Volume 44, Issue 1 p. 96-106
REVIEW ARTICLE
Open Access

Anti-tumor and cardiotoxic effects of microtubule polymerization inhibitors: The mechanisms and management strategies

Ryota Tochinai

Corresponding Author

Ryota Tochinai

Department of Veterinary Pathophysiology and Animal Health, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan

Correspondence

Ryota Tochinai, Department of Veterinary Pathophysiology and Animal Health, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.

Email: [email protected]

Search for more papers by this author
Yoshiyasu Nagashima

Yoshiyasu Nagashima

Department of Veterinary Pathophysiology and Animal Health, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan

Search for more papers by this author
Shin-ichi Sekizawa

Shin-ichi Sekizawa

Department of Veterinary Pathophysiology and Animal Health, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan

Search for more papers by this author
Masayoshi Kuwahara

Masayoshi Kuwahara

Department of Veterinary Pathophysiology and Animal Health, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan

Search for more papers by this author
First published: 26 July 2023
[Correction added on 15 August 2023, after first online publication: Funding Information section has been removed.]

Abstract

Microtubule polymerization inhibitors (MPIs) have long been used as anticancer agents because they inhibit mitosis. Microtubules are thought to play an important role in the migration of tumor cells and the formation of tumor blood vessels, and new MPIs are being developed. Many clinical trials of novel MPIs have been conducted in humans, while some clinical studies in dogs have also been reported. More attempts to apply MPIs not only in humans but also in the veterinary field are expected to be made in the future. Meanwhile, MPIs have a risk of cardiotoxicity. In this paper, we review findings on the pharmacological effects and cardiotoxicity of MPIs, as well as the mechanisms of their cardiotoxicity. Cardiotoxicity of MPIs involves not only the direct effects of MPIs on cardiomyocytes but also their effects on vascular function. For example, hypertension induced by impaired vascular function also contributes to the exacerbation of myocardial damage, and blood pressure control may be useful in reducing cardiotoxicity. By combined administration of MPIs and other anticancer agents, MPI efficacy may be enhanced, thereby potentially allowing to keep MPI dosage low. Measurement of myocardial injury markers in blood and echocardiography may be useful for monitoring cardiotoxicity. In particular, two-dimensional speckle tracking may have high sensitivity for the early detection of MPI-induced cardiac dysfunction. The exploration of the potential of new MPIs while understanding their toxicity and how to deal with them will lead to the further development of cancer chemotherapy.

1 INTRODUCTION

Microtubules are a type of cytoskeletal structures in eukaryotic cells that play critical roles in a multitude of cellular processes, including spindle formation, morphogenesis, and intercellular and axonal transport. Microtubule functions are regulated by repeated polymerization and depolymerization. Substances that inhibit polymerization or depolymerization of microtubules are found in various organisms, including plants, and have been utilized as active ingredients of drugs since ancient times. In recent years, new pharmacological effects of microtubule polymerization inhibitors (MPIs) have been discovered, and clinical trials of new compounds, especially as anti-tumor agents, have been conducted. This is particularly the case with humans, but it is also foreseeable that there will be more research and clinical trials aiming for clinical application in the veterinary field (Abma, de Spiegelaere, et al., 2018). Meanwhile, although clinical trials have shown favorable anti-tumor results, it has also become clear that MPIs have cardiotoxicity. Therefore, this review focuses on the pharmacological actions and cardiotoxicity mechanisms of MPIs and proposes some strategies for cardiotoxicity management.

2 PHARMACOLOGICAL EFFECTS OF MPIS

Microtubules, which are vital components of the eukaryotic cytoskeleton, play crucial roles in various cellular processes, such as spindle formation during cell division (Forth & Kapoor, 2017), the maintenance of cell morphology (Vega & Solomon, 1997), and the facilitation of intracellular and axonal transport (Stebbings, 1995; Yogev et al., 2016). Their cylindrical structures are composed of α-tubulin and β-tubulin dimers and have a fibrous architecture with an outer diameter of approximately 25 nm (Morris & Fornier, 2008). The longitudinally aligned structure of tubulin dimers of α-tubulin and β-tubulin is called a protofilament, and microtubules are hollow tubes formed by 13 protofilaments aligned horizontally (Aher & Akhmanova, 2018). The tubulin dimers dynamically maintain the microtubule structure through repeated polymerization and depolymerization (Figure 1).

