Clioquinol: To harm or heal

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.

Keywords: ABC transporters; Alzheimer's disease; Cancer; Clioquinol; Neurodegenerative diseases; Pharmacogenomics; SNPs.

Figure 1.

Chemical structures of substrates of ABCC4, ABCC5 and ABCC11, and other related compounds. Clioquinol (5-choloro-7-iodo-8-quinolinol), PBT2 (5,7-dichloro-2-((dimethylamino) methyl) 8-quinolinol) and 8-hydroxyquinoline are ionophore/chelator drugs. 6-Mercaptopurine, 6-thioguanine, 5-fluorouracil, Ara-C (cytosine arabinoside), pemetrexed and 6-thioguanine nucleotides are cancer and immunosuppressor drugs and substrates of ABCC4 and ABCC11 transporters. cAMP and cGMP are natural ABCC4, ABCC5 and ABCC11 substrates.

Figure 2.

Schematic illustration of the role of SNP rs17822931 (G538A; G180R) in ABCC11 functional activity (modified from (Toyoda, Gomi, Nakagawa, Nagakura, & Ishikawa, 2016)). The G180R variant lacks N-linked glycosylation (red circles) necessary for stable protein expression, and is subsequently targeted for rapid proteasomal degradation (Toyoda, et al., 2009). The precursors of the odorous compounds are not loaded into apocrine vesicles that are released by the cell, and therefore, the loss of transporters results in dry earwax and odorless sweat. Loading apocrine vesicles by the WT protein is shown by the purple arrow.

Figure 3.

A model for the role of integrin in consolidation of LTP. Cellular integrins modulate their molecular conformation, rapidly and reversibly changing from a low ligand-binding affinity non-adhesive (bent) state to a high ligand-binding adhesive state (extended) under the control of “inside-out” signaling originating from GPCRs. The addition of integrin antagonists or anti-integrin function-blocking antibodies, as well as their genetic disruption in murine models, results in the reduction of LTP stabilization and a deficiency in hippocampal-dependent working memory (McGeachie, Cingolani, & Goda, 2011). The model includes two major steps: 1) Immediately after induction of LTP, integrins that normally stabilize synaptic structure are inactivated. This results in integrin disengagement as well as disassembly of the postsynaptic actin network and extracellular matrix (ECM). 2) LTP consolidation. Large morphological changes and synaptic reassembly after LTP induction allow for the insertion of new molecules and the expansion of the synapse. After a period of instability, new integrins are inserted and engaged stabilizing the new morphology and function of the synapse via transition from low to high integrin affinity (McGeachie, et al., 2011).

Figure 4.

A model that summarizes hypotheses relating cAMP accumulation with the pathogenesis of SMON, AD and other diseases. Excessive accumulation of cAMP that may result from SNPs in ABCC4 and ABCC11 transporters targeted by clioquinol, can trigger apoptosis that can be devastating. In certain cancers, where cAMP efflux supports malignant cell survival, blocking the efflux represents a novel cancer targeting mechanism. In Japanese and Taiwanese women, SNPs in ABCC transporters that lower transporter activity can have a natural protective role against cancer. Additional accumulation of cAMP resulting from the effects of clioquinol can enhance the expression of CRE-driven genes that may indirectly affect synaptic plasticity. Cytosolic cAMP can directly modulate the integrin activation state and thus regulate synaptic plasticity.