Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
5-Year IF – 2.0, IF – 1.9, JCI (2024) – 0.43
Scopus CiteScore – 4.3
Q1 in SJR 2024, SJR score – 0.598, H-index: 49 (SJR)
ICV – 161.00; MNiSW – 70 pts
Initial editorial assessment and first decision within 24 h

ISSN 1899–5276 (print), ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

2021, vol. 30, nr 12, December, p. 1293–1301

doi: 10.17219/acem/139398

Publication type: review

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

Download citation:

  • BIBTEX (JabRef, Mendeley)
  • RIS (Papers, Reference Manager, RefWorks, Zotero)

Cite as:


Rakoczy K, Szlasa W, Saczko J, Kulbacka J. Therapeutic role of vanillin receptors in cancer. Adv Clin Exp Med. 2021;30(12):1293–1301. doi:10.17219/acem/139398

Therapeutic role of vanillin receptors in cancer

Katarzyna Rakoczy1,A,B,D, Wojciech Szlasa1,C,D,E, Jolanta Saczko2,E,F, Julita Kulbacka2,A,C,E,F

1 Students’ Research Group, Faculty of Medicine, Wroclaw Medical University, Poland

2 Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Poland

Abstract

Natural products play significant roles in the development of novel drugs. One of such compounds is vanillin – a natural substance commonly used in food. Anticancer potential of the substance is continually encouraging researchers to conduct further investigations. A rising number of publications describe the role of 4-hydroxy-3-methoxybenzaldehyde (vanillin) in the process of inhibiting tumor growth. Four vanilloid receptors play significant roles in the response of cancer cells to the natural compound. Each of these proteins can be individually affected by vanillin; thus, the substance either leads to inhibition of the cell proliferation or increases the Ca2+ level. The TRPV1, a non-selective cation channel permeable to calcium, acts on cancer development and progression. Thus, vanilloid receptors have the potential to become the target for therapeutical research. Moreover, selective inhibitors of the receptor have proved their efficacy in vitro. CK2α is an antiapoptotic, cancer-sustaining protein and, therefore, the inhibitor of apoptosis. Thus, drugs that exhibit allosteric and ATP-competitive inhibition of the protein might be crucial for cancer therapy. CAMK4 is a protein kinase expression associated with a wide array of cancers. Also, MARK4 is another kinase responsible for the stability of microtubules, overexpressed in many cancer types. Studies concerning this protein revealed that microtubule impairment might be a cancer therapy direction.

This review aims to demonstrate the crucial role of described vanilloid receptors in inhibiting the proliferation of cancer cells and to prove the usefulness of using vanillin and its derivatives in the process of drug design.

Key words: vanillin, cancer, TRPV1 protein, CK2α protein, CAMK4 protein

Introduction

Vanilla extract consists of various natural substances. One of its most prominent components is vanillin (C8H8O3), a hydrophilic and phenolic aldehyde. The chemical structure of vanillin is comprised of aldehyde, hydroxyl and ether groups located around an aromatic ring. This compound is mostly known for its aromatic flavor and specific odor.1 Vanillin can be of both synthetic and natural origin. When extracted from the seedpods of Vanilla planifolia, the compound remains conjugated with β-D-glucose and initially lacks its taste properties. However, in the course of production, free vanillin is released from the glucoside by hydrolytic enzymes.2 Vanillin may be synthesized from small molecule natural compounds. Clove oil is the source of eugenol, which, through the oxidation of a vinyl group (attached to the aromatic ring), forms vanillin. In a similar way, vanillin may be synthesized from coniferyl alcohol (from spruce tree lignin) and from ferrulic acid (from rice). Interestingly, the vanillin precursor guaiacol may be found in petroleum.2 Due to its relatively simple structure, vanillin-like fragments are likely to be found in higher mass molecules. Following metabolism, radiation, heat and decomposition, vanillin may be released. For instance, irradiation of curcumin solution leads to the generation of free vanillin, feruloylmethane and acetone. In addition, vanillin remains one of the products of metabolism of curcumin.3

Vanillin has a significant antitumor potential,4 and its activity may be more valuable than previously considered.5 The antimutagenic effects of 4-hydroxy-3-methoxybenzaldehyde seem to be due to its influence on cell redox homeostasis and DNA repair pathways. However, not only does vanillin exhibit antimutagenic properties, but it is also considered to be an antimutagen.6, 7, 8 Moreover, it has been shown to have antioxidant,9, 10 antimicrobial,11 analgesic,12, 13 and anti-erythrocyte-sickling14 properties. Taking the quintessential properties of the discussed phenolic aldehyde into consideration, the process by which the described organic compound affects certain cells is worth further discussion and warrants closer analysis.

