Repurposing Terbutaline and Milrinone for Cancer Therapy: A Comprehensive Review

Abstract

Cancer remains a leading cause of mortality worldwide, necessitating innovative therapeutic strategies. Drug repurposing offers a cost-effective approach to cancer treatment by identifying new anticancer applications for existing drugs. Terbutaline, a β2-adrenergic receptor agonist, and Milrinone, a phosphodiesterase-3 inhibitor, are traditionally used as positive inotropic agents but have shown potential anticancer effects. This review explores their mechanisms of action in cancer, focusing on their roles in modulating cyclic adenosine monophosphate (cAMP) levels, oxidative stress, and the tumor microenvironment. Terbutaline influences β2-adrenergic signaling, impacting cell proliferation, angiogenesis, and immune evasion. Milrinone, through PDE3 inhibition, elevates cAMP, promoting apoptosis and reducing tumor growth. Both agents exhibit anti-inflammatory and anti-angiogenic properties, suggesting their potential as adjuvant therapies in oncology. Despite promising preclinical data, clinical validation is required to confirm their efficacy and safety in cancer patients. This review highlights the therapeutic promise of repurposing Terbutaline and Milrinone, emphasizing the need for further research to optimize their application in cancer therapy.

1. Introduction

Cancer remains a leading cause of morbidity and mortality worldwide, with its incidence and associated death rates continuing to rise despite decades of intensive research and advances in diagnostic and therapeutic technologies [1]. As a disease characterized by immense biological complexity and heterogeneity, cancer presents unique challenges that demand innovative and multifaceted approaches to treatment. At the cellular and molecular levels, cancer is driven by an intricate interplay of genetic mutations that promote unchecked proliferation [2], epigenetic dysregulation that alters gene expression without changes in DNA sequence [3], and dynamic interactions within the tumor microenvironment (TME), which encompasses immune cells, stromal components, extracellular matrix, and vascular networks [4]. These elements together enable tumor cells not only to survive and proliferate but also to evade immune surveillance, adapt to hostile conditions, and resist therapy.

Conventional treatment modalities, including chemotherapy, radiotherapy, and more recently developed targeted therapies, have been successful in certain cancer types and patient populations. However, they are often limited by issues such as non-specific toxicity, off-target effects, and the development of drug resistance. Treatment resistance, whether intrinsic or acquired, remains one of the greatest obstacles to achieving durable responses and improving overall survival in cancer patients. Tumor heterogeneity, both between and within individuals, further complicates therapeutic intervention. Tumors can rapidly evolve under selective pressure from treatment, leading to the emergence of more aggressive and treatment-resistant clones. This adaptability underscores the urgent need for novel therapeutic strategies that are not only effective but also adaptable to the evolving biology of cancer.

In recent years, drug repurposing has gained substantial attention as a strategic response to these challenges. Unlike traditional drug development, which often requires over a decade of research and billions of dollars in investment, drug repurposing offers a pragmatic and accelerated path to new treatments. This strategy involves identifying new therapeutic indications for existing drugs that have already undergone extensive testing and regulatory approval for other conditions. As such, many repurposed agents come with known pharmacokinetics, pharmacodynamics, toxicity profiles, and manufacturing processes, which significantly reduces the cost, time, and risk associated with bringing a new drug to market.

Within oncology, drug repurposing has emerged as a powerful approach to uncover previously unrecognized anticancer effects of non-oncologic medications. Several well-known examples underscore its promise, including the repositioning of metformin (originally an antidiabetic agent), propranolol (a beta-blocker), and thalidomide (an immunomodulatory agent) for various cancer types [5,6,7,8]. These successes have paved the way for broader exploration into other therapeutic classes. One particularly intriguing category that has recently garnered interest comprises positive inotropic agents, drugs primarily used to enhance myocardial contractility in heart failure and related cardiovascular disorders.

Positive inotropes such as Terbutaline and Milrinone are increasingly being recognized for their potential to modulate pathways implicated in oncogenesis and tumor progression [9]. These agents are capable of influencing a variety of intracellular processes through mechanisms involving cAMP signaling, nitric oxide modulation, calcium flux, and reactive oxygen species (ROS) regulation. Elevated levels of cAMP, for instance, have been associated with reduced cancer cell proliferation, enhanced apoptosis, and alterations in mitochondrial dynamics, suggesting a potentially favorable profile for anticancer intervention. Moreover, by improving vascular function and perfusion, these agents might indirectly enhance the delivery and efficacy of other cancer therapies, such as chemotherapeutic agents or immune checkpoint inhibitors. Beyond their pharmacological activity, Terbutaline and Milrinone are particularly attractive from a translational standpoint due to their well-characterized clinical use and safety records. Their inclusion in repurposing efforts aligns with regulatory frameworks that encourage the exploration of known drugs for new applications, potentially expediting the path to clinical implementation in oncology. Their pharmacokinetic parameters, such as bioavailability, half-life, metabolic pathways, and excretion, are already well-defined, which facilitates the design of clinical trials and dosing protocols tailored for cancer patients.

