The physicochemical characteristics of CA have been extensively studied (19–22). Peters and Caldwell (19) demonstrated that CA naturally exists in the form of trans-CA. CA (C₉H₈O; Fig. 1) is also known as cinnamon aldehyde, 3-phenyl-2-propenalin and trans-CA (20). CA is a yellow oily liquid with low solubility in water, and soluble in ethanol and chloroform (21). Due to its aldehyde structure, when CA comes into contact with air and light, it gradually oxidizes into cinnamic acid (21). Zinn et al (22) demonstrated that there may be four possible stereoisomers of CA.

To comprehend the mechanism of action of the drug and provide guidance for clinical practice, it is crucial to investigate pharmacokinetic parameters. Furthermore, ensuring the safety and effectiveness of the drug in clinical settings is imperative.

Bickers et al (23) revealed that CA is an active aldehyde that can be converted to cinnamyl alcohol. As a result, CA is unstable in the body and has the potential to be metabolized to cinnamic acid and converted to cinnamyl alcohol (23). In addition, Vasconcelos et al (24) demonstrated that, in vivo, it is possible that trans-CA decomposes to cinnamic acid by enzyme catalysis before it can elicit its antibacterial activity, and thus, could be considered unstable in blood. In a study by Zhao et al (25), the pharmacokinetics of CA in rats were assessed using a highly sensitive gas chromatography-mass spectrometry technique. The rats in the experiment received CA orally at a dose of 500 mg/kg and intravenously at a dose of 20 mg/kg. The results indicated that the bioavailability of intravenous administration of CA was superior to that of oral administration (25). In another study, the researchers utilized gas chromatography-mass spectrometry to measure the concentration of CA and its metabolite cinnamyl alcohol in rat tissues at the same time and investigated their distribution patterns. According to the study findings, the spleen exhibited the highest concentrations of both CA and cinnamyl alcohol among the major organs of rats, including the heart, liver, spleen, lungs, kidneys and brain. Additionally, there was no detectable long-term buildup of CA in the rat tissues (26).

To improve the stability and bioavailability of CA, researchers have designed a series of new dosage forms (27–32). For example, Zhao et al (27) developed a novel intravenous submicron CA (SME-CA) emulsion that not only successfully improved the solubility and absorption of CA, but also had lower toxicity and higher antitumor effects. Furthermore, SME-CA improved the tissue distribution in the kidney, liver, spleen and brain, and a 27% higher concentration was found in the brain compared with CA (27).

The advantages of convenience and good adherence make oral administration the preferred route for drug delivery (28). Researchers have mainly considered oral administration when studying CA dosage forms. For example, Wu et al (29) made CA into CA solid lipid nanoparticles, which increased the oral bioavailability of CA by >1.69 times. Furthermore, CA-solid lipid nanoparticles had a higher absorption rate under intestinal pH conditions compared with CA (29). Liu et al (30) developed a self-emulsifying drug delivery system (SEDDS) containing CA to overcome the shortcomings of poor solubility and limited absorption of CA. Compared with the free CA group, the CA-SEDDS group exhibited higher accumulation of CA and cinnamic acid in various tissues, especially in the kidney (30). In addition, Cai et al (31) investigated the ability of SEDDS to deliver lipophilic aldehyde CA-SEDDS in rat mucus, mucin solution, and Caco-2 and Caco-2/HT29 co-culture monolayers. The results of the study showed that CA-SEDDS exhibited excellent mucus permeability in mucus and mucin solutions, which was 5.1- and 2.8-fold higher, respectively, than that in the free CA group. CA-SEDDS penetration increased by 2.5-fold compared with that of free CA when using the mucus-secreting co-culture cell model as a barrier. The relative oral bioavailability of CA-SEDDS was 242% compared with CA (31).

Furthermore, Dong et al (32) examined the oral bioavailability of CA from the perspective of a microemulsion-mucus system. CA microemulsion (CA-ME) was prepared, and the results demonstrated that CA-ME had the highest absorption in the ileum compared with CA solution. Pharmacokinetic experiments indicated that the relative bioavailability of CA-ME was 2.5 times higher than that of CA solution (32).