Vanillin receptors overview and their role in carcinogenesis

Vanillin may exert its antitumor potential by targeting membrane and intracellular receptors. The current literature suggests that this compound acts on 4 main proteins (transmembrane channel TRPV1) and 3 cytoplasmic peptides – MARK4, CAMK4 and CK2 (Figure 1).

TRPV1

The TRPV1 receptor belongs to the transient receptor potential gene superfamily that includes 28 separate genes, grouped into 6 subfamilies: TRPC, TRPV, TRPP, TRPM, TRPA, and TRPML.15, 16, 17 Each of these genes encode a non-selective cation channel responsible for a variety of functions in the organism.15, 16 These channels function as a molecular gateway, which transforms stimuli of both chemical and physical origins into action potentials. Moreover, these channels are the major transducers for a multitude of biological functions, including vision, taste, olfaction, mechanonsensation, osmosensation, and nociception.16, 18, 19 The products encoded by transient receptor potential (TRP) superfamily genes are crucially important sensory receptors, and among the members of the family, there is a group of thermoreceptors,20 which detect hot (TRPV1 and TRPV2) and cold (TRPA1) temperatures – from adverse stimuli to harmless ones (TRPV3, TRPV4 and TRPM8).15, 20 However, these channels are activated not only by temperature stimuli, but also by chemical substances like menthol (TRPM8), camphor (TRPV3), mustard oil (TRPA1), wasabi (TRPA1), and capsaicin (TRPV1).20, 21, 22, 23, 24, 25

The TRPV1 is a non-selective cation channel that is permeable to calcium and is gated by noxious heat, vanilloids, extracellular protons, and endocannabinoids.18, 21 This channel is a tetrameric membrane protein that contains 4 indistinguishable subunits gathered around an aqueous pore in the central part of the channel.26 Each subunit of this multimeric protein consists of 6 transmembrane segments (S1, S2, S3, S4, S5, and S6) with an amphipathic region between the 5th and 6th segment that forms the channel conductive pore (Figure 2). Glutamic acid docks into the ampiphatic region in a pH-sensitive manner and gates the whole ionic current through the channel.21 In the cytoplasmic N-terminus of the protein, there are 3 ankyrin domains. These domains present consensus sequences for protein kinases and conciliate the protein-protein model of cytosolic protein interactions. The C-terminus domain includes phosphoinositide calmodulin binding (CAM) domains and phosphorylation sites.15 In addition, this receptor exhibits the TRP-like motif, which plays the role of an associative domain for the whole receptor to interact with other membrane-bound proteins.27

With regard to the involvement of TRPV1 in cancer, the receptor is now the most important target for the treatment of chronic pain in bone cancer.28 For this reason, the search for TRPV1 specific antagonists is becoming a promising direction in drug discovery and development.29 As a regulator of inflammation and calcium signaling pathways, the TPRV1 channel can affect the development and progression of cancer.30 The receptor is also upregulated in various neoplasms, including breast and urothelial cancers,31 and this relationship may find an application in the therapies targeting tumors.32 The anticancer potential of TRPV1 activation arises from an increased permeability of the cell membrane for chemotherapy agents.33, 34 The effects of receptor activation depend on the preliminary sensitization of TRPV1. The activation of TRPV1 in neurons leads to the release of pro-inflammatory substance P and calcitonin-related peptide (CGRP).35, 36 However, the summarized systemic effect of TRPV1 knockout turned out to be anti-inflammatory.37 Most of the studies aiming to evaluate the proliferation of cancer cells with the use of selective TRPV1 antagonists have shown that the inhibition of the channel is not related to a higher probability of cancer.38 In addition, a study by Hwang et al. showed that TRPV1 is not involved in carcinogenesis induced by activation of the Akt pathway.39

The other example are vanilloids, which induce TRPV1-unrelated apoptosis in oral cancer.40 Activation of calcium signaling has been widely evaluated for its potential application in the activation of the intrinsic apoptotic pathway in cancer.41 The assumption is that activation of calcium inflow to the cytoplasm and the mitochondria would result in programmed cell death. However, in the case of TRPV1, the effect varies between analyzed cell lines and, curiously, is related to the level of TRPV1 expression.31 Namely, breast cancer cell lines (MDA-MB231, MCF7) that express the TRPV1 channel are not sensitive to the administration of its selective agonist – vanilloids. However, after the transfection with the cDNA of the channel, the sensitivity increases significantly.