Terbutaline, a β2-adrenergic receptor agonist, is primarily indicated for the management of asthma and other obstructive pulmonary disorders [10,11]. Its main mechanism of action involves the activation of β2-adrenergic receptors, which leads to relaxation of bronchial smooth muscle via increased cAMP levels. However, β2-adrenergic signaling also plays a role in multiple cellular processes that are relevant to cancer biology [12]. Studies have demonstrated that stimulation of β2-ARs can influence cell cycle progression and apoptosis [13], while also modulating the immune landscape of tumors and contributing to angiogenic signaling [14]. These mechanisms suggest that Terbutaline, through β2-AR activation, may either promote or suppress tumor growth depending on the context—a duality that warrants thorough investigation to clarify therapeutic potential.

Milrinone, a selective PDE3 inhibitor, is used clinically for its inotropic and vasodilatory effects in patients with acute or chronic heart failure. By inhibiting PDE3, Milrinone prevents the breakdown of cAMP, resulting in elevated intracellular concentrations of this signaling molecule [15]. Increased cAMP has a cascade of downstream effects, including activation of protein kinase A (PKA), modulation of mitochondrial function, and enhancement of apoptotic signaling pathways [16]. In cancer models, these effects have been associated with decreased tumor cell viability, increased oxidative stress tolerance, and suppression of metastatic behaviors [17]. Moreover, the vasodilatory properties of Milrinone may support improved tumor perfusion, creating an environment more favorable to the penetration of anticancer drugs and oxygenation, both critical factors in effective treatment.

Although several studies have explored the role of β2-adrenergic signaling and cAMP modulation in cancer biology, there is a notable lack of comprehensive reviews specifically focusing on the potential repurposing of Terbutaline and Milrinone as anticancer agents. Existing reviews have largely examined β-adrenergic pathways in the context of stress and cancer progression or have focused on broader classes of phosphodiesterase inhibitors without addressing the unique pharmacological profiles and clinical data associated with these two drugs [18,19,20,21]. To the best of our knowledge, no prior review has systematically analyzed the mechanistic rationale, preclinical evidence, and translational implications of repurposing these positive inotropic agents for oncology. Therefore, this review aims to provide a comprehensive and integrated analysis of the emerging evidence supporting the repositioning of Terbutaline and Milrinone as adjunctive or standalone anticancer therapies. By examining their underlying molecular mechanisms, pharmacological properties, and documented effects on key tumorigenic pathways, we seek to outline a rational framework for their potential role in oncology. Furthermore, we discuss the broader implications of repurposing cardiovascular drugs in cancer therapy, particularly within the context of integrative and personalized medicine, highlighting how these well-characterized agents might contribute to innovative and cost-effective cancer treatment strategies that can be readily incorporated into clinical practice.

2. Drug Profiles

2.1. Terbutaline

Terbutaline is a selective β2-adrenergic receptor agonist that belongs to the class of sympathomimetic agents [10,22]. It is a synthetic derivative structurally classified within the phenylethanolamine family (Figure 1), and it mimics the physiological actions of endogenous catecholamines such as epinephrine and norepinephrine. Unlike non-selective adrenergic agonists, Terbutaline exhibits a high degree of specificity for β2-adrenergic receptors, with minimal cross-reactivity at β1-adrenergic sites. This receptor selectivity is pharmacologically advantageous as it reduces the risk of β1-mediated cardiovascular side effects, including tachycardia and hypertension [23]. As a result, Terbutaline is widely used for its potent smooth muscle relaxant properties, particularly in pulmonary and obstetric medicine, without inducing significant hemodynamic disturbances [24].

At the molecular level, the pharmacodynamics of Terbutaline are mediated through its interaction with β2-adrenergic receptors, which are G protein-coupled receptors (GPCRs) expressed predominantly on bronchial smooth muscle cells, but also present in other tissues including vascular smooth muscle, skeletal muscle, and uterine tissue. Upon ligand binding, the β2-receptor undergoes a conformational change, leading to the activation of the Gs protein, which in turn stimulates adenylate cyclase. The resultant increase in intracellular cyclic adenosine monophosphate (cAMP) levels initiates a cascade of downstream signaling events. One of the primary effectors of cAMP is protein kinase A (PKA), which phosphorylates a series of proteins involved in the regulation of smooth muscle tone. A key PKA target is myosin light chain kinase (MLCK), whose inhibition leads to reduced phosphorylation of the myosin light chain and subsequent muscle relaxation [25] (Figure 2).

Clinically, Terbutaline has played a pivotal role in the management of respiratory conditions such as asthma, chronic obstructive pulmonary disease (COPD), and bronchospasm associated with allergic reactions or exercise-induced airway constriction [26,27]. Its rapid onset of action and short duration make it well-suited for the acute management of bronchoconstriction. Depending on the clinical scenario, it can be administered via several routes, including inhalation, oral tablets, or subcutaneous injection, each with distinct pharmacokinetic characteristics. Inhaled administration offers rapid symptom relief, typically within 15 min, with bronchodilator effects lasting approximately 4 to 6 h. However, oral formulations suffer from low bioavailability (14–15%) due to extensive first-pass hepatic metabolism, which limits systemic exposure [28]. Outside of respiratory medicine, Terbutaline has also been explored for its tocolytic effects, particularly in the management of preterm labor. By relaxing uterine smooth muscle through the same β2-AR-mediated cAMP signaling pathway, Terbutaline can delay labor onset. While it is effective as a short-term measure to postpone delivery, especially to allow for corticosteroid administration for fetal lung maturation, its use is constrained by dose-dependent adverse effects such as maternal tachycardia, hypotension, anxiety, and hyperglycemia (Table 1) [29,30]. These side effects are especially pronounced when the drug is administered intravenously or at high systemic doses, necessitating careful monitoring and individualized risk–benefit analysis in obstetric applications.

