Repurposing of nervous system drugs for cancer treatment: recent advances, challenges, and future perspectives.

Introduction

Neurotransmitters, pivotal in regulating physiological processes, also play a crucial role in the pathophysiology of various diseases, making their study central to neurology, psychiatry, and internal medicine [ 1 ]. Approved neurological drugs are employed to manage a myriad of disorders and undergo stringent evaluations to ensure their safety and efficacy in addressing the complex dynamics of neurotransmitters in disease states [ 2 ]. The historical perspective on the relationship between the nervous system and cancer dates to around 400 BC, when Hippocrates and Galen first proposed a link between cancer and ‘melancholia’—attributed to an excess of black bile [ 3 , 4 ]. Despite its eventual dismissal, this early theory hinted at a significant, albeit overlooked, connection.

The nervous system’s integral role in cancer has only been recently acknowledged, marking a paradigm shift in oncology. The discovery that nerve fibers can actively participate in tumor progression through processes such as xenogenesis illuminates the nervous system’s profound impact on cancer. These fibers, by infiltrating tumor tissues, release neurotransmitters that interact with receptors on stromal and cancer cells, influencing tumor growth and dissemination. This complex interaction underscores a re-emerging field known as cancer neuroscience, which explores the nervous system’s role in the onset, growth, and spread of cancer.

In the late nineteenth century, James Paget’s seed and soil theory further enriched our understanding of the tumor microenvironment (TME), emphasizing its significance in cancer progression [ 5 , 6 ] . This theory, supported by discoveries around tumor neo-angiogenesis and the role of immunity in tumor formation, set foundational insights into cancer biology [ 7 ]. Yet, the potential involvement of nerves within the TME was largely overlooked until a resurgence of interest demonstrated that peripheral and central nervous systems could converge within the TME, contributing to cancer pathology [ 8 – 11 ].

The process of drug approval in neurology and psychiatry exemplifies ongoing challenges related to drug lag—delays that underscore the urgent need for more efficient processes to meet unmet medical needs effectively [ 12 ]. Furthermore, drug repurposing or repositioning has emerged as a significant strategy in pharmaceutical development, leveraging existing medications for new therapeutic purposes [ 13 ]. This approach not only bypasses the costly and time-consuming preclinical research phase but also exploits the known safety profiles and side effects of existing drugs, thereby reducing the risks associated with new drug development [ 14 – 16 ] (Fig. 1 ).

As we integrate insights from neurology, psychiatry, and oncology, repurposing nervous system drugs offers a promising avenue for developing novel, effective cancer therapies [ 17 , 18 ]. This interdisciplinary approach aims to transcend traditional boundaries, harnessing our understanding of neural mechanisms to innovate cancer treatment strategies [ 17 – 20 ]. By exploring the bidirectional crosstalk between the brain and tumors, we aim to uncover potential control loops that connect the TME with specific brain areas, influencing cancer development and progression. In this review, we will discuss the current state and future directions of cancer neuroscience, including ongoing clinical trials and the potential repurposing of neuropsychiatric drugs in oncology, setting the stage for transformative advances in treating malignancies.

Neurotransmitters and neural signaling in cancer

In the intricate interplay of cancer progression, neurotransmitters emerge as pivotal elements that extend their influence beyond traditional neural functions, impacting various aspects of tumor development and metastasis. This section explores how nervous system drugs, initially intended for neurological and psychiatric conditions, are now being repurposed to modulate these neurotransmitters and their pathways to offer novel cancer therapies.

Overview of neurotransmitters involved in cancer progression

Neurotransmitters play a pivotal role in cancer progression by influencing various aspects of tumor development and metastasis. Peptidergic neurotransmitters, such as neuropeptide Y (NPY), act as powerful angiogenic factors, directly stimulating endothelial cell proliferation, migration, and capillary formation [ 21 ]. Similarly, dopamine regulates angiogenesis by inhibiting the phosphorylation of key proteins involved in vascular endothelial growth factor (VEGF) signaling. Furthermore, TME is significantly influenced by the surrounding neural landscape. The release of neurotransmitters by nerves can intensify tumor growth and facilitate metastasis, establishing a positive feedback loop that not only sustains but also accelerates cancer progression [ 22 ]. The body’s stress response activates critical neural pathways, notably the sympathetic nervous system (SNS) and the hypothalamic–pituitary–adrenal (HPA) axis, which further promotes cancer progression through the release of neurotransmitters and hormones [ 23 – 25 ]. The role of the HPA axis, particularly the paraventricular nucleus (PVN) of the hypothalamus, underscores the broader systemic impact of neural signaling on cancer [ 26 ]. The PVN, an essential autonomic control center, influences stress responses that have been linked to cancer progression through the production of glucocorticoids [ 27 ]. These glucocorticoids modulate immune responses, potentially decreasing control over cancer cells, as evidenced in studies where stress correlates with increased tumor growth and poor survival outcomes [ 28 – 30 ]. Adrenergic signaling, especially through norepinephrine, is associated with increased tumor cell proliferation and the upregulation of proangiogenic factors [ 27 ]. Norepinephrine and epinephrine, acting through specific adrenoceptors, enhance the synthesis of proangiogenic factors, thereby promoting tumor growth [ 31 ]. Neurotransmitters are thus intricately linked with the regulation of primary tumor growth and metastasis, highlighting their crucial role in cancer pathogenesis [ 32 ]. The interaction between neurotransmitters and the TME reveals a complex network where neurotransmitters function not merely as chemical messengers but as potent modulators of the tumor landscape. This includes the stimulation of stromal cells, immune cells, and alterations in the extracellular matrix, all contributing to a more conducive environment for cancer progression [ 33 ]. Innovative therapeutic strategies are emerging from the repurposing of nervous system drugs to target these neurotransmitter pathways in cancer. For example, Darifenacin, which pharmacologically targets acetylcholine signaling, has shown potential in preventing tumor relapse in EGFR-mutant lung cancer by influencing drug tolerance mechanisms [ 34 ]. This suggests a promising frontier where drugs initially developed for neurological disorders could be utilized to interfere with cancer cell signaling and microenvironmental manipulation. Moreover, the relationship between neurotransmitters and the development of metastatic niches is increasingly recognized. Neurotransmitters can induce changes in the TME that facilitate metastasis, including enhancing angiogenesis and lymph genesis and modifying inflammatory responses [ 35 ]. This underscores the potential of targeting neurotransmitter pathways as a strategy to not only treat primary tumors but also to prevent and treat metastatic disease.