Details are in the caption following the image
Microtubule structure and roles in tumor growth.

Malignant tumors with high mitotic frequency are strongly affected by the inhibition of spindle fiber formation by MPIs, resulting in the suppression of tumor growth (Penna et al., 2017).

In non-dividing cells, microtubules are important components of the cytoskeleton, involved in extracellular signal uptake and intracellular molecular transport (Stebbings, 1995). Microtubules extend into the leading edge using the centrosome located near the cell nucleus as a scaffold and play an important role in polar cell morphology and directional cell migration. Microtubules also function as the rails for intracellular molecular transport. Motor proteins that move along microtubules regulate gene expression and subcellular localization of proteins necessary for cell migration (Garcin & Straube, 2019). MPIs inhibit tumor cell migration, thus reducing tumor metastasis and invasion (Chanez et al., 2015).

In vascular endothelial cells, microtubules influence cell polarity; thus when microtubule function is disrupted, network formation between vascular endothelial cells is impaired (Schwartz, 2009). Therefore, the inhibition of microtubules in endothelial cells of tumor blood vessels leads to the disruption of tumor vessel function and tumor regression.

Colchicine, combretastatins, vinca alkaloids, and eribulin are some examples of MPIs known to date. These compounds interfere with microtubule polymerization by binding to their respective binding sites present on β-tubulin subunits in microtubules (Morris & Fornier, 2008; Smith et al., 2010; Woods et al., 1995). Each MPI is considered to have its unique set of characteristic pharmacological effects, and in recent years, MPI compounds with multiple microtubule-binding sites have also been found (Natsume et al., 2000). Thus, MPIs exert various pharmacological effects by interfering with the polymerization of tubulin dimers. For example, colchicine has long been used (Talbott, 1953) as a treatment for inflammatory diseases such as gout because it suppresses inflammatory signals and increases anti-inflammatory mediators. Various MPIs have also been applied as anticancer agents because they inhibit cell division by preventing the formation of spindle threads (Bhattacharyya et al., 2008; Islam & Iskander, 2004; Kawano et al., 2016). Moreover, MPIs possess clinically relevant anti-angiogenic and vascular-disrupting properties in solid tumors. Combretastatins, ZD6126, and 2-methoxyestradiol, which are thought to bind to colchicine-binding sites on β-tubulin in microtubules, have been well studied for their vascular disruption effects (Blakey et al., 2002; D'Amato et al., 1994; Salmon & Siemann, 2006). The direct anti-proliferative effects of MPIs on vascular endothelial cells partially account for their anti-vascular actions (Schwartz, 2009).

In addition, microtubules, as key components of the cytoskeleton, play important roles in extracellular signal uptake, intracellular molecular transport, polar cell morphology, and directional cell motility in the non-dividing stage of cells. It has been reported that MPIs inhibit capillary network formation (Bayless & Davis, 2004), and the roles mentioned above are presumed to be involved in changes in vascular endothelial cells. Upon being stimulated to migrate, an endothelial cell undergoes a process of elongation and polarization, resulting in the development of a distinct front and back. This polarization is characterized by the formation of a lamellipodium at the leading edge, along with a trailing cell body (Lauffenburger & Horwitz, 1996). MPIs attenuate this process in endothelial cell morphology, resulting in the disruption of vascular structure maintenance. MPIs also impair focal adhesion formation or lead to misassembled focal adhesions in endothelial cells, respectively (Honoré et al., 2008; Kanthou & Tozer, 2002; Lu et al., 2006).

