Ferulic Acid Anticancer Activity

[Nadal Braymiller]

Canceris a significant disease that poses a major threat to human health. The main therapeutic methods for cancer include traditional surgery, radiotherapy, chemotherapy, and new therapeutic methods such as targeted therapy and immunotherapy, which have been developed rapidly in recent years. Recently, the tumor antitumor effects of the active ingredients of natural plants have attracted extensive attention. Ferulic acid (FA), (3-methoxy-4-hydroxyl cinnamic), with the molecular formula is C10H10O4, is a phenolic organic compound found in ferulic, angelica, jujube kernel, and other Chinese medicinal plants but is also, abundant in rice bran, wheat bran, and other food raw materials. FA has anti-inflammatory, analgesic, anti-radiation, and immune-enhancing effects and also shows anticancer activity, as it can inhibit the occurrence and development of various malignant tumors, such as liver cancer, lung cancer, colon cancer, and breast cancer. FA can cause mitochondrial apoptosis by inducing the generation of intracellular reactive oxygen species (ROS). FA can also interfere with the cell cycle of cancer cells, arrest most cancer cells in G0/G1 phase, and exert an antitumor effect by inducing autophagy; inhibiting cell migration, invasion, and angiogenesis; and synergistically improving the efficacy of chemotherapy drugs and reducing adverse reactions. FA acts on a series of intracellular and extracellular targets and is involved in the regulation of tumor cell signaling pathways, including the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT), B-cell lymphoma-2 (Bcl-2), and tumor protein 53 (P53) pathways and other signaling pathways. In addition, FA derivatives and nanoliposomes, as platforms for drug delivery, have an important regulatory effect on tumor resistance. This paper reviews the effects and mechanisms of antitumor therapies to provide new theoretical support and insight for clinical antitumor therapy.

Malignant tumors are a multifactor and multistep disease, the incidence of which has increased in recent years [1], but the pathogenesis has not been fully elucidated, so there is no effective aetiological treatment. In 2023, 1,958,310 new cancer cases and 609,820 cancer deaths are projected to occur in the United States [2]. Globally, there will be an estimated 28.4 million new cancer cases by 2040, a 47 percent increase over the number of new cases in 2020 [3]. This trend reflects the growing burden that cancer imposes on global health systems and highlights the need for continued efforts to prevent, detect, and treat this disease.

Current cancer treatments include surgical intervention, radiation, and chemotherapy drugs, which often kill healthy cells and cause a host of adverse reactions in patients. With the continuous development of medicine, new therapies such as induction chemotherapy and targeted therapy have been applied to cancer treatment. Compared with traditional chemoradiotherapy, the survival time of patients has been significantly extended with these new therapies, but the adverse reactions and quality of life have not been fundamentally improved [4, 5]. Therefore, the continuous exploration of safe and efficient antitumor treatments is still the main research direction of contemporary oncology. Natural plant components play a significant role in the prevention and treatment of cancer, have significant efficacy in improving the clinical symptoms, quality of life, and prognosis of cancer patients, and have gradually become an important means of cancer prevention and treatment.

Ferulic acid (FA), a phenolic substance widely found in plant cell walls [6,7,8], is an important active component of many traditional Chinese medicines. It has stable physical and chemical properties, outstanding pharmacological activity, and few toxic and side effects on the human body. Its pharmacological activities mainly include antioxidant [9,10,11], anti-inflammatory [12, 13], anti-diabetic [14, 15], blood pressure-lowering [16], hepatoprotective [17, 18], and immunoregulatory [19, 20] activities. With the deepening of pharmacological research on FA, it has shown significant antitumor biological activity [21,22,23,24] and is expected to become a potential drug for the treatment of malignant tumors. In this paper, progress related to the antitumor mechanism of FA was reviewed to provide new ideas for solving the current problems of poor efficacy, high toxicity, and drug resistance of traditional antitumor drugs.

Tumor cells can grow without limit and resist programmed death caused by genes. This malignant behavior of tumors not only increases the difficulty of treatment but is also an important cause of cancer-related death. Apoptosis is the most important form of programmed cell death [25]. FA has a significant effect on inducing apoptosis.