Nerve signaling pathways in cancer

In the dynamic landscape of cancer biology, nerve signaling pathways play a crucial role by profoundly influencing various carcinogenic pathways within the TME. The interplay between nerve signaling and cancer progression involves complex interactions that trigger key pathways promoting tumor growth and spread. For example, the Hepatocyte Growth Factor (HGF)/c-Met pathway is critical in facilitating perineural invasion in pancreatic cancer [ 36 ]. Activation of this pathway stimulates the mTOR/NGF axis, enhancing the migration and invasion capabilities of cancer cells and promoting their intrusion into surrounding nerve tissues [ 24 ]. Nerves within the TME act as significant promoters of cancer growth and dissemination by activating diverse signaling pathways in both cancer cells and their microenvironment [ 37 , 38 ]. This nerve involvement suggests a broad impact on the multiple pathways governing cancer progression. Sustained adrenergic signaling, for instance, promotes intertumoral innervation through the induction of Brain-Derived Neurotrophic Factor (BDNF), underscoring the essential role of tumoral innervation in cancer development by facilitating the release of growth-promoting catecholamines [ 39 ]. Nerve Growth Factor (NGF) plays a pivotal role in enhancing gastric cancer progression through aberrant cholinergic signaling. This occurs when cholinergic stimulation of the gastric epithelium leads to increased NGF expression, which in turn, expands enteric nerves and supports carcinogenesis [ 39 ]. Similarly, muscarinic acetylcholine signaling has been implicated in gastrointestinal cancers, revealing how neuronal signals can regulate cancer progression within the TME [ 40 ]. Genomic analyses in colorectal cancer have identified critical interactions between neuroactive ligand-receptor interactions and the Ras signaling pathway during the knockdown of DDX21, further emphasizing the influence of neural elements in cancer dynamics [ 41 ]. Moreover, nerve signaling intricately interacts with various other carcinogenic pathways to modulate cancer behavior. For example, in pancreatic cancer, increased levels of NGF, linked to poor prognosis, have been shown to enhance the potential for neural invasion [ 42 ]. Conversely, cholinergic signaling via muscarinic receptors appears to suppress pancreatic cancer growth and reduce cancer stemness, highlighting the modulatory effects of parasympathetic inputs on tumor dynamics [ 26 ]. The interplay extends to the modulation of critical pathways such as TGF-β, which serves a dual role in cancer by acting as a tumor suppressor in early stages while promoting progression in later stages [ 25 ]. The Notch and Wnt signaling pathways are also crucial, with ADAM17 identified as a promoter of lymph node metastasis in gastric cancer, emphasizing their importance in the broader context of cancer progression [ 43 ]. Furthermore, the Hippo pathway plays a vital role in regulating tissue size and preventing tumorigenesis, thereby maintaining cellular homeostasis [ 44 ]. In colon cancer, the ISLR protein promotes cancer progression by influencing the epithelial-mesenchymal transition, a key process in tumor aggressiveness [ 45 ]. These examples illustrate the complex and multifaceted interaction between nerve signaling pathways and carcinogenic pathways, highlighting their collective influence on the modulation of various signaling cascades within the TME. From enhancing pancreatic cancer progression via the HGF/c-Met pathway to affecting the immune landscape through IL-6/JAK2/STAT3 pathways, the intricate relationships between neural inputs and cancer pathways shape the progression and potential metastasis of tumors. Understanding these molecular interactions is crucial for developing targeted therapies that can disrupt these pathways, offering new avenues for inhibiting cancer growth and spread.

Approved drugs in internal medicine

In the field of oncology, repurposing nervous system drugs such as beta-blockers, calcium channel blockers, and statins offers promising therapeutic potentials due to their direct and indirect influences on neural signaling pathways that are increasingly recognized as pivotal in cancer progression.

