Cell-of-Origin Targeted Drug Repurposing for Triple-Negative and Inflammatory Breast Carcinoma with HDAC and HSP90 Inhibitors Combined with Niclosamide

Abstract

We recently identified a cell-of-origin-specific mRNA signature associated with metastasis and poor outcome in triple-negative carcinoma (TNBC). This TNBC cell-of-origin signature is associated with the over-expression of histone deacetylases and zinc finger protein HDAC1, HDAC7, and ZNF92, respectively. Based on this signature, we discovered that the combination of three drugs (an HDAC inhibitor, an anti-helminthic Niclosamide, and an antibiotic Tanespimycin that inhibits HSP90) synergistically reduces the proliferation of the twelve tested TNBC cell lines. Additionally, we discovered that four out of five inflammatory breast carcinoma cell lines are sensitive to this combination. Significantly, the concentration of the drugs that are used in these experiments are within or below clinically achievable dose, and the synergistic activity only emerged when all three drugs were combined. Our results suggest that HDAC and HSP90 inhibitors combined with the tapeworm drug Niclosamide can achieve remarkably synergistic inhibition of TNBC and IBC. Since Niclosamide, HDAC, and HSP90 inhibitors were approved for clinical use for other cancer types, it may be possible to repurpose their combination for TNBC and IBC.

Epigenetic Dysregulation and Its Correlation with the Steroidogenic Machinery Impacting Breast Pathogenesis: Data Mining and Molecular Insights into Therapeutics

“…Studies have reported that inhibition of Class I and Class II HDACs, especially 1, 2, 4, and 6, using trichostatin A and sodium butyrate affects cell proliferation on the part of mir-204 and ERα in MCF7 and MDA-MB-231 cells [49][50][51]. Recently, a combination of HDACIs (entinostat + vorinostat + belinostat), anti-HSP90 inhibitor (tanespimycin), and anti-helminthic inhibitor (niclosamide) has been shown to synergistically inhibit cell proliferation in TNBC and inflammatory BC cell lines [52]. In a clinical phase II trial with 43 patients with ER+/PR breast tumors, a combination of SAHA/vorinostat and tamoxifen (a selective ER modulator) demonstrated a ~50% reduction in tumors [53].…”

Multitargeting HDAC Inhibitors Containing a RAS/RAF Protein Interfering Unit

“…The known HDAC inhibitors can be structurally divided into three parts: (i) a cap-based group that identifies the HDACs’ active pocket; (ii) a zinc-ion-binding group (ZBG) that chelates zinc ions at the bottom of the catalytic pocket of HDACs; and (iii) a linking group that connects the cap-based group and the ZBG . As these HDAC inhibitors generally do not work well in solid tumors and are susceptible to drug resistance, they are usually used in combination with other drugs to maximize their potency and reduce the toxicity and side effects with low doses. , Thanks to a large hydrophobic zone on the surface of the HDAC protein, multitarget inhibition can be achieved when some functional groups or pharmacophores act as the cap-based group . Thus, HDAC inhibitors provide an excellent prototype for exploring and validating the concept of multitarget chimeric drugs.…”

“…38 As these HDAC inhibitors generally do not work well in solid tumors and are susceptible to drug resistance, 48 they are usually used in combination with other drugs to maximize their potency and reduce the toxicity and side effects with low doses. 49,50 Thanks to a large hydrophobic zone on the surface of the HDAC protein, multitarget inhibition can be achieved when some functional groups or pharmacophores act as the cap-based group. 38 Thus, HDAC inhibitors provide an excellent prototype for exploring and validating the concept of multitarget chimeric drugs.…”

PIWI-interacting RNA-17458 is oncogenic and a potential therapeutic target in cervical cancer

“…Epigenetic regulation of mRNA performs an important role in the occurrence and development of cancer 5 , 6 . Modification of m6A modification, one of over 100 chemical modifications, means that mRNA can be modified by methylation at the N6 position of adenine and has been reported to play a crucial role in tumorigenesis and progression 7 .…”