Overall, these studies (29–32) have demonstrated the potential of various drug delivery systems, such as solid lipid nanoparticles, SEDDSs and microemulsions, to enhance the oral bioavailability and absorption of cinnamic acid.

In 2022 globally, there were nearly 2.5 million new cases and over 1.8 million deaths from lung cancer (33). By 2022, lung cancer had become a leading cause of both incidence and mortality (33). The global burden of lung cancer is increasing. By 2035, China will become the country with the highest number of new cases (36). Therefore, in addition to controlling the incidence factors of lung cancer, finding novel chemotherapy drugs is also the key to solving the problem.

Using a 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induced rasH2 mouse lung cancer model, it was demonstrated that CA reduced the combined incidence of lung adenocarcinoma and cancer. Specifically, in male rasH2 mice, the incidence decreased from 86 to 31%. The underlying mechanism may be to reduce the proliferation of tumor-initiating cells (37).

A previous study (38) provided evidence that suggested a combination of berberine and CA could reduce the susceptibility of mice to ammonia-induced lung cancer. The combined treatment activated AMP-activated protein kinase (AMPK), and inhibited the proliferation and growth of tumor cells in mice with methane-induced lung cancer. Additionally, the combined treatment effectively targeted the mTOR signaling pathway, which is a critical signaling pathway for cell proliferation and survival, thereby blocking tumor cell proliferation and survival (38). Furthermore, it has been observed that the combination of berberine and CA induced apoptosis of A549 cells, and inhibited cell proliferation, autophagy and wound healing, while upregulating AMPK and downregulating aquaporin 1 in vitro (38). A549 and NCI-H460 lung cancer cell lines were found to respond well to CA treatment. Additionally, CA treatment led to the induction of apoptosis in these cells, with the degree of induction being dependent on the concentration of CA used. Notably, the researchers observed a substantial increase in the expression levels of circular RNA hsa_circ_0043256 following CA treatment (39). This upregulation was found to serve a crucial role in triggering apoptosis in the cells (39). Furthermore, CA has the potential to disrupt abnormal cell growth, promote apoptosis and effectively hinder the advancement of lung cancer cells by interfering with the Wnt/β-catenin signaling pathway (40). Another study explored the effects of combining CA with hyperthermia on non-small cell lung cancer cells, specifically A549 cells. The research results indicate that the combination therapy of CA and hyperthermia could inhibit the growth and proliferation of A549 cells, and induce cell apoptosis by regulating the activity of reactive oxygen species (ROS) and the mitogen-activated protein kinase family. Especially when combined with hyperthermia therapy at 42°C and 43°C, CA could inhibit cell proliferation (41). Furthermore, CA induces apoptosis in non-small cell lung cancer cells by regulating Janus kinase/STAT, the NF-κB signaling pathway and RNA degradation (42).

Overall, these findings (37–42) suggest that CA possesses chemo-preventive properties and may have potential therapeutic benefits in lung cancer treatment. However, these studies were conducted in vitro or on animal models, and further clinical trials are required to validate the effectiveness and safety of these treatments in humans.

In 2022, there were over 1.9 million new cases of colorectal cancer (including anal cancer) and 904,000 associated deaths globally (33). Surgery for patients with CRC is considered to be the most effective approach, but postoperative complications can affect the quality of life to a certain extent (43). In addition, Sargent et al (44) demonstrated that patients with colon cancer still have relatively low 5-year survival rates in chemotherapy, with high recurrence rates. The 1–5 year recurrence rates are 12, 14, 8, 5 and 3%, respectively. The median time from recurrence to death is 12 months (44). Therefore, in addition to controlling the factors of direct bowel cancer incidence, research and development of novel chemotherapy drugs is also the key to solving this problem.

