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Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production.

ABSTRACT: Despite recent therapeutic advancements, multiple myeloma (MM) remains incurable and new therapies are needed, especially for the treatment of elderly and relapsed/refractory patients. We have screened a panel of 100 off-patent licensed oral drugs for anti-myeloma activity and identified niclosamide, an anti-helminthic. Niclosamide, at clinically achievable non-toxic concentrations, killed MM cell lines and primary MM cells as efficiently as or better than standard chemotherapy and existing anti-myeloma drugs individually or in combinations, with little impact on normal donor cells. Cell death was associated with markers of both apoptosis and autophagy. Importantly, niclosamide rapidly reduced free light chain (FLC) production by MM cell lines and primary MM. FLCs are a major cause of renal impairment in MM patients and light chain amyloid and FLC reduction is associated with reversal of tissue damage. Our data indicate that niclosamides anti-MM activity was mediated through the mitochondria with rapid loss of mitochondrial membrane potential, uncoupling of oxidative phosphorylation and production of mitochondrial superoxide. Niclosamide also modulated the nuclear factor-?B and STAT3 pathways in MM cells. In conclusion, our data indicate that MM cells can be selectively targeted using niclosamide while also reducing FLC secretion. Importantly, niclosamide is widely used at these concentrations with minimal toxicity.

SUBMITTER: Khanim FL

PROVIDER: S-EPMC3255256 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production.

Khanim F L FL Merrick B A M E BA Giles H V HV Jankute M M Jackson J B JB Giles L J LJ Birtwistle J J Bunce C M CM Drayson M T MT

Blood cancer journal 20111021 10

Despite recent therapeutic advancements, multiple myeloma (MM) remains incurable and new therapies are needed, especially for the treatment of elderly and relapsed/refractory patients. We have screened a panel of 100 off-patent licensed oral drugs for anti-myeloma activity and identified niclosamide, an anti-helminthic. Niclosamide, at clinically achievable non-toxic concentrations, killed MM cell lines and primary MM cells as efficiently as or better than standard chemotherapy and existing anti ...[more]

PMID: 22829072

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Project description:Lysosome trafficking plays a significant role in tumor invasion, a key event for the development of metastasis. Previous studies from our laboratory have demonstrated that the anterograde (outward) movement of lysosomes to the cell surface in response to certain tumor microenvironment stimulus, such as hepatocyte growth factor (HGF) or acidic extracellular pH (pHe), increases cathepsin B secretion and tumor cell invasion. Anterograde lysosome trafficking depends on sodium-proton exchanger activity and can be reversed by blocking these ion pumps with Troglitazone or EIPA. Since these drugs cannot be advanced into the clinic due to toxicity, we have designed a high-content assay to discover drugs that block peripheral lysosome trafficking with the goal of identifying novel drugs that inhibit tumor cell invasion. An automated high-content imaging system (Cellomics) was used to measure the position of lysosomes relative to the nucleus. Among a total of 2210 repurposed and natural product drugs screened, 18 "hits" were identified. One of the compounds identified as an anterograde lysosome trafficking inhibitor was niclosamide, a marketed human anti-helminthic drug. Further studies revealed that niclosamide blocked acidic pHe, HGF, and epidermal growth factor (EGF)-induced anterograde lysosome redistribution, protease secretion, motility, and invasion of DU145 castrate resistant prostate cancer cells at clinically relevant concentrations. In an effort to identify the mechanism by which niclosamide prevented anterograde lysosome movement, we found that this drug exhibited no significant effect on the level of ATP, microtubules or actin filaments, and had minimal effect on the PI3K and MAPK pathways. Niclosamide collapsed intralysosomal pH without disruption of the lysosome membrane, while bafilomycin, an agent that impairs lysosome acidification, was also found to induce JLA in our model. Taken together, these data suggest that niclosamide promotes juxtanuclear lysosome aggregation (JLA) via modulation of pathways involved in lysosome acidification. In conclusion, we have designed a validated reproducible high-content assay to screen for drugs that inhibit lysosome trafficking and reduce tumor invasion and we summarize the action of one of these drugs.

Project description:Alongside the wide distribution throughout sub Saharan Africa of schistosomiasis, the morbidity associated with this chronic parasitic disease in endemic regions is often coupled with infection-driven immunomodulatory processes which modify inflammatory responses. Early life parasite exposure is theorized to drive immune tolerance towards cognate infection as well as bystander immune responses, beginning with in utero exposure to maternal infection. Considering that 40 million women of childbearing-age are at risk of infection worldwide, treatment with Praziquantel during pregnancy as currently recommended by WHO could have significant impact on disease outcomes in these populations. Here, we describe the effects of anthelminthic treatment on parasite-induced changes to fetomaternal cross talk in a murine model of maternal schistosomiasis. Praziquantel administration immediately prior to mating lead to clear re-awakening of maternal anti-parasite immune responses, with persistent maternal immune activation that included enhanced anti-schistosome cytokine responses. Clearance of parasites also improved capacity of dams to endure the additional pressure of pregnancy during infection. Maternal treatment also drove lasting functional alterations to immune system development of exposed offspring. Prenatal anthelminthic treatment skewed offspring immune responses towards parasite clearance and reduced morbidity during cognate infection. Maternal treatment also restored offspring protective IgE antibody responses directed against schistosome antigens, which were otherwise suppressed following exposure to untreated maternal infection. This was further associated with enhanced anti-schistosome cytokine responses from treatment-exposed offspring during infection. In the absence of cognate infection, exposed offspring further demonstrated imprinting across cellular populations. We provide further evidence that maternal treatment can restore a more normalized immune profile to such offspring exposed in utero to parasite infection, particularly in B cell populations, which may underlie improved responsiveness to cognate infection, and support the WHO recommendation of anthelminthic treatment during pregnancy.

Dataset Information

Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production.

Publications

Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production.

Similar Datasets

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