The biological effects of TRPV1 activation may also arise from its interactions with the other transmembrane proteins, especially those from TRP family.42 In the case of a therapeutic approach, selective inhibitors of TRPV1 have proven their efficacy in vitro. The application of a TRPV1 activator simultaneously with standard chemotherapy agents (cisplatin, 5-Fluoruracil, Pirarubicin), leads to a synergistic effect.43, 44, 45 The standalone effect of TRPV1 activation in thyroid adenocarcinoma cells has been proven effective as well.46

CK2α

Although casein kinase II (CK2) is not an oncogene, its activity is significant in various types of cancers, especially hematological malignancies.47, 48, 49 The antiapoptotic properties of this kinase are associated with an ability to sustain cancer growth. The CK2α subunit is the antiapoptotic protein by which vanillin might induce apoptosis in cancer cells through the inhibition of NF-κB phosphorylation and activation.50 An interaction between the receptor and 4-hydroxy-3-methoxybenzaldehyde inhibits the kinase function of CK2. A guaiacol functional group interacts with the positively charged region of the CK2α ATP blinding pocket. The potency of the inhibitory activity of vanillin is approximately equivalent to the effects induced by other substances, like feruloyl methane or ferulic aldehyde. The use of vanillin and its derivatives in the design of specific CK2 inhibitors may prove to be very successful.51 Protein kinase 2 is associated with the increased growth and proliferation of cancer cells.52 This kinase acts as a potent inhibitor of apoptosis, allowing the cells to proliferate. Moreover, increased expression is related to the level of dysplasia among cancer cells.53 The CK2 mechanism of action involves activation of the NF-κB pathway by the phosphorylation (and further degradation) of its inhibitor IκB.54 This kinase is also involved in the induction of drug resistance.55 In addition, CK2 inhibitors cause the suppression of angiogenesis56 and the cancer-specific, PTEN-related energetic shift.57 Various drugs have been tested for allosteric and ATP-competitive inhibition of CK2 in cancer therapy,58 with the latter including the small molecule inhibitors TBB, DMAT, IQA, CX-4945, and CX-5011.59 The ATP analogues contain the 2-aminothiazole-derived compounds.59 Moreover, some CK2 inhibitors have proven efficacious in preclinical studies, like CX4945 for high-risk pediatric leukemias.47 Aside from the novel chemotherapy agents, curcumin and its degradation products (ferulic acid, vanillin, feruloylmethane and coniferyl aldehyde) turned out to be potent CK2 inhibitors.51

CAMK4

Human calcium/calmodulin-dependent protein kinase IV (CAMK4), a member of the Ser/Thr kinase family, is associated with different types of cancer. Vanillin is considered a potential anticancer agent, and therefore its compatibility with the receptor binding pocket of this kinase has been investigated. It has been found that this molecule binds strongly to the active site cavity of CAMK4.60 As further research has shown, the anti-cancer potential of vanillin is related to its interaction with the described receptor, successfully inhibiting the proliferation of HepG2 (human hepatocyte carcinoma) and SH-SY5Y neuroblastoma cells.61 Moreover, vanillin treatment does not only affect tumor proliferation directly, but it also reduces ROS production and mitochondrial membrane depolarization, which eventually leads to the apoptosis in human hepatocyte carcinoma and neuroblastoma cells.62 Therefore, targeting CAMK4 as a novel therapeutic prospect might result in the common usage of vanillin (a natural chemical molecule) and its derivatives, which could be crucial when it comes to minimizing possible side effects.62 CAMK4 is also involved in the calmodulin-dependent protein kinase kinase 2 (CAMKK2) signal transduction pathway. Due to its activation of various transcription factors, neuronal communication and immune response, CAMK4 was considered a molecular target for anticancer therapy.63 Nuclear localization of CAMK4 is associated with the malignant potential of ovarian cancer.64 It has also been detected in lung and hepatocellular carcinomas.64 Indeed, hepatic cancer is essentially regulated by the CAMKK2/CAMK4 pathway.61 The CAMK4 has been examined as a potential target in the case of various malignancies, including hepatocellular carcinoma (HCC), breast cancer, neuroblastoma, prostate cancer, and acute myelogenous leukemia (AML).65 Vanillin has proven to be efficacious against cancer through binding to CAMK4 in HepG2 and SH-SY5Y cancer cells.62 Also, ellagic acid and quercetin were shown to inhibit the activity of this kinase.63 In addition, the natural inhibitor of CAMK4 – miR-129-5p – was found to inhibit MAPK and therefore the proliferation, migration and invasion of hepatic cells.66

