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-κB 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.

The role of STAT3 in autophagy

“…A wide range of RTKs phosphorylate STAT3 directly or via SRC kinase, and several studies have proven that blocking kinases such as KDR, PDGFRB, and ALK results in enhanced autophagy by subsequent inhibition of the STAT3 pathway (Table 3). 14,41,42,50,[74][75][76][77][78][79][80][81][82][83] Currently, several JAK-STAT inhibitors are being examined in clinical trials for cancer therapy. For example, in a phase II clinical trial to treat metastatic pancreatic cancer, ruxolitinib together with capecitabine showed a benefit for overall survival and progression-free survival compared with a placebo plus capecitabine used in second-line therapy, promoting the application of JAK-STAT inhibitors in cancer therapy.…”

Potential Therapeutics: Toe Hold in the Fight against Zika Virus

“…It seems that inhibition by niclosamide occurs at a post-entry step, such as replication [40,41]. Niclosamide is a category B drug, which indicates that no risk to fetuses has been found in animal studies due to its low toxicity in mammals [42]. The WHO recommends that niclosamide may be used during pregnancy because it has not been shown to be mutagenic, teratogenic or embryotoxic [43].…”

Molecular mechanisms of niclosamide antitumor activity

“…Для поиска новых препаратов, которые были бы эффективны для лечения миеломной болезни, Khanim и соавт. провели скрининг более 100 известных препаратов с разной терапевтической специфичностью для выявления соединений, обладающих цитотоксической активностью в той концентрации, которая достигается в сыворотке крови при их клиническом применении, в отношении трёх линий клеток миеломы человека [17]. В результате такого скрининга высокая активность в отношении клеток миеломы была обнаружена у никлозамида.…”

“…Исследуя механизм действия никлозамида, авторы показали, что он способен индуцировать образование АМК, в том числе, супероксидного аниона (СОКС) в митохондриях клеток множественной миеломы человека [17].…”

“…Как правило, это происходит в результате увеличения проницаемости внутренней мембраны митохондрий для протонов и уменьшения, вследствие этого, разности электрохимического потенциала. Никлозамид быстро, в течение 1 мин, приводил к снижению митохондриального мембранного потенциала и разобщению окислительного фосфорилирования и дыхания в клетках миеломы линии H929 и JJN3 [17]. Эти данные позволяют полагать, что основной мишенью действия никлозамида в клетках являются митохондрии.…”