CB403 (Fig. 1) is a cinnamaldehyde derivative that inhibits the activity of cyclin-dependent kinases (CDKs), particularly CDK1, CDK2 and CDK4, thereby halting cell cycle progression. Simultaneously, CB403 also suppresses the expression of cyclin D1, exerting antitumor effects (45). In addition, Lee et al (46) demonstrated that 2-hydroxycinnamaldehyde (HCA; Fig. 1) inhibits the growth of SW620 colon cancer cells by reducing the expression of c-Jun and c-Fos, inhibiting the DNA binding activity of activator protein 1, and inducing cell apoptosis (46). The CA derivative CB-PIC (Fig. 1) has marked cytotoxicity and induces apoptosis in SW620 human colon cancer cells by activating the AMPKα and ERK signaling pathways (47). Furthermore, CB-PIC is able to overcome drug resistance in chemotherapy cancer cells by inhibiting multidrug resistance protein 1 and its upstream STAT3 and AKT signaling pathways (48). At the same time, combining CA with chemotherapy drugs has shown promise in enhancing the sensitivity of cancer cells to these drugs. For instance, when CA is combined with 5-fluorouracil (5-FU), CA increases the sensitivity of CRC cells to 5-FU by reducing the expression of thymidylate synthase, ERCC1, DNA topoisomerase 1 and BRCA1, increasing the percentage of apoptotic cells to 92.7% (49). This finding suggests that utilizing CA as an adjunct therapy with 5-FU may lead to improved treatment outcomes for patients with CRC.

Research has indicated that CA exerts its antitumor effects by activating nuclear factor erythroid 2-related factor (Nrf2) (50). A study has found that inhibition of the PI3K/AKT signaling pathway can inhibit tumor cell proliferation and promote apoptosis (51). For example, researchers have found that CA can induce apoptosis in colon cancer cells by inhibiting the PI3K/Akt signaling pathway. Additionally, CA upregulates the expression of E-cadherin while downregulating the expression of matrix metalloproteinase-2 (MMP2) and MMP9 (52). Furthermore, Zhang et al (53) demonstrated that CA induced cell apoptosis by inhibiting the PI3K/Akt signaling pathway. In addition, the study revealed a decrease in Ki-67 expression in the CA group, along with the accumulation of numerous apoptotic cells (53). Nguyen and Kim (54) reported that HCA, a derivative of CA, induced apoptosis in colon cancer cells via heat shock transcription factor 1-mediated BAG cochaperone 3 expression. An inhibitory effect of CA on the hypoxia-activated Wnt/β-catenin pathway has been observed, leading to an augmented sensitivity of CRC cells to oxaliplatin, and enhancing the apoptosis of cancer cells (55). The presence of Escherichia coli has been linked to the advancement of colon cancer. A study conducted by Kosari et al (56) revealed that CA exhibited regulatory effects on the expression of the clbB gene, thereby mitigating the biofilm-forming capability of E. coli. CA (75 µM) treatment could induce apoptosis, necrosis and cell cycle slowing in Caco-2 and SW-620 cells after 72 h of treatment (57). Nile et al (13) revealed that, after cinnamaldehyde-rich cinnamon extract treatment, the number of HCT116 and HT-29 cells in the G₁ phase was decreased, the number of cells in the sub-G₁ phase was increased, and the number of cells in the G₂ phase was stagnant compared with the number of untreated cells. In addition, CA was also able to induce apoptosis in cancer cells by increasing intracellular ROS levels (13).

These findings suggest the potential of CA and its derivatives to inhibit colon cancer growth and promote apoptosis of colon cancer cells.

In 2022, there were ~2.3 million new cases of breast cancer in women globally, with 666,000 associated deaths (33).

