Elsevier

Pharmacology & Therapeutics

Volume 199, July 2019, Pages 155-163
Pharmacology & Therapeutics

Clioquinol: To harm or heal

https://doi.org/10.1016/j.pharmthera.2019.03.009Get rights and content

Abstract

Clioquinol, one of the first mass-produced drugs, was considered safe and efficacious for many years. It was used as an antifungal and an antiprotozoal drug until it was linked to an outbreak of subacute myelo-optic neuropathy (SMON), a debilitating disease almost exclusively confined to Japan. Today, new information regarding clioquinol targets and its mechanism of action, as well as genetic variation (SNPs) in efflux transporters in the Japanese population, provide a unique interpretation of the existing phenomena. Further understanding of clioquinol's role in the inhibition of cAMP efflux and promoting apoptosis might offer promise for the treatment of cancer and/or neurodegenerative diseases. Here, we highlight recent developments in the field and discuss possible connections, hypotheses and perspectives in clioquinol-related research.

Introduction

Clioquinol (5-Chloro-7-iodo-quinolin-8-ol) (Fig. 1) was first developed in 1899 as a topical antiseptic. It was subsequently repurposed to treat traveler's diarrhea, as well as certain fungal and protozoal infections of the gastrointestinal tract (Cahoon, 2009). For many years, it was considered safe, and in the 1930s clioquinol became available over-the-counter in Europe, the US and Asia.

Section snippets

Subacute myelo-optic neuropathy: clioquinol's fall from grace

While versatile and used worldwide, clioquinol became associated with a mysterious illness primarily confined to Japan. Between 1958 and 1970, Japanese physicians observed a number of cases that, at first, were characterized by mild abdominal pain and/or diarrhea (Kono, 1971). These symptoms were often followed by a myelitis-like illness that exhibited an array of neuropathological changes consisting of “pseudosystemic degeneration involving the peripheral nerves, post-lateral columns of the

Clioquinol makes a comeback against neurodegenerative diseases

One of clioquinol's first-identified mechanisms of action relates to its ability to interact with metals. The idea that the accumulation of the “wrong” metals in the human brain can cause Alzheimer's disease (AD) dates back to the late 1970s (Eichhorn, 1979). In a more recent study, researchers found a significant decrease in serum manganese level in AD subjects vs. healthy individuals but concluded that neither lead nor manganese levels represented biomarkers in the studied cohort (Hare et

Clioquinol may be a rising star against cancer too

Due to multiple reported cellular effects, clioquinol has also been studied for use against cancer, where modulating membrane transport is of interest. Originally, ATP binding cassette (ABC) transporters (see glossary) attracted attention because of their abilities to efflux the nucleoside-like drugs that are used for chemotherapy in cancer or immunosuppression in autoimmune diseases (Fig. 1). The idea that ABC transporters have normal physiological functions, that include active transport of

ATP-binding cassette transporters, potential culprits in clioquinol-associated subacute myelo-optic neuropathy?

Clioquinol's potential involvement with ABC transporters brings us back to SMON. Could transporter inhibition contribute to its neuropathological symptoms? We propose that a natural (genetic) impairment of normal transporter function or capacity, combined with increased transport inhibition by clioquinol, could trigger the etiology of SMON. Toward this end, we focus on the fact that SMON was almost completely confined to the Japanese population and was seldom reported in other countries (Kono,

ABCC4

The ABCC4 SNP rs3765534 (G2269A, E857K) dramatically reduces transporter function by interfering with protein membrane localization (Krishnamurthy et al., 2008). This SNP is widespread in the Japanese population (> 18% allelic frequency) but is significantly less in all other studied groups: Ashkenazi Jews, Africans north of the Sahara, Pacific Islanders, European Americans, African Americans, Middle Easterners and Chinese Americans (Krishnamurthy et al., 2008). In Japanese patients with

Possible beneficial effects of single nucleotide polymorphisms in ABCC transporters

It noteworthy that SNPs in cAMP transporters are not entirely harmful. They may provide benefits for other conditions, like cancer. While the physiological function of ABCC11 beyond earwax and axillary glands is unclear, a role in cancer is possible. Caucasians and African–Americans showed approximately four-fold higher rates of breast cancer mortality as compared to women of Japanese and Taiwanese origin. The international mortality and frequency rates for breast cancer were reported to be

Could clioquinol's effect on cAMP be relevant to clioquinol's action in Alzheimer's disease?

The ability to modify the efficacy of synaptic transmission in response to neural activity is termed synaptic plasticity. It underlies the capacity of neuronal networks to adjust to external stimuli, and to process information. Long-term plasticity, occurring over tens of minutes to years, appears to impact memory and learning. Experimentally studied as long-term potentiation (LTP; see glossary), it may represent the measurable cellular correlate of learning and memory. Consequently, the

The cAMP/PKA/CREB signaling pathway as a possible target in Alzheimer's disease

Discovered in a screen designed to identify compounds that block the efflux of a cAMP fluorescent derivative, clioquinol was reported to up-regulate CREB Ser133 phosphorylation (see Fig. 3 in reference (Perez, Smagley et al., 2016)). It was also shown that mice expressing a constitutively active form of CREB (VP16-CREB) in hippocampal neurons facilitated LTP (Li et al., 2013). The enhanced expression of CRE-driven genes facilitated the priming of synapses leading to the stimulation of synaptic

Concluding remarks and future perspectives

The public health impact of AD is expected to increase in the next 30–50 years, yet there is no effective preventative strategy or treatment that will dramatically reverse its debilitating effects. The main difficulty is our lack of understanding of the disease pathogenesis. A deeper understanding of the AD pathological process will help us to identify better therapeutic targets and will facilitate the development of new therapeutic strategies and drugs aimed at overcoming the disease

Acknowledgments

This work was supported by the National Institutes of Health (USA) grants: UNM Comprehensive Cancer Center CCSG P30 CA118100 grant, the UNM Autophagy Inflammation and Metabolism CoBRE P20 GM121176 grant, the UNM Clinical and Translational Science Center grant UL1TR001449 and NIH Minority Institutional Research Training Program Award T32 HL007736.

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Glossary

ATP-binding cassette (ABC) transporter
A superfamily of active transporters that use energy from ATP hydrolysis to pump substrates across cell membranes. Certain ABC pumps participate in drug efflux from cancer cells, thus contributing to drug resistance. Defects in transport function may lead to drug sensitivity and adverse drug reactions. ABCC (subfamily C) members are also known as multidrug resistance proteins (MRPs). ABCC4 (MRP4), ABCC5 (MRP5) and ABCC11 (MRP8) are reported to efflux cyclic

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