The expression of p53, a key tumor suppressor gene [26], is altered in most cancers. The loss of p53 function is often a prerequisite for the development of cancer [27]. Niu et al. [28] showed that FA could induce the apoptosis of gastric cancer SDC-7901 cells, and the mechanism involved FA-mediated upregulation of the mRNA and protein expression of p53. Umut et al. [29] observed that FA could increase the expression level of p53 in MIA PaCa-2 pancreatic cancer cells while reducing the expression levels of cyclin D1 and cyclin-dependent kinase (CDK) 4/6. In addition, FA was found to reduce colony formation and inhibit cell invasion and migration. The results suggested that FA could promote the apoptosis of MIA PaCa-2 cells by increasing the expression of p53, thus showing an antitumor effect. Folate-mediated metabolism is crucial to the stability and function of the genome and affects the occurrence and development of tumors [30]. Kumar et al. [31] evaluated the targeted efficacy of chitosan-coated FA-loaded solid lipid nanoparticles and folate conjugate (FFA) in colon cancer. Compared with the control cells, FFA-treated HT-29 cells showed increased p53 levels, increased apoptosis, and loss of mitochondrial membrane potential. Further studies showed that FFA could trigger the release of cytochrome C in colon cancer cells, and the expression of cysteinyl aspartate-specific proteinase (caspase)-9 and -3 increased after FFA treatment. Together, these results indicate that FFA can activate p53-mediated intrinsic apoptosis, suggesting that these targeted biomaterials could be used as an effective drug in cancer therapy.

Bcl-2 plays an important role in controlling cell apoptosis and enhancing cell survival. miR-34 is abnormally expressed in the tumor process and is considered a tumor suppressor microRNA due to its synergistic effect with the tumor suppressor gene p53 [32]. Increasing the expression of miR-34a can inhibit Bcl-2 and increase apoptosis [33]. In a human cervical cancer xenograft model, FA treatment was found to reduce tumor weight in a dose-dependent manner, increase miR-34a expression, downregulate Bcl-2 protein expression, and upregulate caspase-3 protein expression [34]. Therefore, the inhibitory effect of FA on the growth of transplanted tumors of human cervical cancer in nude mice may be realized by upregulating miR-34a, thus inhibiting the expression of its target gene Bcl-2, initiating the apoptotic pathway and promoting cell apoptosis. Zhang et al. [35] used FA treatment on gastric cancer MGC-803 cells, and the results showed that FA could upregulate the expression of Bcl-2-associated X (Bax) mRNA and protein and downregulate the expression of Bcl-2 mRNA and protein, thus effectively inducing the apoptosis of MGC-803 cells and inhibiting their proliferation. These results suggest that the mechanism of FA-induced apoptosis may be related to the activation of the endogenous mitochondrial apoptosis pathway. Isoferulic acid, an isomer of FA, also significantly inhibited the proliferation of human renal carcinoma A-498 cells, induced cleaved caspase-3 expression, and promoted the apoptosis of A-498 cells; moreover, isoferulic acid dose-dependently downregulated the expression of β-catenin and MYC proto-oncogene (c-Myc), inducing apoptosis [36]. Therefore, isoferulic acid is considered a potential candidate for the treatment of renal carcinoma.

Yue et al. [37] evaluated the potential effects of FA's nitrate compound FXS-3 on the proliferation and metastasis of lung cancer A549 cells. The results showed that FXS-3 can inhibit the activity of A549 cells by upregulating the Bax/Bcl-2 ratio mediated by the c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK)/p38signaling pathways, which provides an important scientific basis for the development of FA derivative anticancer drugs. Nitric oxide has a wide range of potential applications in tumor therapy [38]. Zhang et al. [37] designed and synthesized an FA-nitric oxide donor conjugate. After this coupling was applied to A549 lung cancer cells, it was found that it could upregulate the expression levels of Bax and JNK by downregulating the expression of,Bcl-2, P38 and ERK, thus inhibiting the proliferation of A549 cells and inducing their apoptosis.

ROS are a group of short-lived and highly active oxygen-containing molecules that can induce DNA damage and genotoxic stress, as well as initiate oxidative stress-induced tumor cell death [39]. After treatment with FA, Cao et al. [40] observed an increase in ROS production and a decrease in superoxide dismutase activity and glutathione content in EC-1 and TE-4 oesophageal cancer cells. In addition, FA could promote the release of lactate dehydrogenase (LDH) and the activation of caspase-3 in oesophageal cancer cells, thus inducing cell apoptosis. Rosaria et al. [41] found that FA can activate the ERK1/2 pathway through the participation of ROS and play a proapoptotic role in human glioblastoma U-87 MG cells by reducing the expression levels of Bcl-2, ERK1/2, and c-Myc.

Zinc oxide nanoparticles are effective carriers for the targeted delivery of anticancer drugs to tumor cells [42]. Babu et al. [43] conjugated zinc oxide nanoparticles with FA (ZnONPs-FA) to act on hepatoma Huh-7 and HepG2 cells. The results showed that ZnONPs-FA could induce oxidative DNA damage and apoptosis by inducing ROS production. Therefore, ZnONPs-FA may be a promising drug for the treatment of liver cancer.

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