Beta-blockers and cancer therapy

Beta-blockers, traditionally employed to manage cardiovascular diseases, exhibit significant anticancer properties by interfering with the beta-adrenergic signaling pathways [ 46 ]. These pathways are integral to the sympathetic nervous system's regulation of cellular processes, including cancer cell proliferation and metastasis. For example, propranolol, a non-selective beta-blocker, modulates the tumor microenvironment by reducing cancer growth and enhancing responses to immune checkpoint inhibitors like anti-CTLA4 [ 47 , 48 ]. This drug induces apoptosis in various cancer types through the inhibition of the AKT signaling pathway and the activation of the ROS/JNK pathway, particularly in ovarian cancer cells [ 47 ]. Furthermore, propranolol's ability to inhibit proliferation and angiogenesis adds to its therapeutic repertoire, highlighting its potential to disrupt cancerous activities mediated by sympathetic nervous system stimulation [ 49 , 50 ].

Calcium channel blockers in oncology

Calcium channel blockers are another class of cardiovascular drugs with implications in cancer treatment due to their effect on calcium channels, which are crucial in neural transmission and cellular signaling [ 51 ]. These drugs, by modulating calcium influx in cancer cells, can influence various cellular functions essential for tumor growth and survival. For instance, the T-type calcium channels, when blocked, can significantly reduce the proliferation of hepatocellular carcinoma cells [ 52 ]. This suggests a potential for these blockers to disrupt cancer cell signaling that is akin to neural signal modulation in the nervous system [ 53 ].

Statins as anticancer agents

Statins, well-known for their cholesterol-lowering effects, also modulate biochemical pathways related to the mevalonate pathway, a critical pathway in both cholesterol synthesis and protein prenylation involved in cell signaling [ 54 ]. By inhibiting this pathway, statins can reduce tumor cell proliferation and induce apoptosis, showcasing a broad spectrum of anticancer activities that include modulation of inflammation and immune responses—processes governed by neurochemical signaling in the body [ 55 ]. Furthermore, statins inhibit the prenylation of G-proteins, which are crucial in signaling pathways that involve cellular communication similar to neurotransmission, thereby affecting cancer cell growth and metastasis [ 56 , 57 ]. The role of these drugs extends beyond traditional applications, impacting neurochemical pathways that are increasingly linked to cancer pathogenesis. By modulating these pathways, repurposed nervous system drugs can provide new avenues for cancer therapies, potentially leading to more effective and less toxic treatment modalities. This approach not only underscores the importance of the nervous system in cancer progression but also highlights the potential of neural signaling pathways as targets for innovative cancer therapies.

Approved drugs in neurology and psychiatry

Neural signaling drugs, initially designed to manage neurological and psychiatric disorders, have increasingly shown potential relevance in the field of oncology [ 58 ]. This interest has been sparked by observational studies and clinical cohorts that suggest these drugs may influence cancer risk and progression in unforeseen ways. Large-scale epidemiological studies have particularly highlighted intriguing associations between the use of specific neural signaling drugs and the altered risks of developing certain cancers. For instance, evidence from retrospective cohort studies has indicated that patients taking specific classes of antidepressants may exhibit a lower incidence of certain types of cancer [ 59 ]. Such findings suggest that the mechanisms of action of these drugs, originally intended to modulate neurotransmitter levels, may also interfere with pathways involved in oncogenesis and tumor growth. Furthermore, prospective cohort studies play a crucial role in this research area by following patients over extended periods. These studies assess the long-term effects of neural signaling drugs on both cancer incidence and its progression, providing valuable longitudinal data that can help define potential therapeutic benefits and mechanisms by which these drugs may exert anticancer effects. These insights open up new avenues for repurposing existing neurological and psychiatric drugs as potential adjunct therapies in oncology, leveraging their established safety profiles and mechanisms for innovative cancer treatments. This approach not only promises to enhance the therapeutic arsenal against cancer but also underscores the importance of interdisciplinary research in discovering novel uses for existing medications (Table 1 ).

The insights obtained from clinical relevance studies and cohort analyses have been instrumental in highlighting the potential of neural signaling drugs for cancer therapy. These findings not only affirm the drugs' impact on cancer progression and patient outcomes but also set the stage for a more in-depth examination of their underlying anti-tumor mechanisms. Understanding the foundational elements of how neural signaling drugs influence cancer biology is crucial. It allows us to contextualize and deepen our discussions on the specific anti-cancer mechanisms of these drugs. This is particularly important as we explore the subsequent sections of this review, which delve into the mechanistic pathways through which these drugs exert their effects on tumor cells. By establishing a clear connection between the observed clinical effects and the molecular mechanisms at play, we can more effectively evaluate the potential of repurposing neurological and psychiatric drugs as novel cancer therapies. This approach not only promises to expand the therapeutic options available to oncologists but also enhances our understanding of cancer as a multi-faceted disease that intersects with neurological and psychiatric domains.

Antidepressants

As part of exploring the repurposing of neural signaling drugs for cancer treatment, significant attention has been directed towards antidepressants. These drugs, originally designed to modulate neurotransmitter levels in psychiatric disorders, have shown promising anticancer properties across various studies. This section highlights the potential of antidepressants as anticancer agents, integrating their mechanisms of action and existing evidence into the broader context of neural signaling pathways in cancer. This novel approach capitalizes on the diverse pharmacological properties of these drugs beyond their primary indications. Studies have shown that antidepressants like selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase (MAO) inhibitors, and tricyclic antidepressants exhibit anticancer effects through various mechanisms [ 77 ]. The Repurposing Drugs in Oncology (ReDO) project has identified licensed non-cancer drugs, including antidepressants, with evidence of anticancer activity, paving the way for exploring new treatment options [ 78 – 80 ].

