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  • We found that several anticancer

    2023-11-30

    We found that several anticancer drugs inhibit 5-HT3 leukotriene receptor antagonist current in vitro. Several studies have suggested that 5-HT3 receptor antagonists have anti-mitogenic and apoptotic effects on colorectal and breast cancer cell lines (Ataee et al., 2010, Hejazi et al., 2015). Irinotecan is used frequently to treat colorectal cancer (Shike et al., 1990), and doxorubicin and epirubicin are used to treat breast cancer (Gianni et al., 2009). Although the effects of 5-HT3 receptor antagonists are not necessarily the effects of all anticancer drugs, the modulation of 5-HT-induced 5-HT3 receptor current by some anticancer drugs might be an integral part of their anticancer effect. As with any therapeutic drug, it is desirable for anticancer drugs to have minimal side effects for maximal clinical benefit (Narang and Desai, 2009). Most of the drugs that modified 5-HT3A and 5-HT3AB receptor currents in this study were antagonists, although mitoxantrone and topotecan potentiated 5-HT-induced 5-HT3AB currents (Fig. 1, Fig. 2). Interestingly, most anticancer drugs showing modulation of the 5-HT3 receptor currents had molecular weights of around 500 (Fig. 4). Prediction of the affinity for a receptor binding pocket using molecular weight is simple, but not perfect (Velec et al., 2005). There were four drugs with molecular weights of around 500 which did not affect the currents. Molecular weights of around 500 might be necessary but not sufficient for binding to 5-HT3 receptor. To predict of the affinity is needed to examine molecular conformation, electrostatic forces etc. However, our results suggest that anticancer drugs designed with a molecular weight of around 500 have the potential of being 5-HT3 receptor antagonists. Mitoxantrone showed a bell-shaped dose-response curve (Fig. 1, Fig. 2). The 5-HT3 receptor agonist m-chlorophenylbiguanide induces a concomitant open-channel block at the 5-HT3 receptor, and binding of a ligand at a secondary site prevents either the binding of agonists at the primary site or the possible conformational change needed for activation of the receptor unit (Bindslev, 2008, Hapfelmeier et al., 2003). At the lower concentration (1µM) mitoxantrone potentiated the response of 5-HT3AB to 5-HT, whereas high concentrations inhibited both the 5-HT3A and the 5-HT3AB receptor, indicating that the 5-HT3AB receptor contains a high affinity binding site for potentiation, and that 5-HT3A and 5-HT3AB receptors contain a secondary low-affinity binding site for inhibition of the receptor response. In summary, we have shown that several commonly used anticancer drugs modulate the response of the 5-HT3 receptor and have molecular weights of approximately 500.
    Acknowledgements Funding: This work was supported by a Grant-in-Aid for Young Scientists (B) (25861560) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
    Introduction The 5-HT2A receptor is densely expressed in various cortical areas (e.g. prefrontal cortex, piriform and enthorinal cortex) and subcortical areas, such as basal ganglia (e.g. caudate nucleus and accumbens) and the limbic system (Pompeiano et al., 1994). It plays an important role in a wide range of psychological functions, from sensorimotor function, emotion regulation, motivation, learning and memory to executive control (Zhang and Stackman, 2015). Dysfunctions of this receptor system have been suggested to contribute to several major neuropsychiatric disorders, such as schizophrenia, major depression, autism and Alzheimer's disease (Aznar and Hervig Mel, 2016, Fakhoury, 2016). Overall, the 5-HT2A receptor appears to be an important neuromodulatory system that has a broad impact on basic brain functions. Maternal behavior in rats is a naturally expressed and highly motivated behavior with its onset and maintenance critically dependent on many psychological functions that the 5-HT2A receptor is intimately involved in. In addition, the 5-HT2A receptor system and various sex hormones (e.g. estrogen, prolactin) that are fundamentally important for maternal behavior show various reciprocal interactions (Fink et al., 1996, Liang and Pan, 2000). Thus, it is logic to think that this receptor system should play a role in maternal behavior. This idea also fits well with the observation that the 5-HT2A receptor is found in the brain regions important for olfactory processing (e.g. piriform and enthorinal cortex, endopiriform nucleus, and olfactory bulb/anterior olfactory nucleus), an important function necessary for maternal behavior. Surprisingly, at this time, there is no direct evidence supporting a role of 5-HT2A receptor in the regulation of rat maternal behavior. The only available evidence is that drugs with a certain antagonist and agonist action on 5-HT2A receptor, such as clozapine or DOI (2,5-dimethoxy-4-iodo-amphetamine), respectively, disrupt maternal behavior upon acute treatment (Li et al., 2004, Zhao and Li, 2009a, Zhao and Li, 2009b, Zhao and Li, 2012). However, because both clozapine and DOI also have an action on 5-HT2C receptor, and activation of 5-HT2C alone is able to cause a severe disruption of maternal behavior care (Chen et al., 2014, Wu et al., 2016), it can be said that the maternal-disruptive effect of clozapine and DOI is due to their actions on 5-HT2C receptor alone. Furthermore, recent work shows that selective blockade of 5-HT2A receptor alone is ineffective to alter maternal care (Chen et al., 2014), casting a doubt on the involvement of the 5-HT2A receptor in maternal behavior.