA caused rapid disruption of dynamic F-actin filaments and polymerization of G-actin, followed by reduction of cell size, binucleation and cell division, without cellular collapse. In M1, but not in M2, ChA caused marked activation of SAPK/JNK and NFkappaB, with slight or no effects on Akt, STAT-1/-3, ERK-1/2, and p38 MAPK, seemingly accounting for the better survival of M1 and TNFalpha secretion. In a microfluidically-supported human tumour biochip model, circulating ChA-treated M1 markedly reduced tumour cell viability through enhanced release of TNFalpha. Together, ChA may cause an anti-tumoural microenvironment by depletion of M2 and activation of M1, suggesting induction of G-actin nucleation as potential strategy to target tumour-associated macrophages in addition to neoplastic cells.

Authors: C. Pergola, K. Schubert, S. Pace, J. Ziereisen, F. Nikels, O. Scherer, S. Huttel, S. Zahler, A. M. Vollmar, C. Weinigel, S. Rummler, R. Muller, M. Raasch, A. Mosig, A. Koeberle, O. Werz

Date Published: 31st Jan 2017

Publication Type: Not specified

Myxochelins target human 5-lipoxygenase

Abstract (Expand)

Extracts of the predatory myxobacterium Pyxidicoccus fallax HKI 727 showed antiproliferative effects on leukemic K-562 cells. Bioactivity-guided fractionation led to the isolation of the bis-catechol … myxochelin A and two new congeners. The biosynthetic origin of myxochelins C and D was confirmed by feeding studies with isotopically labeled precursors. Pharmacological testing revealed human 5-lipoxygenase (5-LO) as a molecular target of the myxochelins. In particular, myxochelin A efficiently inhibited 5-LO activity with an IC50 of 1.9 muM and reduced the proliferation of K-562 cells at similar concentrations.

Authors: S. Schieferdecker, S. Konig, , H. M. Dahse, ,

Date Published: 16th Feb 2015

Publication Type: Not specified

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