Metabolically, Terbutaline undergoes biotransformation primarily in the liver. Its principal metabolic route involves sulfation catalyzed by sulfotransferase enzymes, especially SULT1A3, which is abundantly expressed in hepatic and intestinal tissues. These enzymes conjugate Terbutaline into inactive metabolites that are predominantly excreted via the renal route. Approximately 60% of the administered dose is recovered in the urine, either unchanged or as conjugates. The drug’s elimination half-life ranges from 3 to 6 h, which necessitates multiple daily administrations for sustained therapeutic effect, particularly in oral or inhaled forms [31]. This relatively short half-life makes Terbutaline more suitable for acute symptom management rather than chronic control, except when used in combination with long-acting agents. In addition to its well-established role in bronchodilation and smooth muscle relaxation, β2-adrenergic signaling mediated by Terbutaline extends to metabolic regulation. Activation of β2-ARs in hepatocytes and skeletal muscle fibers stimulates glycogenolysis, leading to increased glucose availability in the bloodstream, a mechanism that serves the body’s “fight or flight” response but may pose challenges in patients with diabetes or metabolic syndrome [32]. Thus, Terbutaline should be used with caution in individuals predisposed to hyperglycemia, and blood glucose levels should be monitored during prolonged or high-dose therapy.

Emerging research also suggests a potential oncological dimension to β2-adrenergic receptor activation. A growing body of evidence indicates that β2-ARs are expressed in various human cancers, including breast, lung, prostate, and pancreatic tumors. Their activation may influence tumor progression, not only through direct effects on cancer cells—such as increased proliferation, migration, and resistance to apoptosis—but also via modulation of the tumor microenvironment, including angiogenesis and immune evasion. These findings have led to the hypothesis that Terbutaline, through its effects on β2-AR signaling pathways, could be explored as a candidate for drug repurposing in oncology. Although the evidence is still preliminary, ongoing studies aim to characterize whether β2-agonists may inhibit or promote tumor growth in a context-dependent manner, necessitating rigorous preclinical and clinical investigations.

In summary, Terbutaline is a versatile pharmacological agent with well-documented applications in respiratory and obstetric medicine. Its mechanism of action, centered around β2-adrenergic receptor activation and subsequent cAMP elevation, confers smooth muscle relaxation and rapid symptomatic relief. Its pharmacokinetic and safety profiles are well-characterized, making it a dependable therapeutic option in acute settings. Furthermore, its metabolic and emerging oncogenic implications highlight the broader significance of β2-AR signaling in human physiology and disease, positioning Terbutaline as a drug of interest for future translational research.

2.2. Milrinone

Milrinone is a bipyridine derivative that functions as a selective phosphodiesterase-3 (PDE3) inhibitor, primarily targeting cardiac and vascular smooth muscle tissues (Figure 3) [33,34].

By inhibiting PDE3, an enzyme responsible for the degradation of cyclic adenosine monophosphate (cAMP), Milrinone effectively increases intracellular cAMP levels. This elevation in cAMP enhances protein kinase A (PKA) activity, which in turn promotes calcium influx into cardiomyocytes and leads to improved myocardial contractility [35]. Simultaneously, increased cAMP levels in vascular smooth muscle result in relaxation and vasodilation, contributing to reduced afterload and improved cardiac output (Figure 4) [36].

Milrinone’s dual inotropic and vasodilatory (inodilator) effects form the basis of its clinical application in the management of acute decompensated heart failure and low-output states following cardiac surgery [37,38]. Its dual inotropic and vasodilatory properties make it effective in improving hemodynamic parameters, particularly in settings where conventional treatments, such as β-adrenergic agonists, are insufficient or contraindicated [39]. By acting independently of β-adrenergic receptors, Milrinone provides hemodynamic support without desensitizing cardiac receptors or increasing myocardial oxygen demand as significantly as other inotropes.

Pharmacokinetically, Milrinone is administered intravenously due to its poor oral bioavailability. It displays a rapid onset of action and is distributed in a biphasic manner, with an elimination half-life of approximately 2.3 h in individuals with normal renal function. The drug is minimally metabolized, with over 80% excreted unchanged in the urine. Consequently, renal function plays a crucial role in determining Milrinone’s clearance, and dose adjustments are essential in patients with renal impairment to prevent drug accumulation and toxicity [40].

Despite its efficacy, Milrinone is associated with adverse effects, including hypotension, arrhythmias, and thrombocytopenia (Table 1), which can limit its use in certain patient populations [40]. Additionally, prolonged use may increase the risk of ventricular arrhythmias and mortality in chronic heart failure patients, highlighting the need for careful monitoring.