Microtubules are thought to play an important role in the maintenance of epithelial-mesenchymal transition, that is, maintaining the transformation of epithelial cells with low motility into mesenchymal cells that are actively invasive and metastatic. Epithelial-mesenchymal transition is known to occur in epithelial malignant tumors (Mani et al., 2008). During cell migration, asymmetric microtubule distribution regulates the polarization in the cells (Kaverina & Straube, 2011). Microtubules regulate the leading edge of the cell coordinated with actin dynamics downstream of Ras-related C3 botulinum toxin substrate 1 (Rac1) (Wittmann et al., 2003). Stabilized microtubules between them act as the rails for intracellular molecular transport. Microtubule minus-end targeting proteins (−TIPs) additionally regulate the assembly of microtubule-organizing centers, such as centrosomes and spindle poles, while facilitating microtubule attachment to cellular membrane structures, including the cell cortex, Golgi complex, and the cell nucleus (Akhmanova & Steinmetz, 2019). Together with motor proteins moving on the microtubules, they support the movement of cell adhesion factors to the leading edge and transcription factors into the nucleus. This provides the gene expression necessary for directional cell motility and subcellular protein localization, and MPIs have been reported to inhibit these functions. It has also been reported that eribulin reduces malignancy by inhibiting epithelial-mesenchymal transition and promoting tumor differentiation (Kawano et al., 2016; Oba & Ito, 2018; Yoshida et al., 2014). Administration of eribulin showed anti-tumor effects via inhibition of epithelial-mesenchymal transition in xenograft model mice (Yoshida et al., 2014). It has been also suggested that eribulin-induced remodeling of abnormal tumor vasculature leads to a more functional microenvironment that may reduce the aggressiveness of tumors due to elimination of inner-tumor hypoxia (Funahashi et al., 2014).

These mechanisms are thought to be responsible for the anti-tumor effects of MPIs, and several MPIs have been widely used in veterinary and human medicines (Table 1). The development of new compounds is also being actively pursued, and many clinical trials are underway to utilize novel MPIs such as combretastatin A4 phosphate (fosbretabulin; CA4P), AVE8062 (Ombrabulin), combretastatin 1A phosphate (OXi4503), ZD6126, MPC-6827 (Azixa), NPI-2358 (Plinabulin), and 2-methoxyestradiol (Panzem), as anticancer drugs against solid tumors (Abma, de Spiegelaere, et al., 2018; Blakey et al., 2002; Dark et al., 1997; Eskens et al., 2014; Hwu et al., 2010; Millward et al., 2012; Patterson et al., 2012; Tozer et al., 1999; Tsimberidou et al., 2010).

TABLE 1. Examples of microtubule polymerization inhibitors used in human cancer therapy.
Drug Status Cancer type Reference
Vinblastine Approved by FDA in 1961 Generalized Hodgkin's disease, lymphocytic lymphoma, histiocytic lymphoma, mycosis fungoides, advanced carcinoma of the testis, Kaposi's sarcoma, Letterer–Siwe disease, choriocarcinoma, carcinoma of the breast United States National Library of Medicine (2023b, 2023c, 2023d, 2023e)
Vincristine Approved by FDA in 1963 Acute leukemia, Hodgkin's disease, non-Hodgkin's malignant lymphomas, rhabdomyosarcoma, neuroblastoma, Wilms' tumor
Vinorelbine Approved by FDA in 1994 Locally advanced or metastatic non-small cell lung cancer
Eribulin Approved by FDA in 2016 Metastatic breast cancer, liposarcoma
Combretastatin A4 phosphate (fosbretabulin) Clinical trials Ovarian cancer, neuroendocrine tumors, thyroid cancer, head and neck cancer, fallopian tube carcinoma, primary peritoneal carcinoma, solid tumor, central nervous system tumor United States National Library of Medicine (2023a)
AVE8062 (ombrabulin) Clinical trials Malignant neoplasm, solid tumor, sarcoma, non-small cell lung cancer, ovarian cancer
Combretastatin A1 phosphate (OXi4503) Clinical trials Acute myelogenous leukemia, neoplasm metastasis, solid tumor
ZD6126 Clinical trials Renal cell carcinoma, colorectal cancer
MPC-6827 Clinical trials Glioblastoma, melanoma, brain neoplasm, refractory solod tumor
NPI-2358 (plinabulin) Clinical trials Solid tumor, lymphoma, non-small cell lung cancer, small cell lung cancer, multiple myeloma, bladder carcinoma
2-Methoxyestradiol (Panzem) Clinical trials Multiple myeloma, solid tumor, carcinoid tumor, glioblastoma, ovarian cancer, prostate cancer, renal cell carcinoma