Tricyclic Antidepressants (TCAs) TCAs have been found to modulate bioelectric signaling, influencing cell growth, migration, and metastasis in various cancer types [ 81 ]. For instance, imipramine has been shown to induce apoptosis in glioblastoma cells through extrinsic and intrinsic pathways while suppressing ERK/NF‐κB signaling, suggesting its potential as a therapeutic agent for glioblastomas [ 61 , 63 ]. Additionally, tricyclic antidepressants have been identified as inhibitors of small cell lung cancer and other neuroendocrine tumors, highlighting their potential for targeted cancer therapy [ 82 ].

Selective Serotonin Reuptake Inhibitors (SSRIs) The multifaceted effects of antidepressants extend beyond neurotransmission modulation to include immunomodulation, antioxidant, neuroprotective, analgesic, and anti-inflammatory activities, which can impact cancer progression [ 83 ]. Sertraline, an antidepressant, has been found to target crucial cellular pathways involved in tumorigenesis, such as the TNF-MAP4K4-JNK pathway and the PI3K/Akt/mTOR antiapoptotic pathway, suggesting its potential in cancer treatment [ 84 ]. Fluoxetine, a commonly used antidepressant, has demonstrated anticancer effects by suppressing glioblastoma through AMPA receptor-mediated calcium-dependent apoptosis, highlighting its potential as an adjunct therapy for brain tumors [ 85 ]. Furthermore, fluoxetine has been shown to inhibit DNA repair mechanisms and NF-ĸB signaling in non-small cell lung cancer, suggesting its role in reducing metastatic potential in lung tumors [ 86 ]. The combination of selective serotonin reuptake inhibitors (SSRIs) with sorafenib has been found to synergistically inhibit the AKT/mTOR pathway in hepatocellular carcinoma cells, indicating a potential strategy for enhancing the efficacy of existing cancer therapies [ 87 ].

Monoamine Oxidase Inhibitors (MAOIs) MAOIs, another class of antidepressants, have demonstrated anti-inflammatory effects in addition to their primary use in central nervous system disorders [ 88 ]. MAO-A inhibition has shown promise in the treatment of prostate and lung cancer, indicating the potential of repurposing these drugs for cancer therapy [ 89 ]. Moreover, the combination of curcumin with sodium valproate has been investigated in bipolar disorder treatment, highlighting the potential synergistic effects of combining drugs with different mechanisms of action for psychiatric conditions [ 90 ].

Antipsychotics

The repurposing of antipsychotic drugs for cancer therapy has garnered attention due to evidence from clinical cohort studies suggesting potential anticancer effects of these medications [ 91 ]. Antipsychotics, including dopamine antagonists and atypical antipsychotics, have shown promise in inhibiting cancer growth through various mechanisms of action. Studies have indicated that patients receiving antipsychotic medications may have a lower incidence of cancer, prompting further exploration into the potential therapeutic benefits of these drugs in oncology [ 92 ]. This section delves into various antipsychotics, highlighting their potential anticancer effects and the mechanisms by which they might exert these effects.

Phenothiazines One of the key mechanisms through which antipsychotics exert their anticancer effects is by targeting specific receptors or signaling pathways involved in cancer progression. For example, dopamine D2-like receptor antagonists, such as trifluoperazine and thioridazine, have demonstrated efficacy in cancer therapy by inhibiting cancer stem-like cells (CSCs) [ 93 ]. These findings underscore the importance of understanding the molecular targets of antipsychotics in the context of cancer treatment. Additionally, the role of autophagy modulation by antipsychotic drugs in eliciting anticancer effects has been explored. Antipsychotics have been found to induce autophagy in various cancer cells, offering a potential avenue for enhancing the efficacy of standard cancer therapies [ 94 ]. By understanding the interplay between autophagy and cancer cell survival, researchers can leverage this knowledge to develop novel treatment strategies that exploit the autophagic regulatory circuitry in cancer cells.

Atypical Antipsychotics Olanzapine and Risperidone have been investigated for their role in managing cancer-related symptoms and cachexia. Beyond symptom control, they may also exhibit direct anticancer properties through their antagonistic effects on various neurotransmitter receptors, including serotonin and dopamine receptors, which could influence the tumor environment and cell death mechanisms [ 95 ]. Additionally, Aripiprazole as a partial agonist has been noted for its potential to modulate immune responses within the tumor microenvironment, suggesting a novel approach to enhancing the efficacy of existing cancer therapies [ 96 ]. Furthermore, studies have shown that antipsychotics like penfluridol can synergize with inhibitors of glycolysis to suppress cancer growth, suggesting a potential combination therapy approach for certain types of cancer, such as gallbladder cancer [ 97 ]. By elucidating the molecular mechanisms underlying the synergistic effects of these drug combinations, researchers can optimize treatment regimens for improved therapeutic outcomes.

Antiepileptics

Antiepileptics, primarily used to manage seizures by modulating neural activity, also exhibit properties that may be effective in combating cancer. Antiepileptic drugs have been studied for their effects on various biological mechanisms beyond epilepsy, including epigenetic processes [ 98 ]. The relationship between seizures, epilepsy, and cancer is complex, with considerations for drug interactions between antiepileptic drugs and chemotherapeutic agents needing careful evaluation [ 98 ]. Recent investigations have explored the anticancer properties of antiepileptic drugs, highlighting potential pathways that intersect between cancer and epilepsy [ 99 ]. The repurposing of antiepileptic drugs, such as valproic acid, carbamazepine, and lamotrigine, for cancer therapy has garnered significant attention in recent years. This section examines the anticancer potential of several antiepileptics, focusing on their mechanisms of action and potential therapeutic benefits.