Table 1. Adverse effects of Terbutaline and Milrinone.

Adverse Effects	Terbutaline	Milrinone	References
Cardiovascular	Tachycardia, hypotension	Hypotension, arrhythmias	[30,40]
Metabolic	Hyperglycemia	Electrolyte imbalances	[41,42]
Neurological	Tremors, nervousness	Headache, dizziness	[43,44]
Hematological	N.A *	Thrombocytopenia	[45]
Other	Nausea, muscle cramps	Nausea, increased mortality (chronic heart failure)	[46,47,48]

* Not Applicable.

Table 1. Adverse effects of Terbutaline and Milrinone.

Adverse Effects	Terbutaline	Milrinone	References
Cardiovascular	Tachycardia, hypotension	Hypotension, arrhythmias	[30,40]
Metabolic	Hyperglycemia	Electrolyte imbalances	[41,42]
Neurological	Tremors, nervousness	Headache, dizziness	[43,44]
Hematological	N.A *	Thrombocytopenia	[45]
Other	Nausea, muscle cramps	Nausea, increased mortality (chronic heart failure)	[46,47,48]

* Not Applicable.

3. Mechanistic Relevance in Cancer

3.1. Role of β2-Adrenergic Signaling

The β2-adrenergic receptor (β2-AR) is a G protein-coupled receptor (GPCR) primarily known for its role in the regulation of smooth muscle relaxation, cardiovascular function, and bronchodilation [49]. However, accumulating evidence suggests that β2-AR signaling also plays a critical role in tumor biology [50,51]. This receptor is expressed in various cancer types, including breast [52], lung [53], liver [54], prostate [55], and colorectal cancers [56], and its activation can influence multiple cellular processes relevant to tumor growth and progression. Notably, β2-AR signaling in cancer exhibits a dual role that depends on tumor type, β2-AR expression levels, and downstream signaling context. In some tumor models, β2-agonists exert anti-tumor effects by elevating intracellular cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA) and exchanges protein directly activated by cAMP (EPAC), leading to reduced proliferation, increased apoptosis, and metabolic reprogramming [57,58,59,60]. For instance, β2-AR activation has been shown to inhibit mesenchymal phenotypes and cell motility in oral squamous cell carcinoma (OSCC) [61] and to reduce tumor growth in breast cancer xenografts via downregulation of the Raf-1/Mek-1/Erk1/2 pathway [62]. Additionally, Bravo-Calderón et al. demonstrated that increased β2-AR expression correlated with improved overall survival rates in OSCC patients [63]. Similarly, the β2-AR agonist ARA-211 (pirbuterol) led to tumor regression in breast and colon cancer xenograft models [64].

Conversely, in other contexts, β2-adrenergic signaling promotes tumor growth through mechanisms such as increased angiogenesis via VEGF upregulation [14,65], stabilizing hypoxia-inducible factor 1-alpha (HIF-1α) [54], and facilitating immune evasion [66]. High β2-AR expression has been associated with poor prognosis in cancers like multiple myeloma [67].

Beyond direct effects on tumor cells, β2-AR signaling also shapes the tumor microenvironment. It can stimulate angiogenesis, ensuring an adequate blood supply for rapidly proliferating cancer cells [65,68], and modulate immune responses, potentially suppressing anti-tumor immunity [69].

Therefore, whether β2-agonists like Terbutaline act as tumor suppressors or promoters may vary depending on the tumor microenvironment, receptor density, and the balance of downstream signaling pathways activated upon receptor stimulation (Figure 5).

Overall, the impact of β2-adrenergic signaling in cancer appears highly context-dependent. While some evidence supports its anti-tumor potential through cAMP-mediated pathways and suppression of mesenchymal traits, other studies indicate a role in tumor progression via angiogenesis, immune modulation, and activation of pro-survival signaling cascades. This duality underscores the need for further research to delineate the conditions under which β2-agonists like Terbutaline could serve as effective anticancer agents rather than contributors to tumor growth.

Influence of β₂-Adrenergic Signaling on the Tumor Microenvironment

The β₂-adrenergic signaling pathway plays a crucial role in regulating the tumor microenvironment (TME) by influencing key processes such as inflammation, angiogenesis, extracellular matrix remodeling, and immune response modulation [51]. Β2-ARs are widely expressed in various cell types, including tumor cells [70], fibroblasts [71], endothelial cells [72], and immune cells [73], making this pathway a significant factor in cancer biology.

β₂-AR activation can impact tumor-associated inflammation by modulating the release of both pro- and anti-inflammatory cytokines [74]. Studies suggest that β₂-adrenergic stimulation can reduce the production of tumor necrosis factor-alpha (TNF-α), a cytokine linked to chronic inflammation and tumor growth [75]. However, the same pathway can also activate transcription factors such as NF-κB, which promote a pro-inflammatory environment that supports tumor progression [76]. This dual effect indicates that the influence of β₂-adrenergic signaling in cancer may vary depending on the tumor type and the physiological context.

