Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline

Abstract

In searching for small-molecule compounds that inhibit proliferation and survival of diffuse large B-cell lymphoma (DLBCL) cells and may, therefore, be exploited as potential therapeutic agents for this disease, we identified the commonly used and well-tolerated antibiotic doxycycline as a strong candidate. Here, we demonstrate that doxycycline inhibits the growth of DLBCL cells both in vitro and in mouse xenograft models. In addition, we show that doxycycline accumulates in DLBCL cells to high concentrations and affects multiple signaling pathways that are crucial for lymphomagenesis. Our data reveal the deneddylating activity of COP-9 signalosome (CSN) as a novel target of doxycycline and suggest that doxycycline may exert its effects in DLBCL cells in part through a CSN5-HSP90 pathway. Consistently, knockdown of CSN5 exhibited similar effects as doxycycline treatment on DLBCL cell survival and HSP90 chaperone function. In addition to DLBCL cells, doxycycline inhibited growth of several other types of non-Hodgkin lymphoma cells in vitro. Together, our results suggest that doxycycline may represent a promising therapeutic agent for DLBCL and other non-Hodgkin lymphomas subtypes.

From rapalogs to anti-aging formula

“…Doxycycline suppresses tumor growth and metastasis in mice [223, 224]. Importantly, doxycycline is a component of an anti-metastatic combination, which includes doxycyclin, aspirin, lisin and mifepristone [225].…”

Mitochondrial dysfunction and potential anticancer therapy

“…The tetracycline analog minocycline was shown to reduce angiogenesis in vitro . Doxycycline induces apoptosis in pancreatic cancer cells, inhibits the adhesion and migration of melanoma cells, and decreases tumor growth of diffuse large B‐cell lymphomas . Possible mechanism includes activation of c‐Jun N‐terminal kinase followed by ΔΨ m change and apoptosis …”

Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes

“…A few previous studies have used gene set enrichment analysis to connect disease signatures with drug signatures and identified candidate drugs for cancer, neurological, and gastrointestinal disorders, as suggested by subsequent effect studies in cell lines and animal models (3)(4)(5)(6). However, it remains to be shown whether such signature connections can be used to identify compounds with pathophysiological relevance for humans.…”