Valproic Acid (VPA) Studies have highlighted the potential of valproic acid in combination with other compounds to suppress proliferation and migration in highly metastatic lung cancer cells [ 100 ]. This effect is believed to be mediated through signaling pathways involving EGFR/VEGFR2/c-Met-Akt-NFjB, suggesting a broad therapeutic application in lung cancer treatment. Moreover, valproic acid has been investigated for its radio sensitizing effects, with studies demonstrating its dependence on the activity of CHK2, a key player in DNA damage response pathways [ 101 ]. The synergistic effects of valproic acid with other anticancer drugs have also been explored, with studies demonstrating enhanced cytotoxicity when combined with agents targeting DNA or topoisomerase II [ 102 ]. This synergism has been attributed to the ability of HDAC inhibitors like valproic acid to modulate gene expression and promote apoptosis in cancer cells. Moreover, valproic acid has shown protective effects against hypoxic-ischemic brain injury in neonatal rats, suggesting its potential therapeutic role beyond cancer treatment [ 103 ]. However, concerns regarding side effects and interactions with other drugs have also been raised, such as the potential for pancytopenia with valproic acid use [ 104 ] and pharmacokinetic interactions leading to hepatotoxicity when co-administered with irinotecan [ 105 ].

Lacosamide As a third-generation antiepileptic drug, lacosamide functions by enhancing the delayed inactivation of voltage-gated Na + channels [ 106 ]. Another significant mechanism involves the inhibition of histone deacetylase, suggesting potential antitumor properties that warrant further investigation. This inhibitory effect may contribute to blocking cell cycle progression in glioma cells, possibly through the upregulation of miR-195-5p. Additionally, researchers have suggested that lacosamide may affect the transcription of other miRNAs (such as miR-107), which could reduce cell proliferation, trigger apoptosis, and limit cellular motility and invasiveness [ 107 ]. Experimental data from one group revealed that targeting CRMP2 phosphorylation with (S)-lacosamide hindered glioblastoma cell growth across various glioblastoma cell lines, and in vivo studies also demonstrated (S)-lacosamide’s effectiveness in reducing glioblastoma progression [ 108 ] (Table 2 ).

Mechanistic insights

Impact on cancer cell proliferation and apoptosis

Neural signaling drugs play a crucial role in impacting cancer cell proliferation by modulating various signaling pathways involved in cell growth, survival, and resistance mechanisms. This section explores how these drugs impact cancer cell proliferation by inhibiting growth and division, providing a critical mechanism by which these medications could be repurposed for cancer treatment (Fig. 2 ).

Regulation of Signaling Pathways Drugs like antidepressants and antipsychotics often target neurotransmitter systems, which can also play roles in tumor cell proliferation. Dopamine and serotonin, typically associated with neurological functions, have been implicated in several key processes such as cell cycle regulation and apoptosis in cancer cells. For instance, certain antipsychotics are known to inhibit dopamine receptors, which can lead to inhibit the PI3K/Akt signaling pathways that promote cancer cell growth and survival [ 191 ]. Phenelzine, traditionally used as an antidepressant, has shown efficacy against melanoma and glioblastoma by inhibiting monoamine oxidase A (MAO-A), an enzyme that regulates the levels of neurotransmitters such as dopamine and serotonin [ 192 , 193 ].

Modulation of Ion Channels and Transporters Neural signaling drugs, particularly antiepileptics, by altering the function of ion channels, can affect various cellular processes critical for cancer progression such as cell cycle regulation, apoptosis, and metastasis. Valproic acid, a well-known antiepileptic drug, its ability to modulate ion channels, particularly calcium channels, plays a role in inducing cell cycle arrest and apoptosis in cancer cells [ 188 , 194 ]. Furthermore, Carbamazepine affects voltage-gated sodium channels, which are essential for the conduction of electrical signals in neurons. Its role in cancer involves altering these channels to disrupt cancer cell signaling and survival [ 195 ].

Induction of Apoptosis Some neural signaling drugs induce apoptosis directly by activating intrinsic and extrinsic apoptotic pathways. For instance, Fluoxetine, a well-known SSRI, has been shown to induce apoptosis in various cancer cell lines including breast cancer and glioblastoma. The mechanism involves the activation of mitochondrial pathways, leading to caspase activation and subsequent cell death [ 121 ].

Moreover, Thioridazine, an antipsychotic drug known for blocking dopamine D2 receptors, has been found to induce apoptosis in cancer stem cells, particularly in glioblastoma and breast cancer models. It influences cell cycle arrest and apoptosis through modulation of the PI3K/Akt signaling pathway [ 196 ].