Jeong et al (45) demonstrated that CB403, a derivative of CA, arrested breast cancer cells in mitosis by increasing the expression levels of cyclin B1. In addition, CB403 did not affect mouse body weight, while inhibiting tumor growth (45). A research team has synthesized biocompatible CA functionalized magnetic nanoparticles (CPGF NPs), which inhibit the proliferation of breast cancer cells by inducing apoptosis. The IC₅₀ of CPGF NPs was found to be 0.363 and 0.368 µM in MDA-MB-231 and MCF7 cells, respectively, while the IC₅₀ of free CA for MDA-MB-231 and MCF7 cells was 192.3-fold and 773.6-fold higher than that of CPGF NPs. This indicated that the CPGF NPs formulation of CA was substantially more effective in inhibiting the growth of breast cancer cells compared with free CA alone (58). In a study by Rad et al (59), it was demonstrated that cinnamon extract induced apoptosis in MCF7 and MDA-MB-231 cell lines by modulating antioxidant enzyme activity and activating the caspase pathway. Compared with healthy individuals, patients with breast cancer exhibit visibly elevated plasma visfatin concentrations, and lower survival rates are observed in patients with increased visfatin gene expression levels (60). However, the promotional effects of visfatin on breast cancer can be curtailed by the inhibitory actions of CA (60). By conducting experiments on breast cancer cells, researchers have demonstrated that CA stimulated the apoptosis of cancer cells by inhibiting their proliferation, invasion and migration (61). Through in vitro experiments, researchers revealed that cinnamon bark extract could inhibit the proliferation of breast cancer cells and induce apoptosis (62). Researchers have designed a reasonable co-loading drug formulation, using simple but practical graphene oxide to encapsulate mesoporous silica nanoparticles, modify hyaluronic acid (HA), and realize the co-delivery of CA and doxorubicin (DOX) to enhance their combined therapeutic effect on tumor cells and reduce their application defects (63). The combined use of CA and DOX exhibited higher cytotoxicity against MCF7 human breast cancer cells, which was related to CA-induced activation of the intrinsic apoptotic pathway in MCF7 cells (63). Through cell cycle analysis, it was found that the combined treatment of measles virus with baicalein or CA can induce apoptosis in breast cancer cells, thereby further enhancing therapeutic efficacy (64). Compared with monotherapy, combination therapy has a stronger inhibitory effect on breast cancer cells (63). Schuster et al (65) revealed that CA in combination with chlorogenic acid could disrupt the mitochondrial integrity of breast cancer cells, thereby promoting breast cancer cell death. At the same time, it did not affect the growth of normal breast epithelial cells (65). In one study, docetaxel (DTX)/arginine-glycine-aspartic nanoparticles were prepared by nanoprecipitation/self-assembly using CA-Oxi-αCD material as a carrier (66). Through the endogenous ROS and acidic environmental stimulation of nanoparticles, the acetal bond between CA and αCD in the nanoparticles is broken to achieve the efficient release of the drug DTX. The selective and complete release of the drug is realized, and the accumulation and therapeutic effect of the drug in the tumor site are improved (66).

Research indicates that CA holds promise for the treatment of breast cancer. It has the potential to impede the growth and survival of breast cancer cells, and induce apoptosis through various mechanisms. Additional research and clinical trials are needed to establish the exact role and effectiveness of CA in breast cancer treatment and advance its development as a potential therapeutic option.

In 2022, liver cancer claimed the lives of >750,000 individuals worldwide, ranking it as the third highest cause of cancer-related death (33). Natural compounds have fewer side effects and lower toxicity than traditional chemotherapy drugs and are expected to be a potential treatment option for liver cancer (67).

CA promotes the apoptosis of cancer cells. CA induces cell apoptosis by upregulating Bax expression, and downregulating Bcl-2 and X-linked inhibitor of apoptosis (XIAP) expression (68). However, when CA is combined with vitamin E, the promoting effect of CA on the release of apoptotic factors in the mitochondria of hepatocellular carcinoma cells can be inhibited by vitamin E, thereby inhibiting apoptosis (68). A study has indicated that 2′-benzoyloxycinnamaldehyde and HCA, derivatives of CA, inhibit the activity of farnesyl transferase, thereby delaying the onset of liver cancer (69). There is evidence to suggest that CA activated the ERK1/2, Akt and JNK signaling pathways, which in turn led to Nrf2 nuclear translocation, which ultimately increased the expression of phase II enzymes, making them exert effective chemoprevention effects (70). CA induces apoptosis in HepG2 cells by downregulating the expression levels of Bcl-XL, and upregulating the expression levels of CD95 (apolipoprotein A-I), p53 and Bax proteins (71). Researchers have identified that CA instigated apoptosis in human hepatocellular carcinoma cells by triggering the mitochondrial death pathway. Following CA treatment, there was a decrease in the protein levels of anti-apoptotic factors XIAP and Bcl-2, while the protein levels of the pro-apoptotic factor Bax were elevated (72). 2-Methoxycinnamaldehyde inhibits the activity of DNA topoisomerases I and II, thereby inhibiting the proliferation of Hep 3B cells. In addition, it can also induce lysosomal vacuolization, increase the volume of acidic organelles and promote apoptosis of cancer cells (73). A study has shown that cinnamon oil could reduce the incidence of hepatocellular carcinoma, and reduce liver damage and tumor growth (74). A derivative of CA, known as CB-PIC, can hinder the phosphorylation of STAT3 and diminish the expression of genes associated with STAT3. This process subsequently induces apoptosis in hepatocellular carcinoma cells (75).

