"Cholinergic side Effect-Free anticancer drugs: paving the way for safer and more effective cancer treatment"

Cancer is a leading cause of mortality worldwide, and various anticancer medications have been developed that target different biological pathways involved in cancer growth and progression. Topoisomerase 1 (Top1) is an essential enzyme involved in unwinding supercoiled DNA, and it serves as a key target for several anti-cancer drugs. Irinotecan (FDA approved drug), a semi-synthetic camptothecin derivative, is an effective Top1 toxin that eliminates human cancer cells. Cancer patients suffer from the cholinergic syndrome caused by irinotecan and other Top1 inhibitors. Irinotecan-treated patients have developed cholinergic syndrome due to acetylcholinesterase (AChE) enzyme inhibition. It appears that irinotecan or its metabolites directly interact with AChE and inhibit its role of converting acetylcholine to choline, leading to an accumulation of acetylcholine and subsequent symptoms of the cholinergic syndrome. The phytochemicals present in Phyllanthus emblica, commonly referred to as amla, have been studied to determine their therapeutic effects. As an alternative treatment for cancer, this study explores the potential of phytochemicals found in amla to target and inhibit the Top1 protein. Additionally, the study aims to identify a non-inhibitor for AChE. Molecular docking studies assessed phytochemical binding affinities to Top1 and AChE enzymes, and ADME analyses were performed to assess their drug-likeness properties. Subsequently, molecular dynamic simulation was employed to assess the stability of these compounds. The results suggest that new anticancer medications that do not inhibit AChE or fresh Top1 inhibitors that use the camptothecin scaffold may alleviate some of the irinotecan's side effects.Communicated by Ramaswamy H. Sarma.