Interaction with Growth Factors and Hormones Neural signaling drugs can impact cancer treatment by interacting with growth factors and hormones that regulate key processes in tumor growth and metastasis. SSRIs, such as fluoxetine and sertraline, have been shown to impact the expression of Vascular Endothelial Growth Factor (VEGF), which plays a significant role in angiogenesis in tumors [ 197 ]. Sertraline has been observed to inhibit the mTOR signaling pathway, which is closely linked to cell growth and proliferation, and this inhibition can lead to autophagic cell death in cancer cells [ 90 ]. Additionally, sertraline has been shown to induce apoptosis in ovarian carcinoma cells, further supporting its potential as an anticancer agent [ 65 , 198 ]. The ability of sertraline to enhance the cytotoxic effects of other cancer therapies, such as erlotinib, indicates its potential role in combination therapies aimed at improving treatment outcomes in resistant cancer types [ 199 ]. Besides, Fluoxetine has been shown to enhance the expression of VEGF in astrocytes, suggesting a potential role in promoting angiogenesis under certain conditions. [ 200 ] This enhancement of VEGF expression may contribute to the complex interplay between SSRIs and cancer biology, particularly in the context of tumor growth and metastasis. Furthermore, fluoxetine has been reported to inhibit DNA repair mechanisms and modulate the NF-κB signaling pathway, both of which are crucial for cancer cell survival and metastasis [ 89 ]. Valproic acid, used primarily as an antiepileptic, has been studied for its effects on hormone receptor status in breast cancer cells. It can alter estrogen receptor expression, thereby sensitizing the responsiveness of breast cancer cells to hormonal therapies [ 201 ].

Immune modulation

Neural signaling drugs have also shown significant implications for immune modulation in cancer treatment. The immune system plays a crucial role in cancer progression and response to therapy, and understanding how neural signaling drugs influence immune responses can open new therapeutic avenues. Here are specific mechanisms through which these drugs modulate the immune system in the context of cancer:

Modulation of Cytokine Production Many neural signaling drugs can alter the production of cytokines, which are critical mediators of immune responses. For instance, SSRIs like fluoxetine and sertraline are known to modulate cytokine production. They have been shown to reduce levels of pro-inflammatory cytokines such as IL-6 and TNF-α, which are involved in promoting inflammation that can support tumor growth and metastasis [ 196 ]. Amitriptyline, a TCA, has been observed to influence cytokine levels in various models. It can modulate the production of both pro-inflammatory and anti-inflammatory cytokines, potentially balancing the immune response in the tumor microenvironment [ 202 ]. Furthermore, Risperidone, an atypical antipsychotic, has been studied for its effects on cytokine production. Risperidone can decrease the secretion of pro-inflammatory cytokines in immune cells, potentially affecting the inflammatory state within tumors [ 121 , 203 ].

Influence on Immune Cell Activity Drugs that affect neurotransmitter levels can also influence the function of immune cells. The antipsychotic drug chlorpromazine has been shown to enhance the cytotoxic activity of natural killer (NK) cells against tumor cells [ 204 ] . Moreover, Diazepam can modulate the inflammatory response by affecting macrophage cytokine production and phagocytic activity, which plays a critical role in tumor-associated inflammation and immune response [ 205 , 206 ].

Impact on Immune Checkpoint Pathways Immune checkpoints are crucial regulators of immune responses and have become significant targets in cancer therapy. Some neural signaling drugs can indirectly influence the activity of immune checkpoints, potentially enhancing the efficacy of checkpoint inhibitors. Valproic acid, has been shown to affect the expression of PD-L1 on tumor cells, which is a critical immune checkpoint molecule that tumors use to suppress immune responses. By modifying PD-L1 expression, valproic acid can potentially enhance the efficacy of PD-1/PD-L1 checkpoint inhibitors used in cancer immunotherapy [ 207 , 208 ]. SSRIs have been reported to reduce symptoms of immune cell exhaustion in chronic diseases, which may also have implications in cancer therapy. These drugs can modulate the functioning of exhausted T cells, which are often characterized by increased expression of various checkpoint proteins like PD-1 [ 209 – 211 ] . Furthermore, certain antipsychotics have been investigated for their potential to affect the CTLA-4 immune checkpoint, another critical pathway that cancer cells exploit to evade immune detection. These drugs may influence the regulatory T cells (Tregs) which are often involved in the activation of the CTLA-4 pathway [ 212 – 214 ] .

Clinical evidence and trials in repurposing neural signaling drugs for cancer treatment

Despite promising in vitro and preclinical studies demonstrating the anticancer properties of neural signaling drugs, clinical research in this area remains limited. Currently, most available clinical studies are descriptive and retrospective, primarily assessing correlations between treatment with these drugs and outcomes such as prognosis, recurrence risk, or survival rates. Such studies, while informative, do not provide conclusive evidence of efficacy and may not account for all variables influencing cancer progression (Table 3 ).

The potential for repurposing neural signaling drugs in oncology continues to be a promising avenue of research. To fully harness this potential, future investigations should prioritize the following areas:

Comprehensive Clinical Trials There is a need for larger and more rigorous clinical trials that can conclusively determine the safety and efficacy of neural signaling drugs across various types of cancer. These studies should be designed to overcome the limitations of retrospective analysis by including prospective methodologies and control groups to ensure robust and reliable results.

Combination Therapy Strategies Exploring combination therapies that integrate neural signaling drugs with standard cancer treatments could open new therapeutic avenues. These studies should aim to uncover synergistic effects that could enhance the overall effectiveness of cancer treatment regimens, potentially leading to improved patient outcomes.

Mechanistic Studies Further research is required to elucidate the molecular mechanisms by which neural signaling drugs impact cancer cells. Understanding how these drugs interact with specific cancer-related pathways can lead to the development of targeted therapies tailored to the genetic and molecular profiles of individual tumors. This approach could refine treatment strategies and increase the precision of cancer therapies.