3 CARDIOTOXICITY OF MPIS IN CLINICAL PRACTICE

While MPIs have a variety of attractive pharmacological effects, they are also known to have toxic effects. The toxicity of MPIs include cardiotoxicity, gastrointestinal toxicity, neurotoxicity, skeletal muscle toxicity, hematologic toxicity, and hepatic toxicity (Abma, de Spiegelaere, et al., 2018; Dowlati et al., 2002; Finkelstein et al., 2010; Mampaey et al., 2022; Takashima et al., 2016; Tochinai et al., 2014; Vaughn et al., 2009). In particular, cardiac symptoms have been reported in cases of colchicine misadministration and ingestion of plants containing colchicine and as adverse effects of cancer chemotherapy with vincristine or combretastatins (Calvo-Romero et al., 2001; Dowlati et al., 2002; Mullins et al., 2000). MPIs have a long history of clinical use and are thought to have been used as anti-inflammatory agents as far back as the time of Hippocrates in ancient Greece. Nevertheless, for such usage, MPIs have been administered at relatively low doses with little or no cardiotoxic manifestations. Peripheral neurotoxicity and hematologic toxicity have often been the dose-limiting factors, and not much attention was paid to cardiotoxicity. However, compounds that act on tumor blood vessels have been developed more recently, and in cancer chemotherapy cases in which these compounds are administered at maximum tolerated doses, cardiotoxicity has been reported (Subbiah et al., 2011). It is hoped that MPI cardiotoxicity can be overcome, and there is growing interest in it recently.

The most well-known cardiotoxicity of anticancer drugs other than MPIs is that of anthracycline, an anticancer antibiotic. Anthracycline shows acute cardiotoxicity that occurs during or shortly after administration, subacute cardiotoxicity that occurs 2–3 weeks after administration, and chronic cardiotoxicity that occurs more than 1 year after administration. Dose-dependent cardiomyopathy is seen, especially in chronic cardiotoxicity (Yeh & Bickford, 2009). Possible mechanisms for the development of this cardiomyopathy include oxidative stress, induction of apoptosis, mitochondrial dysfunction, and altered Ca kinetics (Yeh & Bickford, 2009). It is also widely known that trastuzumab, a human epidermal growth factor receptor type 2 (HER 2) inhibitor, induces heart failure. The cardiotoxicity of trastuzumab differs from that of anthracycline and is not dependent on cumulative dose. The mechanism of cardiotoxicity may be related to the fact that HER 2 is involved in cardiac development and the maintenance of myocardial function, but the details are not clear (Minami et al., 2010). Furthermore, it is known that cyclophosphamide, an alkylating agent, induces heart failure during the first few days after administration, and bevacizumab and sunitinib, which are anticancer agents that inhibit angiogenesis, also induce heart failure (Albini et al., 2010; Subbiah et al., 2011). Vascular endothelial cell damage is thought to be involved in these cardiotoxic effects.

On the other hand, previous papers on MPI-induced cardiotoxicity have reported cases in which electrocardiographic changes were observed, or blood troponin I, a marker of myocardial injury, was detected after MPI administration (Table 2) (Abma, de Spiegelaere, et al., 2018; Dowlati et al., 2002; Hwu et al., 2010; LoRusso et al., 2008; Mampaey et al., 2022; Patterson et al., 2012; Tsimberidou et al., 2010). In particular, the cardiotoxic effects of CA4P have been reported to occur within minutes to a day after administration (Cooney et al., 2004; Dowlati et al., 2002) and are known to occur with high frequency (Subbiah et al., 2011). In addition to elevation of myocardial injury marker levels in the blood, electrocardiographic changes such as ST-segment elevation, ST depression, ST-segment prolongation, and QT-interval prolongation were detected. While ischemia caused by abnormalities in the coronary arteries may account for these changes, it has been reported that in some cases, coronary artery constriction was not detected on coronary angiography (Bhakta et al., 2009), suggesting that factors other than coronary artery abnormalities may be responsible for myocardial cell injury.

TABLE 2. Findings in electrocardiography, cardiac histopathology, echocardiography, and molecular biological analysis induced by microtubule polymerization inhibitors.
Drug Species Findings in electrocardiography, cardiac histopathology, echocardiography, and molecular biological analysis Reference
Combretastatin A4 phosphate (fosbretabulin) Human QTc interval prolongation Dowlati et al. (2002)

ST-T wave changes suspecting ischemia

Cardiac troponin elevation

Dog Elevation of cardiac troponin in blood Abma, de Spiegelaere, et al. (2018); Mampaey et al. (2022)
Decrease in 2D speckle-tracking echocardiography parameters
Rat

Ischemic myocardial necrosis

Apoptosis of vascular endothelial cells in heart

Abnormal ST junction,

QT interval prolongation

Decrease in heart rate, ejection fraction, and cardiac output

Elevation of creatine kinase-muscle/brain and fatty acid binding protein 3, lactate dehydrogenase (LDH)-1 in blood