Another relevant aspect is the role of β₂-AR signaling in angiogenesis, a crucial process for tumor growth and metastatic dissemination [77]. Activation of β₂-AR in endothelial cells can stimulate the expression of vascular endothelial growth factor (VEGF), promoting the formation of new blood vessels that sustain the tumor and facilitate its spread [78]. Furthermore, β₂-agonists can modulate extracellular matrix dynamics by regulating the activity of matrix metalloproteinases (MMPs), enzymes responsible for matrix degradation and increased cellular mobility, thereby enhancing tumor invasion [79,80].

The interaction between β₂-adrenergic signaling and the immune system is also a key factor in cancer progression. β₂-AR activation can suppress the activity of cytotoxic immune cells, such as CD8⁺ T cells and natural killer (NK) cells, thereby reducing the body’s ability to eliminate tumor cells [81]. Additionally, β₂-adrenergic signaling may influence macrophage polarization within the tumor microenvironment, promoting an immunosuppressive profile associated with tumor progression [82,83].

These effects on inflammation, angiogenesis, and immune response highlight the complex role of β₂-adrenergic signaling in shaping the tumor microenvironment. Depending on the biological context, this pathway may either support or inhibit tumor progression. Therefore, further understanding of these mechanisms could pave the way for novel therapeutic approaches that target β₂-adrenergic signaling in cancer.

3.2. Impact of cAMP Modulation and PDE3 Inhibition

Cyclic adenosine monophosphate (cAMP) is a key second messenger that regulates numerous cellular processes, including proliferation, differentiation, apoptosis, and metabolism, playing a complex role in cancer biology as it can act as either a tumor promoter or suppressor depending on the cellular context, tumor type, and activated pathways [84].

The modulation of cAMP levels, particularly through the inhibition of phosphodiesterase-3 (PDE3), has gained attention for its potential therapeutic applications in oncology, as PDE3 enzymes are responsible for degrading cAMP and maintaining its intracellular balance, and their inhibition can lead to increased cAMP levels, which in turn may activate pathways such as protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC), both of which are known to influence processes critical for tumor progression and survival [9,58,59].

Elevated cAMP levels resulting from PDE3 inhibition have been shown to promote apoptosis in cancer cells by enhancing pro-apoptotic signaling and reducing the expression of anti-apoptotic factors while simultaneously exerting anti-proliferative effects by disrupting cell cycle progression, modulating cyclins and cyclin-dependent kinases, and enhancing the activity of CDK inhibitors, all of which contribute to the suppression of tumor growth [84,85,86]. In addition to these direct effects on cancer cells, PDE3 inhibitors may also influence the tumor microenvironment by reducing oxidative stress, which is a key driver of cancer progression, and by modulating the immune response, potentially enhancing the activity of immune cells such as T lymphocytes and macrophages, which play a central role in anti-tumor immunity [87,88].

In addition to its direct effects on cell proliferation and apoptosis, cAMP signaling is increasingly recognized for its interplay with major oncogenic pathways such as PI3K/AKT, MAPK, and Wnt/β-catenin. For example, cAMP/PKA activation can inhibit the PI3K/AKT pathway by phosphorylating and suppressing upstream regulators, thereby promoting apoptosis and reducing cell survival in certain cancer types [59,85,89]. Similarly, cAMP signaling can modulate the MAPK cascade through PKA-mediated phosphorylation of Raf-1, leading to context-dependent effects on cell proliferation and differentiation [90]. Furthermore, cAMP/PKA has been shown to influence Wnt/β-catenin signaling by regulating the stability and nuclear localization of β-catenin, which affects the expression of genes involved in tumorigenesis [91,92]. These points of intersection suggest that the anticancer effects of Terbutaline and Milrinone may, in part, be mediated by their ability to modulate these critical signaling networks. The main points of crosstalk are outlined in

Table 2. Interactions between cAMP signaling and key oncogenic pathways.

Pathway	cAMP Effector	Effect of cAMP Modulation	References
PI3K/AKT	PKA, EPAC	Inhibition of AKT activation, apoptosis	[59,85,89]
MAPK	PKA	Modulation of Raf-1/ERK, proliferation	[90]
Wnt/β-catenin	PKA	Regulation of β-catenin, gene expression	[91,92]

.

Despite these promising findings, challenges remain in translating the modulation of cAMP and PDE3 inhibition into clinical cancer therapies, including the need to identify specific cancer types and subtypes where these approaches are most effective, the development of predictive biomarkers to select patients who are likely to benefit from PDE3 inhibitors, and the careful consideration of safety concerns, particularly in patients with pre-existing cardiovascular conditions, as these drugs are primarily used in this context, making it essential to ensure that their anticancer use does not result in unintended adverse effects.

3.3. Reactive Oxygen Species (ROS) Modulation and Oxidative Stress in Cancer

Reactive oxygen species (ROS) are generated as normal byproducts of cellular metabolism, especially in the mitochondria, but can also be induced by external factors such as radiation and chemical agents [93,94]. These molecules include superoxide anion (O₂•⁻), hydrogen peroxide (H₂O₂), and hydroxyl radical (•OH). While ROS are essential for various cellular functions, including signaling and immune responses, their dysregulation is closely linked to carcinogenesis. Cancer cells typically exhibit elevated ROS levels due to their high metabolic rate and increased energy demands [95]. These reactive molecules can damage essential cellular components such as lipids, proteins, and DNA, leading to genetic mutations that drive carcinogenesis [95]. At the same time, ROS contribute to key oncogenic processes such as proliferation, angiogenesis, invasion, and metastasis [96]. The TME further exacerbates ROS accumulation through factors like hypoxia, chronic inflammation, and metabolic alterations [97,98].