In summary, CA and its derivatives may have potential anti-proliferative and apoptosis-inducing effects on hepatocellular carcinoma cells. However, further research is required to fully understand the mechanisms involved and to determine the therapeutic potential of these compounds in the treatment of hepatocellular carcinoma.

In 2022, there were ~1.4 million new cases of prostate cancer globally, with ~375,000 associated deaths (33).

CA prompts apoptosis in cancer-associated fibroblasts (CAFs) by reducing the mitochondrial membrane potential, while simultaneously increasing the levels of endogenous ROS within CAFs and activating caspase-9 and caspase-3 (76). Mei et al (77) also studied prostate CAFs and found that CA acted on CAFs via a Toll-like receptor 4-dependent signaling pathway and regulated their function so that they no longer inhibit the proliferation of T cells, thus CA plays a certain role in the treatment of tumors. The proteasome is an anticancer target, and proteasome inhibition can promote apoptosis and inhibit tumor growth (78,79). Gopalakrishnan and Ismail (80) found that cinnamon compounds can inhibit the activity of the proteasome, leading to the accumulation of p27 protein, thereby inhibiting the proliferation of prostate cancer cells. Meanwhile, cinnamon compounds also lead to downregulation of vascular endothelial growth factor A (VEGFA) and VEGF receptor, thereby inhibiting the angiogenic capability of tumor cells. Gopalakrishnan et al (81) revealed that cinnamon and its active compounds enhanced the activity of apoptotic markers caspase-8 and caspase-3, leading to the promotion of cancer cell death. This provides a scientific basis for cinnamon as a potential chemoprevention agent for prostate cancer (81).

Current research on using CA for prostate cancer treatment is still limited and further experiments and clinical trials are required to ascertain its specific role and effectiveness. However, the initial results present an encouraging outlook for CA as a prospective therapeutic approach and provide valuable guidance for further investigations related to prostate cancer treatment.

As early as 1983, Moon and Pack (82) observed the cytotoxic effect of CA on L1210 mouse leukemia cells and found that the aldehyde group of the CA molecule directly reacted with amino acids containing thiol groups in the cell, thereby blocking the utilization of amino acids contained in the thiol group in the cell and blocking protein synthesis, resulting in the inhibition of L1210 cell growth (82). In a previous study, researchers found that CA was an effective inducer of cell apoptosis, inducing white blood cell apoptosis through ROS-mediated mitochondrial permeability transition and cytochrome c release, as well as activating cascading reactions of cysteine protease-9 and cysteine protease-3 (83). In addition, CA can also induce apoptosis in leukemia K562 cells by reducing the mitochondrial transmembrane potential via mitochondrial-mediated pathways (84). Furthermore, CA can also inhibit cell proliferation by affecting the cell cycle. Water extract of cinnamon activates p38 MAPK kinase, reduces the expression of cyclin B1 protein and induces G₂/M blockade, and thus, affects the proliferation of cell lines (85). CA exerts its anti-leukemic effect by downregulating the transcription levels of the BCR-ABL gene and reducing the expression of the C-MYC protein (86). There has also been a study indicating that HCA interferes with the growth and transformation process of leukemia cells by inhibiting the activity of Pim-1, thus having an anti-leukemia effect (87). To summarize, while CA shows potential for leukemia treatment, more extensive research is still needed. These findings provide a direction for future research regarding leukemia treatments.

CA exhibits antitumor efficacy against various types of tumors, such as non-small cell lung cancer (41), colon cancer (45), breast cancer (58), liver cancer (73), prostate cancer (78) and leukemia (84). Extensive research has confirmed that the antitumor effects of CA are primarily achieved through the following mechanisms: Inhibiting cell growth and proliferation (37), arresting the cell cycle (45), inducing apoptosis (46), and inhibiting cell migration and invasion (63). A summary of the major cellular signaling pathways involved in the anticancer activity of CA is shown in Fig. 2. Table I shows the antitumor effects of cinnamaldehyde in different types of cancer.