Decrease in cGMP level in myocardium

Tochinai et al. (2016); Tochinai et al. (2018); Nagashima et al. (2023)
Combretastatin A1 phosphate (OXi4503) Human Atrial fibrillation Patterson et al. (2012)
ZD6126 Human Elevation of cardiac troponin in blood LoRusso et al. (2008)
Decrease in left ventricular ejection fraction
MPC-6827 (Azixa) Human Bradycardia Hwu et al. (2010); Tsimberidou et al. (2010)
First-degree atrio-ventricular block
Colchicine Rat

Ischemic myocardial necrosis

Apoptosis of vascular endothelial cells in heart

Prolongation of RR interval, QRS duration, PR interval and QT interval

Tochinai et al. (2013); Tochinai et al. (2014)
Vincristine Rat

Ischemic myocardial necrosis

Apoptosis of vascular endothelial cells in heart

Tochinai et al. (2013)

4 THE EFFECTS OF MPIS ON THE HEART

Microtubules are thought to play many physiological roles in cardiac development, muscle tissue formation, and contraction control (Webster, 2002). For example, microtubules serve as scaffolds for the alignment and polymerization of myotube components. Microtubules are also thought to prevent myofiber contraction by exerting a viscous load within myofibers (Tagawa et al., 1997; Webster & Patrick, 2000).

Administration of colchicine to rats has been reported to attenuate myocardial contraction (Mery et al., 1994). Meanwhile, myocardial injury induced by isoproterenol is mitigated when low doses of vincristine are administered (Panda & Kar, 2015). Isoproterenol-induced myocardial injury is a consequence of work-energy mismatch (Berridge et al., 2016), suggesting that microtubule inhibitors may affect myocardial workload or energy metabolism. It has also been reported that gene expression shifted from lipid metabolism to carbohydrate metabolism in the hearts of rats treated with MPIs (Mikaelian et al., 2010).

In vitro experiments showed that inhibition of microtubule polymerization in rat cardiomyocytes causes changes in the location and membrane potential of mitochondria (Kumazawa et al., 2014; Miragoli et al., 2016). It has also been reported that MPIs induced an increase in the beating rate of cultured cardiomyocytes and enhanced Na+ and Ca2+ influx into the cells (Gómez et al., 2000; Lampidis et al., 1992; Motlagh et al., 2002). As for cell membrane currents, the conclusion remains controversial, as some reports indicate that colchicine does not affect cardiomyocyte contraction and intracellular Ca2+ concentration (Calaghan et al., 2001; Calaghan et al., 2004; Cooper, 2006). The effects of MPIs on human iPS cell-derived cardiomyocytes (hiPS-CMs) have also been analyzed to date. hiPS-CMs express the major ion channels, receptors, transporters, and contractile proteins present in human cardiomyocytes and respond to various bioactive substances in a manner similar to human cardiomyocytes (Babiarz et al., 2012; Guo et al., 2013; Khan et al., 2013; Ma et al., 2011). When impedance, an index of cell morphology and the number of viable hiPS-CMs, as well as the beating rate (Denelavas et al., 2011; Guo et al., 2015; Kustermann et al., 2013; Peters et al., 2015), were analyzed, the results showed that CA4P decreased the beating rate and impedance (Tochinai et al., 2016).

Regarding MPIs-induced histopathological changes in the heart, non-clinical studies in rats have been reported (Table 2) (Nagashima et al., 2023; Tochinai et al., 2013; Tochinai et al., 2014; Tochinai et al., 2016; Tochinai et al., 2018). In addition to the direct effects of MPIs on myocardial cells, effects of MPIs on vessels also affect cardiac function (Figure 2). As mentioned earlier, it is thought that MPI-induced myocardial injury is associated with ischemia. Studies using rats suggest that tissue myocardial hypoxia is induced by administration of colchicine or vincristine (Tochinai et al., 2013). In these animals, apoptosis of vascular endothelial cells has also been observed in cardiac microvessels, suggesting that ischemia is induced when vascular endothelial cells are damaged. It is thought that MPIs are particularly toxic to endothelial cells in cardiac microvessels, compared with those in other blood vessels throughout the body, but details of the mechanism behind this are unknown. CA4P induces more pronounced morphological changes in proliferating human umbilical vein endothelial cells (HUVECs) than in confluent HUVECs (Galbraith et al., 2001). Cardiac vascular endothelial cells show increased proliferative activity than endothelial cells in other tissues (Fernandez et al., 2001; Heron & Rakusan, 1995). These reports suggest that high cell proliferative activity may be one reason why cardiac vascular endothelial cells are more sensitive to MPIs than other tissues.

