The Crystal Structure of the Complex of the Anticancer Prodrug 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11) with Torpedo californica Acetylcholinesterase Provides a Molecular Explanation for Its Cholinergic Action

Abstract

The anticancer prodrug 7-ethyl-10-[4-(1-piperidino)-1-piperidino-]carbonyloxycamptothecin (CPT-11) is a highly effective camptothecin analog that has been approved for the treatment of colon cancer. It is hydrolyzed by carboxylesterases to yield 7-ethyl-10-hydroxycamptothecin (SN-38), a potent topoisomerase I poison. However, upon high-dose intravenous administration of CPT-11, a cholinergic syndrome is observed that can be ameliorated by atropine. Previous studies have indicated that CPT-11 can inhibit acetylcholinesterase (AChE), and here, we provide a detailed analysis of the inhibition of AChE by CPT-11 and by structural analogs. These studies demonstrate that the terminal dipiperidino moiety in CPT-11 plays a major role in enzyme inhibition, and this has been confirmed by X-ray crystallographic studies of a complex of the drug with Torpedo californica AChE. Our results indicate that CPT-11 binds within the active site gorge of the protein in a fashion similar to that observed with the Alzheimer drug donepezil. The 3D structure of the CPT-11/AChE complex also permits modeling of CPT-11 complexed with mammalian butyrylcholinesterase and carboxylesterase, both of which are known to hydrolyze the drug to the active metabolite. Overall, the results presented here clarify the mechanism of AChE inhibition by CPT-11 and detail the interaction of the drug with the protein. These studies may allow the design of both novel camptothecin analogs that would not inhibit AChE and new AChE inhibitors derived from the camptothecin scaffold.

Irinotecan-Induced Dysarthria

“…Because an earlier study demonstrated that the pharmacokinetics of irinotecan were not different in patients developing dysarthria, the isolated dysarthria cannot be explained by differences in systemic clearance of irinotecan [12]. Irinotecan increases cholinergic activity by binding to the active site gorge of acetylcholinesterase resulting in its functional inhibition [7]. Because of its innervation of tongue muscles, the hypoglossal nerve plays an important role in speech and its overstimulation or damage can cause dysarthria.…”

“…Well-known side effects of irinotecan are the result of the induction of an acute cholinergic syndrome and include rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis. This cholinergic activity is caused by binding of irinotecan to the active site gorge of acetylcholinesterase resulting in its subsequent functional inhibition [7]. Here, we describe the case of a patient with metastatic rectal carcinoma who received second-line therapy with irinotecan and developed isolated transient dysarthria following each administration of irinotecan.…”

Irinotecan-induced dysarthria: A case report and review of the literature

“…Irinotecan, but not SN-38, has been found in the CNS in non-human primates and possesses significantly higher binding affinity for acetylcholinesterase as compared to SN-38. 9,11 Notably, one of the patients described by Hamberg et al experienced less severe symptoms with the second infusion without any significant differences in plasma drug concentrations. The tachyphylaxis observed in our patient and three others described by Hamberg may indicate a down-regulation of hypoglossal acetylcholine receptors with repeated exposure to irinotecan.…”

Irinotecan-Induced Gastrointestinal Dysfunction Is Associated with Enteric Neuropathy, but Increased Numbers of Cholinergic Myenteric Neurons

“…However, the increase in the absolute number of ChAT-IR neurons alongside neuronal loss can only be due to phenotypic changes in myenteric neurons leading to increased ChAT expression as opposed to preferential loss of other neurons. Furthermore, it has been shown previously that IRI binds to the active site of acetylcholinesterase resulting in functional inhibition of the enzyme and increased persistence of extracellular acetylcholine (Dodds and Rivory, 1999; Harel et al, 2005). …”