The regulation of oxidative stress in tumor cells involves the activation of a series of antioxidant defense mechanisms, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase [99]. However, in cancer cells, these mechanisms often fail to fully neutralize ROS, creating a state of persistent oxidative stress that promotes tumor survival and adaptation [100]. Additionally, ROS play a crucial role in activating redox-sensitive transcription factors such as NF-κB, AP-1, HIF-1α, and NRF2, which regulate inflammation and oxidative stress responses [101]. This interaction fosters a vicious cycle where oxidative stress induces inflammation, and inflammation further amplifies ROS production, reinforcing tumor progression [102].

Given their dual role in cancer biology, targeting ROS represents a promising therapeutic approach. Strategies include inhibiting ROS-generating enzymes, enhancing antioxidant pathways, or leveraging oxidative stress to sensitize tumor cells to treatment. Conventional therapies like chemotherapy and radiotherapy exploit ROS-induced damage to kill cancer cells, highlighting the importance of oxidative stress modulation in treatment efficacy. In this context, drugs such as phosphodiesterase (PDE) inhibitors, which elevate cyclic adenosine monophosphate (cAMP) levels and promote antioxidant activity, have gained attention as potential adjuvants in cancer therapy. Notably, levosimendan has demonstrated the ability to suppress ROS production, possibly through MAPK signaling inhibition or potassium channel activation, reinforcing its anticancer potential.

4. New Potential Therapeutic Applications of Milrinone and Terbutaline

The potential repositioning of Terbutaline and Milrinone as adjuvant therapies in oncology represents a novel and intriguing avenue for enhancing existing cancer treatment strategies. Although both agents are currently employed in the management of cardiovascular and respiratory conditions, emerging evidence suggests that their unique pharmacodynamic profiles may confer significant advantages in the oncological setting. These benefits stem primarily from their ability to modulate key cellular and microenvironmental pathways that are intimately linked to tumor development, progression, and therapeutic resistance.

Terbutaline, a β2-adrenergic receptor (β2-AR) agonist, exerts systemic and cellular effects that extend well beyond bronchodilation. Its activation of β2-ARs has been shown to influence the tumor microenvironment (TME) by attenuating chronic inflammation and oxidative stress—two hallmarks of cancer that promote genomic instability, angiogenesis, and immune evasion [103,104]. Chronic inflammation within the TME fosters the recruitment of immunosuppressive cells and supports a pro-tumorigenic cytokine milieu. Terbutaline’s anti-inflammatory properties may, therefore, contribute to the reprogramming of this environment, rendering it less conducive to tumor progression.

Furthermore, Terbutaline may exert modulatory effects on tumor vasculature. By influencing angiogenic signaling pathways, it has the potential to promote more normalized and functional blood vessel formation. Such vascular remodeling is essential for improving tumor perfusion, which can enhance the delivery and efficacy of cytotoxic drugs and reduce hypoxia-induced resistance to therapy [69,105]. Improved oxygenation not only facilitates the action of chemotherapy and radiotherapy but may also restore immune cell infiltration and activation, thereby supporting the efficacy of immunotherapeutic approaches.

Milrinone, on the other hand, offers a mechanistically distinct but potentially synergistic approach. As a selective phosphodiesterase-3 (PDE3) inhibitor, Milrinone elevates intracellular levels of cyclic adenosine monophosphate (cAMP), a second messenger with a broad range of effects on cell metabolism, apoptosis, and immune modulation [106,107]. Elevated cAMP levels can inhibit cell proliferation and induce apoptotic signaling cascades in cancer cells, particularly those reliant on aberrant survival pathways such as PI3K/Akt or MAPK. This sensitization to apoptosis may significantly enhance the efficacy of concurrent chemotherapy or targeted agents, especially in tumors that have developed resistance mechanisms.

In addition to its pro-apoptotic properties, Milrinone’s vasodilatory effect can also contribute to a more favorable intratumoral environment. By decreasing vascular resistance and increasing perfusion, it may facilitate more uniform drug delivery and oxygenation within the tumor mass [108]. This is particularly relevant in solid tumors, where irregular vasculature often leads to hypoxic regions that limit therapeutic response. Improved drug penetration and oxygen levels may not only potentiate existing treatments but also reduce the selection pressure for resistant tumor clones, thereby enhancing long-term disease control.

However, despite these promising preclinical insights, the clinical implementation of Terbutaline and Milrinone in oncology remains limited by several critical challenges. One of the most pressing issues is the scarcity of robust in vivo and clinical data. Much of the existing evidence derives from in vitro studies or animal models, which, while informative, may not fully capture the complexity of human tumor biology or treatment dynamics. Well-designed clinical trials are urgently needed to assess not only the efficacy of these agents in cancer patients but also their safety profiles in this uniquely vulnerable population.