Details are in the caption following the image
Assumed cardiotoxic mechanisms resulting from vascular endothelial cell damage and the management strategies.

MPIs often induce hypertension (Subbiah et al., 2011). It is speculated that the increase in afterload associated with elevated blood pressure may contribute to the development of myocardial injuries. Although the molecular mechanism of this type of hypertension remains unclear, colchicine has been reported to decrease cGMP levels in isolated rat smooth muscle cells treated with interleukin-1α. Our analysis showed that cGMP concentration tended to decrease in whole rat hearts treated with CA4P (Nagashima et al., 2023), suggesting that cGMP-mediated vasodilatory signaling is suppressed in heart vessels. There are reports that show that osmotic pressure and force loading change the length of microtubules and that tension loading facilitates microtubule formation, suggesting a link to mechanosensing (Desai & Mitchison, 1997; Kaverina et al., 2002; Nasrin et al., 2021). These results suggest that MPIs may alter blood pressure by inhibiting mechanosensing in blood vessels. It has been shown that MPIs inhibit blood-flow-dependent vasodilation in coronary arteries of microtubule-ectomized hearts or in microvessels of skeletal muscles (Liu et al., 2008; Sun et al., 2001) and that MPIs enhance vasoconstriction induced by cold exposure in the aorta (Chitaley & Webb, 2002).

Microtubules are important for axonal transport in neurons, and MPIs have peripheral neurotoxicity. Autonomic toxicity was well recognized from early on with vincristine (Madsen et al., 2019; Tay et al., 2017; Triarico et al., 2021), which has long been used as an anticancer drug. Autonomic regulation of cardiac function is reflected as heart rate variability (Kuwahara, Suzuki, et al., 1994; Kuwahara, Yayou, et al., 1994; Song et al., 2006; Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, 1996). Experimental evidence suggests that administration of colchicine to rats alters heart rate variability, reflecting the changes in autonomic function (Tochinai et al., 2014). While MPIs increase blood pressure, it is possible that myocardial injury is exacerbated by abnormalities in responses to blood pressure changes mediated by the autonomic nervous system, such as the baroreceptor reflex.

5 DETECTION OF CARDIOTOXICITY OF MPIS AND POSSIBLE COUNTERMEASURES

As described above, MPIs have various effects that can lead to myocardial injury. Therefore, in clinical application, it is necessary to monitor signs of cardiotoxicity from various perspectives to detect abnormalities early and take countermeasures.

The administration of CA4P has been shown to induce adverse cardiovascular effects, such as a transient elevation of cardiac troponin I (cTnI) levels, transient systemic arterial hypertension, and electrocardiographic alterations, which include sinus tachycardia, sinus bradycardia, and ventricular arrhythmia. Furthermore, cases of myocardial ischemia and myocardial stunning have been reported following CA4P administration in humans (Bhakta et al., 2009; Dowlati et al., 2002; Subbiah et al., 2011). The assessment of cardiotoxicity following CA4P administration in dogs and rats has been performed through the utilization of traditional echocardiographic parameters (Abma, Smets, et al., 2018; Tochinai et al., 2018): fractional shortening and ventricular diameters from M-mode image analysis; and ventricular volumes and ejection fraction (EF) measured by applying the Simpson method of discs on two-dimensional images. Furthermore, the assessment of left ventricular function has been extended to pulsed-wave tissue Doppler imaging of the free wall. In rats with severe myocardial injury induced by high doses of CA4P, a decrease in EF was detected. However, in dogs, significant differences between pre- and post-CA4P administration were not detected (Abma, de Spiegelaere, et al., 2018; Abma, Smets, et al., 2018). Generally, these conventional echocardiographic measurements do not have enough sensitivity to detect early subclinical ventricular dysfunction (Hamabe et al., 2021; Oikonomou et al., 2019). Recently, it was suggested that two-dimensional speckle tracking may be useful for the early detection of MPI-induced cardiac dysfunction in dogs (Mampaey et al., 2022).

