1.LDL suppresses angiogenesis through disruption of the HIF pathway via NF-κB inhibition which is reversed by the proteasome inhibitor BSc2118.
Yao G1,2, Zhang Q1, Doeppner TR3, Niu F1, Li Q4, Yang Y1, Kuckelkorn U5, Hagemann N3, Li W1, Hermann DM3, Dai Y6, Zhou W7, Jin F1. Oncotarget. 2015 Oct 6;6(30):30251-62. doi: 10.18632/oncotarget.4943.
Since disturbance of angiogenesis predisposes to ischemic injuries, attempts to promote angiogenesis have been made to improve clinical outcomes of patients with many ischemic disorders. While hypoxia inducible factors (HIFs) stimulate vascular remodeling and angiogenesis, hyperlipidemia impairs angiogenesis in response to various pro-angiogenic factors. However, it remains uncertain how HIFs regulate angiogenesis under hyperlipidemia. Here, we report that exposure to low-density lipoprotein (LDL) suppressed in vitro angiogenesis of human brain microvascular endothelial cells. Whereas LDL exposure diminished expression of HIF-1α and HIF-2α induced by hypoxia, it inhibited DMOG- and TNFα-induced HIF-1α and HIF-2α expression in normoxia. Notably, in both hypoxia and normoxia, LDL markedly reduced expression of HIF-1β, a constitutively stable HIF subunit, an event associated with NF-κB inactivation. Moreover, knockdown of HIF-1β down-regulated HIF-1α and HIF-2α expression, in association with increased HIF-1α hydroxylation and 20S proteasome activity after LDL exposure.
2.BSc2118 is a novel proteasome inhibitor with activity against multiple myeloma.
Sterz J1, Jakob C, Kuckelkorn U, Heider U, Mieth M, Kleeberg L, Kaiser M, Kloetzel PM, Sezer O, von Metzler I. Eur J Haematol. 2010 Aug;85(2):99-107. doi: 10.1111/j.1600-0609.2010.01450.x. Epub 2010 Mar 31.
OBJECTIVES: The ubiquitin-proteasome system emerged as a new therapeutic target in cancer treatment. The purpose of this study was to elucidate the effects of the novel proteasome inhibitor BSc2118 on t(4;14) positive and negative multiple myeloma (MM) cells and normal peripheral blood mononuclear cells (PBMNC).
3.Anti-tumor activity of the proteasome inhibitor BSc2118 against human multiple myeloma.
Zang M1, Li Z1, Liu L1, Li F2, Li X3, Dai Y4, Li W5, Kuckelkorn U6, Doeppner TR7, Hermann DM7, Zhou W8, Qiu L9, Jin F10. Cancer Lett. 2015 Oct 1;366(2):173-81. doi: 10.1016/j.canlet.2015.06.011. Epub 2015 Jun 23.
Introduction of bortezomib, the first generation of proteasome inhibitor, has significantly improved the median overall survival of patients with multiple myeloma (MM). However, the dose-limiting adverse events and acquired drug resistance limit its long-term usage. Here, we report in vitro and in vivo anti-MM activity of the irreversible proteasome inhibitor BSc2118. BSc2118 inhibited the chymotrypsin-like (CT-L) proteasome activity, accompanied by accumulation of ubiquitinated proteins. BSc2118 suppressed tumor cell growth through induction of G2/M phase arrest and induced apoptosis via activation of the apoptotic signaling cascade, in association with up-regulation of p53 and p21. Importantly, BSc2118 was active in vitro against MM cells' acquired bortezomib resistance. Of note, BSc2118 also displayed a novel anti-angiogenesis activity both in vitro and in vivo. Lastly, BSc2118 exhibited a broader safety dose range and higher anti-tumor efficacy in vivo in a human MM xenograft mouse model, compared to bortezomib.
4.Biodistribution and Efficacy Studies of the Proteasome Inhibitor BSc2118 in a Mouse Melanoma Model.
Mlynarczuk-Bialy I1, Doeppner TR2, Golab J3, Nowis D3, Wilczynski GM4, Parobczak K4, Wigand ME5, Hajdamowicz M1, Biały LP1, Aniolek O6, Henklein P5, Bähr M7, Schmidt B8, Kuckelkorn U5, Kloetzel PM5. Transl Oncol. 2014 Oct 24;7(5):570-9. doi: 10.1016/j.tranon.2014.07.002. eCollection 2014.
Inhibition of the proteasome offers many therapeutic possibilities in inflammation as well as in neoplastic diseases. However, clinical use of proteasome inhibitors is limited by the development of resistance or severe side effects. In our study we characterized the anti-tumor properties of the novel proteasome inhibitor BSc2118. The sensitivity of tumor lines to BSc2118 was analyzed in comparison to bortezomib using crystal violet staining in order to assess cell viability. The In Vivo distribution of BSc2118 in mouse tissues was tracked by a fluorescent-modified form of BSc2118 (BSc2118-FL) and visualized by confocal microscopy. Inhibition of the 20S proteasome was monitored both in cultured cell lines and in mice, respectively. Finally, safety and efficacy of BSc2118 was evaluated in a mouse melanoma model. BSc2118 inhibits proliferation of different tumor cell lines with a similar potency as compared with bortezomib. Systemic administration of BSc2118 in mice is well tolerated, even when given in a dose of 60 mg/kg body weight.