Pharmacokinetics represents another potential barrier to effective implementation. Both Terbutaline and Milrinone possess relatively short plasma half-lives, which may necessitate continuous infusion or frequent dosing schedules to maintain therapeutic levels [40,109]. Such requirements can complicate treatment protocols and raise concerns regarding patient compliance and quality of life, particularly in the outpatient setting. Additionally, variability in drug absorption, distribution, and metabolism among cancer patients—many of whom are polypharmacy users—must be carefully considered during clinical development.

Safety and tolerability also warrant thorough examination. Terbutaline is associated with several adrenergic side effects, including tachycardia, muscle tremors, and anxiety. These adverse effects may be exacerbated in patients already experiencing cardiovascular strain or systemic stress due to cancer or concurrent therapies [43,110,111]. Likewise, Milrinone’s vasodilatory action, while potentially beneficial in terms of tumor perfusion, can induce hypotension and arrhythmias, posing risks for patients with pre-existing cardiovascular comorbidities or those receiving cardiotoxic chemotherapeutic agents [112].

Adding to the complexity is the context-dependent nature of the pharmacological effects of both drugs. Their actions may vary significantly depending on tumor type, stage, molecular profile, and microenvironmental conditions. For instance, β2-adrenergic signaling may exert pro-tumorigenic effects in certain settings by promoting epithelial–mesenchymal transition or by enhancing metastatic potential. Similarly, cAMP signaling may have dual roles, potentially supporting tumor survival under specific conditions. These nuanced dynamics necessitate a precision medicine approach to drug repurposing, whereby biomarker-driven stratification and individualized treatment planning are used to maximize benefit and minimize harm.

To fully harness the therapeutic potential of Terbutaline and Milrinone in oncology, future research must focus on several key areas. Mechanistic studies are needed to delineate their precise roles in cancer biology, particularly in human-relevant models. Pharmacodynamic profiling and dose optimization studies can help define regimens that balance efficacy and safety. Importantly, clinical trials should aim to identify patient subgroups most likely to benefit—based on tumor type, receptor expression, or genetic signatures—and evaluate synergistic combinations with standard or emerging therapies. In doing so, it may be possible to reposition these well-characterized drugs as valuable components of integrated cancer treatment strategies, offering new hope in the fight against complex and resistant malignancies.

5. Combination Strategies with Existing Therapies

An important area of future investigation involves the potential for Terbutaline and Milrinone to be integrated into combination regimens with established cancer therapies. Although no studies have directly investigated Terbutaline or Milrinone in combination with chemotherapy, radiotherapy, or immunotherapy in cancer patients, evidence from related pharmacological classes suggests potential avenues for such strategies. β2-AR signaling has been implicated in modulating the tumor microenvironment, immune responses, and therapy resistance [113,114]. Conversely, β2-AR activation has also demonstrated anti-inflammatory effects that might potentially synergize with immunotherapy by enhancing immune cell infiltration under certain conditions [74].

Similarly, phosphodiesterase-3 (PDE3) inhibitors elevate intracellular cAMP, which has been associated with pro-apoptotic effects and could sensitize cancer cells to chemotherapy-induced cell death [115,116,117,118]. For instance, PDE inhibition has been shown to increase cisplatin-induced apoptosis in ovarian cancer cells and to reduce invasiveness in hepatocellular carcinoma cells. Moreover, elevated cAMP levels have also been reported to enhance radiosensitivity in lung cancer models [119].

Despite these promising mechanistic rationales, experimental data on direct combinations of Terbutaline or Milrinone with chemotherapy, radiotherapy, or immunotherapy remain limited. Future studies should explore these combinations in both in vitro and in vivo models to define optimal dosing, sequencing, and patient selection. Such approaches could reduce the required doses of conventional therapies, potentially mitigating toxicity while preserving or enhancing anti-tumor efficacy. Careful evaluation of possible drug–drug interactions and potential synergistic or antagonistic effects will be essential to ensure the safe and effective integration of these agents into combination regimens.

6. Future Perspectives

The exploration of nontraditional therapeutic agents, such as Terbutaline and Milrinone, in the context of oncology represents a burgeoning frontier in the search for novel and more effective cancer treatments. Traditionally used for managing conditions such as asthma and heart failure, these drugs have shown potential to influence key biological pathways that are increasingly recognized as relevant in tumor development, progression, and treatment resistance. As cancer biology becomes better understood, the significance of targeting not only cancer cells but also the tumor microenvironment (TME) has come to the forefront of therapeutic innovation. In this evolving landscape, the roles of β2-adrenergic receptor signaling and phosphodiesterase-3 (PDE3) inhibition are emerging as potentially critical modulatory mechanisms that may complement or enhance existing treatment strategies.

A comprehensive understanding of how Terbutaline and Milrinone interact with cancer-related pathways is essential. Future research should aim to delineate the specific molecular and cellular mechanisms by which these drugs affect key processes such as oxidative stress regulation, inflammatory signaling, angiogenesis, and immune cell infiltration. For instance, the β2-adrenergic receptor, which is the pharmacological target of Terbutaline, is involved in the regulation of immune responses and metabolic pathways that may influence tumor behavior in a highly context-dependent manner. Similarly, the elevation of intracellular cAMP via PDE3 inhibition by Milrinone could impact cancer cell apoptosis, proliferation, and differentiation—processes that are differentially modulated across tumor types and microenvironmental conditions. These complexities underscore the necessity of tumor-specific research to avoid generalizations that could compromise clinical efficacy or safety.