Challenges and considerations

Safety and toxicity

When repurposing neural signaling drugs for cancer treatment, the paramount concern is ensuring safety and managing toxicity, given the potential for side effects that may significantly diverge from those observed in their original use for neurological conditions.

Potential Side Effects and Contraindications Although these drugs are generally considered safe for neurological disorders, their application in oncology may introduce unexpected complications. For example, antidepressants could exacerbate fatigue or induce neurological side effects, adversely affecting a cancer patient’s quality of life [ 140 ]. It is vital to meticulously assess these risks in clinical trials.

Impact on Quality of Life The adverse effects of these drugs, such as cognitive impairment from antiepileptics [ 215 ] or the metabolic side effects of some antipsychotics [ 216 ], must be carefully considered. This is particularly important as cancer patients often contend with pre-existing complications arising from their primary illness or other ongoing treatments.

Pharmacokinetics and pharmacodynamics

Understanding the pharmacokinetics and pharmacodynamics of drugs within the oncological context, which may differ from their original indications in neurology or psychiatry, is crucial for effective repurposing.

Drug Metabolism In cancer patients, drug metabolism can be altered by the disease itself or concurrent therapies, potentially impacting the effectiveness and safety profile of the drugs. For instance, enzyme-inducing antiepileptics may interact with chemotherapy agents, affecting their efficacy and toxicity [ 217 ].

Drug Efficacy It is crucial to adjust dosage and delivery methods to align with the cancer treatment profile. Modifications in drug formulation or administration routes may be necessary to achieve desired therapeutic effects within the tumor microenvironment.

Regulatory and ethical considerations

Navigating the complex regulatory and ethical landscape presents significant challenges in the drug repurposing process, especially given the unique requirements for additional evidence in oncology [ 218 ].

Approval Challenges Gaining regulatory approval for repurposed drugs can be particularly challenging when transitioning from neurological to oncological applications. Demonstrating safety and efficacy in the new therapeutic context is essential, often requiring extensive clinical trials.

Ethical Considerations

There are substantial ethical implications to consider when balancing the potential benefits against the risks of using drugs outside their initial indications. This includes careful patient selection, ensuring informed consent, and managing expectations regarding treatment outcomes.

The repurposing of neural signaling drugs for cancer treatment opens promising avenues but is fraught with complexities that necessitate careful scientific, clinical, regulatory, and ethical considerations. The future success in this field will heavily rely on multidisciplinary collaboration, innovative trial designs, and robust regulatory frameworks to facilitate the safe and effective integration of these drugs into cancer therapy regimens.

Future directions and research opportunities

Identification of new candidates

The continuous discovery of neural signaling drugs with potential anticancer properties is vital for expanding the arsenal against various cancer types. Strategies for Discovering Additional Neural Signaling Drugs with Anticancer Potential:

High-throughput Screening Employing high-throughput screening techniques to test existing neural signaling drugs against a wide range of cancer cell lines to identify new anticancer properties [ 219 – 222 ].

Computational Drug Repurposing Using bioinformatics and systems biology to predict potential anticancer effects based on drug-target interactions and pathway analyses [ 223 – 228 ].

Drug Side Effects Exploration Analyzing known side effects of existing drugs to find effects that might relate to anticancer mechanisms, which can reveal unexpected anticancer potential of the drugs [ 229 ].

Drug Structural Modification By modifying the chemical structures of known neural signaling drugs to enhance their selectivity and potency against cancer cells, developing improved versions of drugs better suited for treating specific types of cancer [ 230 , 231 ]. ( Fig. 3 ).

Combination therapies

Combining neural signaling drugs with existing cancer therapies offers the potential to enhance efficacy, overcome resistance, and reduce side effects. Potential for Using Neural Signaling Drugs in Combination with Existing Cancer Therapies:

Synergistic Combinations Identifying combinations where neural signaling drugs enhance the effects of traditional chemotherapies, targeted therapies, or immunotherapies. For instance, pairing HDAC inhibitors like valproic acid with immune checkpoint inhibitors to enhance immune response [ 232 ].

Reducing Side Effects Using neural signaling drugs to mitigate side effects of conventional cancer treatments, such as using certain antipsychotics to reduce nausea induced by chemotherapy [ 163 ].

Clinical Trials Designing and conducting clinical trials to validate the efficacy and safety of these combinations, ensuring that they bring tangible benefits to patient care.

Personalized medicine

Tailoring treatments to individual patient profiles is a cornerstone of modern oncology, improving outcomes by aligning therapies with the genetic and molecular characteristics of tumors. Tailoring Treatments Based on Individual Patient Profiles and Tumor Characteristics:

Genetic Profiling Using genetic and molecular profiling of tumors to identify which patients are likely to respond to specific neural signaling drugs based on the presence of biomarkers.

Pharmacogenomics Integrating pharmacogenomic data to understand how individual genetic variations affect responses to neural signaling drugs, optimizing dosages and combinations to maximize efficacy and minimize toxicity.

Longitudinal Studies Implementing longitudinal studies to track responses over time and adjust treatments as tumors evolve or as patient conditions change.

Challenges of drug repurposing

Repurposing neural signaling drugs presents several challenges that must be addressed to harness their potential fully:

Investment and Financial Risks Gaining upfront investment for repurposing drugs, especially those with a prior failure record, is challenging. Companies specializing in specific R&D areas might find repositioning projects outside their scope.