Studies in rats have reported that administration of antihypertensive drugs is useful in reducing MPIs-induced cardiac injury (Table 3) (Figure 2). Studies with rats have shown that the hypertensive effect of CA4P was attenuated by both nitroglycerin and diltiazem (Ke et al., 2009; Ke et al., 2015). We recently reported that pretreatment with tadalafil, a phosphodiesterase 5 inhibitor, inhibited cardiotoxicity induced by CA4P (Nagashima et al., 2023). Furthermore, hypertension induced by ZD6126 was blocked by nifedipine (Gould et al., 2007).

TABLE 3. Antihypertensive agents useful in the prevention of MPIs-induced cardiac injury.
Drug Antihypertensive drug Mechanism Reference
Combretastatin A4 phosphate (fosbretabulin) Nitroglycerin NO donor Ke et al. (2009)
Diltiazem Ca2+ channel inhibitor Ke et al. (2009); Ke et al. (2015)
Tadalafil Phosphodiesterase 5 inhibitor Nagashima et al. (2023)
ZD6126 Nifedipine Ca2+ channel inhibitor Gould et al. (2007)
  • Abbreviation: MPIs, microtubule polymerization inhibitors.

To secure a margin between the effective dose and the cardiotoxic dose, interventions that increase the drug efficacy of MPIs may also be useful. Bromodomain-containing protein 4 (BRD4) is known for its ability to modulate gene expression via its role in recruiting active positive transcription elongation factor b (P-TEFb) to chromatin, which is of critical importance in the context of cancer development (Chiang, 2009). When the process of mitotic spindle formation is interrupted by the application of MPIs, BRD4 is released from the chromosomes in a transient manner. However, BRD4 is subsequently transported back to the chromosomes once the drug administration ceases, thereby allowing the resumption of mitosis (Nishiyama et al., 2006). Hence, BRD4 plays a significant role in reinitiating mitosis following cell cycle arrest caused by MPIs. We reported that co-administration of JQ1 with CA4P enhances the anti-tumor effect of CA4P (Orihara et al., 2023). In addition to their role in anti-tumor effect, BRD4 inhibitors have been shown to have therapeutic potential in mitigating myocardial inflammation and fibrosis (Duan et al., 2017; Sun et al., 2015). Therefore, MPI-induced myocardial injury may be reduced by BRD4 inhibition. Our study using CA4P-induced cardiac injury model rats indicated that JQ1, a BRD4 inhibitor, has the potential to alleviate CA4P-induced myocardial injury (Orihara et al., 2023). These findings suggest that BRD4 inhibitors may be useful for enhancing the therapeutic effects of MPIs while reducing their cardiotoxicity (Figure 2).

6 CONCLUSIONS

MPIs not only exhibit direct growth inhibitory effects on tumor cells but also exert combine anticancer effects by inhibiting tumor vascular disruption and epithelial-mesenchymal transition. Many new MPI compounds have been discovered, and clinical trials are being performed. Although only a limited number of clinical trials have been conducted in veterinary medicine for new MPIs, compounds going through human clinical trials are considered to have been well tolerated by dogs and/or monkeys during toxicity studies. This suggests that many of the new compounds that have reached human clinical trials may have potential for safe use in veterinary medicine. As more novel compounds are discovered and as research continues to improve drug delivery or combination therapy with multiple drugs, the potential of MPIs may expand even further. Meanwhile, the importance of managing the cardiotoxicity of anticancer drugs is becoming increasingly widely recognized, and MPIs must also be carefully addressed. MPIs exhibit similar clinical manifestations to those of general myocardial ischemia. However, the pathology of MPI cardiotoxicity is not a simple reduction in cardiac nutrient blood flow but rather a complex combination of direct effects to myocardial cells and changes in autonomic-nervous-system-mediated mechanisms that maintain cardiovascular function. It is necessary to understand the mechanisms by which changes occur in the heart and strive for early detection, prevention, and treatment of cardiotoxicity.

ACKNOWLEDGMENTS

Scientific English proofing was supported by Yukiko Kuwata.

    CONFLICT OF INTEREST STATEMENT

    The authors declare that they have no conflict of interest.

    DATA AVAILABILITY STATEMENT

    The data that support the findings of this study are available from the corresponding author upon reasonable request.