One of the most immediate priorities in advancing this research is the initiation of rigorous preclinical studies using diverse cancer models. These studies should include not only two-dimensional cell cultures but also more complex three-dimensional systems, such as spheroids and organoids, which better replicate tumor architecture and microenvironmental interactions. In vivo models, including patient-derived xenografts (PDXs), can provide crucial insight into how these agents perform under physiological conditions. From these foundational studies, clinical trials can then be designed to systematically assess the therapeutic potential of Terbutaline and Milrinone in human populations. These trials must be carefully stratified by tumor type, genetic and molecular profiles, and prior treatment history to accurately identify which patient populations are most likely to benefit from these therapies.

Another vital area of investigation will be the identification of optimal dosing regimens and schedules that maximize therapeutic effect while minimizing toxicity. Because both Terbutaline and Milrinone have relatively short half-lives, conventional administration methods may not provide sustained therapeutic levels. Future research should therefore explore advanced drug delivery systems, such as nanoparticle carriers, liposomal formulations, or sustained-release injectables, which could improve pharmacokinetic profiles and enhance the localization of these agents within tumor tissue. Additionally, the development of tumor-targeted delivery strategies—perhaps guided by ligands specific to tumor-associated antigens—could further reduce systemic side effects and improve efficacy. In parallel, combination therapy approaches represent a particularly promising direction. It is conceivable that Terbutaline and Milrinone could act synergistically with other treatment modalities, such as chemotherapy, radiotherapy, immune checkpoint inhibitors, or targeted therapies. For example, the anti-inflammatory and anti-hypoxic effects of β2-AR activation might enhance immune cell infiltration and function, potentially augmenting the effects of immunotherapy. Likewise, the vascular remodeling and pro-apoptotic effects of Milrinone could improve drug delivery and sensitize tumors to standard cytotoxic agents. Careful preclinical assessment of drug–drug interactions, as well as evaluation of potential additive or antagonistic effects, will be necessary to rationally design combination regimens that deliver maximum therapeutic benefit.

As precision oncology continues to evolve, the integration of biomarker-driven approaches will be essential in realizing the full potential of these repurposed agents. Identifying molecular signatures, such as β2-AR expression levels, cAMP signaling status, or specific mutations, that predict the response to Terbutaline or Milrinone could guide patient selection and help tailor treatment plans. Advances in high-throughput screening, single-cell sequencing, and transcriptomic profiling will provide powerful tools for such stratification, making it feasible to develop highly personalized therapeutic strategies that align with the underlying biology of each patient’s cancer.

The concept of drug repurposing also offers practical advantages that could accelerate the translational pathway of Terbutaline and Milrinone into clinical oncology. Both agents have well-established safety profiles and pharmacokinetic data from their use in non-cancer indications, which may reduce the regulatory burden and streamline early-phase clinical development. However, repurposing them for oncology will still require careful pharmacovigilance, particularly when used in combination with other agents or in patients with complex comorbidities. Interdisciplinary collaboration—bringing together oncologists, pharmacologists, medicinal chemists, and regulatory experts—will be critical to navigate these challenges and ensure that development pathways are both scientifically rigorous and clinically relevant.

Despite these promising avenues, several challenges must be addressed to safely integrate Terbutaline and Milrinone into oncological practice. Both agents are associated with cardiovascular side effects, including tachycardia, arrhythmias, and hypotension, which could pose significant risks in cancer patients who often have pre-existing comorbidities or impaired physiological reserves. These safety concerns necessitate careful patient selection, close monitoring, and potential dose adjustments to mitigate adverse events. Furthermore, their relatively short half-lives may require continuous infusion or frequent dosing, complicating treatment logistics and potentially increasing toxicity. Innovative strategies, such as modified-release formulations or targeted delivery systems, may help to overcome these limitations. Additionally, combining these agents with other therapies at lower doses could minimize toxicity while preserving efficacy. Addressing these clinical challenges will be crucial to realizing the translational potential of Terbutaline and Milrinone in oncology.

In addition to clinical and pharmacological considerations, the broader implications of this research touch on ethical, economic, and healthcare delivery dimensions. The use of affordable, off-patent drugs such as Terbutaline and Milrinone could democratize access to advanced cancer care, particularly in low-resource settings where high-cost novel agents remain out of reach. Their successful integration into treatment protocols would not only diversify the therapeutic arsenal but could also reduce treatment-related financial toxicity for patients and healthcare systems alike. In conclusion, the journey to repurpose Terbutaline and Milrinone as viable therapeutic agents in oncology is still at an early stage, but the existing body of mechanistic and preclinical evidence provides a compelling rationale for continued investigation. By embracing a multidisciplinary, systems-level approach to research and development, it may be possible to unlock new therapeutic opportunities that address currently unmet clinical needs. These agents, if validated through rigorous clinical science, could ultimately become valuable tools in the era of personalized oncology, enhancing treatment efficacy, improving patient outcomes, and contributing to a more accessible and effective cancer care paradigm.