Out-licensing and Collaboration While out-licensing for conducting investigator-sponsored trials through CROs or biotech partnerships might seem viable, finding organizations willing to invest in risky ventures is difficult [ 233 ].

Regulatory and Developmental Challenges Developing new criteria for patient inclusion, study endpoints, and efficacy measures for repositioned drugs incurs significant expenses [ 234 ]. Moreover, toxicological or pharmacokinetic data collected for the original indication may not meet new regulatory standards for cancer treatment.

Patent Issues and Profitability Concerns The limited patent life remaining after initial R&D phases complicates the profitability of repositioning efforts. Adjusting dosage or administration routes to extend patents or creating new “method of use” patents often faces legal and technical hurdles.

Market Dynamics Pharmaceutical companies may find it unprofitable to reposition low-cost drugs for high-cost indications, such as orphan diseases or cancers, despite potential medical usefulness and patient benefit.

While the future of repurposing neural signaling drugs in oncology is promising, addressing these challenges and leveraging advanced research methodologies are crucial. Continued exploration and investment in identifying new candidates, perfecting combination therapies, and personalizing treatment regimens will be essential. These efforts will not only expand the therapeutic options available to oncologists but also provide more precise, effective, and patient-centered cancer care.

Conclusion

Summary of key findings

This review has explored the expansive roles of neural signaling drugs in cancer treatment, underpinning the emerging field of cancer neuroscience which investigates the profound influence of the nervous system on cancer biology. Key findings include:

Mechanistic Insights Neural signaling drugs impact cancer therapy through various mechanisms such as inhibition of cancer cell proliferation, modulation of cytokine production, and immune modulation.

Direct and Indirect Neural Influences Recent research has increasingly shown both direct and indirect influences of the nervous system on cancer initiation, growth, dissemination, and treatment resistance, enriching our understanding of cancer pathogenesis.

Preclinical, Clinical Evidence and Trials Preclinical and clinical trials have provided preliminary evidence supporting the efficacy of neural signaling drugs in cancer treatment, particularly in symptom management and potential enhancement of existing cancer therapies.

Implications for cancer treatment

The repurposing of neural signaling drugs offers substantial implications for cancer treatment:

Integration into Cancer Neuroscience The interaction between the nervous system and cancer—whether promoting or inhibiting tumor development—suggests that nervous system-cancer interactions might be considered a general principle of cancer pathogenesis.

Enhanced Therapeutic Strategies Understanding the role of the CNS and PNS, including glial cells and tumor innervation, can expand therapeutic strategies, potentially leading to more targeted and effective treatments.

Improved Patient Outcomes By leveraging the anti-cancer properties of neural signaling drugs and their role in modulating the tumor microenvironment, oncologists can potentially improve treatment efficacy and patient quality of life.

Future outlook and continued research

The outlook for integrating neural signaling drugs into oncology is promising, highlighted by several areas of potential research and development:

Further Discovery and Understanding Continued research are expected to yield exciting discoveries in cancer neuroscience, particularly concerning mechanisms currently known to influence cancer development and resistance.

Mapping the Nervous System-Cancer Interactome and Connectome There is a crucial need to better understand the intricate interactions between the nervous system and specific cancer types and stages on multiple scales.

Development of Collaborative Networks Future advancements will likely depend on cross-disciplinary collaborations, combining insights from neurology, oncology, and pharmacology to foster innovative treatment approaches.

Clinical Trials and Biomarkers Meaningful clinical trials and the development of biomarkers for nervous system-cancer interactions are essential for advancing personalized medicine and selecting effective therapies for individual patients.

Conclusion

Integrating the principles of cancer neuroscience into the field of oncology using neural signaling drugs represents a transformative approach to cancer treatment. As we deepen our understanding of the nervous system’s impact on cancer, new therapeutic avenues will emerge, potentially revolutionizing how we treat various malignancies. The challenge lies in harnessing this knowledge effectively, requiring an orchestrated effort across multiple disciplines to bring these innovative treatments from bench to bedside.

Acknowledgments

Institutional Review Board

Not applicable.

Author contributions

All authors contributed to the article preparation. Conceptualization, Z.W. Q.W. and C.X. and data analysis, C.X. and Q.W.; writing—original draft preparation, C.X. and Z.W.; writing—review and editing, C.X. Z.W. Q.W. and Y.W.; supervision, Y.W. and Q.W. All authors have read and agreed to the published version of the manuscript.

Funding

The present work was supported by the Program of Shanghai Academic Research Leader (No. 22XD1403500), the Central Guidance on Local Science and Technology Development Fund of Shanghai Province (No. YDZX20223100003006), the Shanghai Municipal Key Clinical Specialty (No. shslczdzk06302), the “Science and Technology Innovation Action Plan” International Science and Technology Cooperation Project (No. 20550760600), the Shanghai Shenkang Hospital Development Center Clinical Technology Innovation Project (No. SHDC12020130), and the Shanghai Jiao Tong University Medicine‐Engineering Fund (No. YG2022ZD).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Informed consent

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Zixun Wang and Chen Xu have contributed equally to this work.

Contributor Information

Qi Wang, Email: 18851901709@163.com.

Yudong Wang, Email: wangyudong@shsmu.edu.cn.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.