MARK4

Microtubule affinity-regulating kinase 4 (MARK4) is a Ser/Thr kinase that belongs to the AMPK-like family.67, 68 This kinase regulates the stability of microtubules, and the cell cycle, signaling, differentiation and polarization69, 70; and its highest expression is observed in kidney, brain and testes.71, 72 Any fluctuations in MARK4 expression can disrupt important cellular pathways, such as mTOR and NF-κB, which may result in countless health disorders.73, 74 For instance, MARK4 has been reported to promote the proliferation of breast cancer cells through the hippo signaling pathway.74 Vanillin is considered to be a potential inhibitor of MARK4 and future anticancer research might target MARK4 overexpression.75, 76, 77 Therefore, exploring the interaction between MARK4 and vanillin may provide an effective tool to fight cancer.78 When it comes to the chemical structure and the process of binding, vanillin connects to this protein kinase only by a single hydrogen bond between A135 and the hydroxyl group of vanillin. However, alongside that connection, there is also a π–π bond with Y134.78 The MARK4 is overexpressed in different types of cancers, and this protein is responsible for the control of cell division in its early stages. This kinase regulates the microtubular system during cell division, and thus could be assigned as a target for novel drugs and naturally derived substances. Several studies have investigated the ability of natural compounds, like vanillin, rutin or rosmarinic acid, to act as inhibitors of MAPK4.78, 79 Also, several novel small molecule drugs have been shown to be potent MAPK4 inhibitors, exhibiting the potential of microtubule impairment for anticancer activity in MCF-7 and HepG2 cells.80 Dietary polyphenolics, ferulic acid, hesperidin, and gallic acid have also been shown to inhibit MARK4.78

Studies examining the use of vanillin to target cancers

The 4-hydroxy-3-methoxybenzaldehyde is considered to be generally non-cytotoxic. However, there is strong evidence confirming that this compound increases the cytotoxicity of cisplatin81 and mitomycin C,82 which are DNA-damaging agents. This fact is evidently related to the capability of vanillin to impair DNA double-strand break repair through the inhibition of DNA-PKcs.81 Even though this organic compound is incapable of directly suppressing the progression of a tumor, it might enhance the efficiency of chemotherapy, as suggested by Marton et al.,83 who showed that vanillin inhibits angiogenesis in a chorioallantois membrane assay of a chick.84 Moreover, vanillin suppresses the activation of NF-ĸB, which is induced by various inflammatory stimuli such as tumor necrosis factor α (TNF-α),50 trinitrobenzene sulfonic acid85 and 12-otetradecanoylphorbol-13-acetate.86 To conclude, even though the intrinsic cytotoxicity of vanillin is low, this organic compound can be used to sensitize cancer cells towards standard chemothrapeutic drugs, which results in the activation of NF-kB,83 and therefore may increase the effectiveness of these treatments.

In vitro studies concerning
vanillin receptors

The administration of 4-hydroxy-3-methoxybenzaldehyde in non-cytotoxic concentrations has shown anticancer potential in in vitro studies on mouse mammary adenocarcinoma 4T1 cells.87 Both invasion and migration were successfully inhibited by the described organic compound. Furthermore, experiments on human HepG2 cells have confirmed the usefulness of 4-hydroxy-3-methoxybenzaldehyde. Vanillin contributed to suppression of the enzymatic activity of matrix metalloproteinase 9 (MMP-9), induced by 12-O-tetradecanoylphorbol-13-acetate and decreased its mRNA level.86 The anticancer potential of vanillin was also shown in research on lung A549 carcinoma cells. The migration of these cells induced by hepatocyte growth factor (HGF) was successfully inhibited by vanillin.87 As demonstrated by these in vitro results, the inhibitory effects of vanillin on the activity of cancer-related proteins make it a very promising potential anticancer agent.

Vanillin is also considered a bio-antimutagen, as it prevents mutagenesis by reducing mutation progress after DNA damage.88 Studies by Rodrigues de Andrade et al. have shown that the application of 4-hydroxy-3-methoxybenzaldehyde decreases mitomycin C-induced and spontaneous ring X-loss.89 Even though mitomycin C-induced mutations were not effectively inhibited by vanillin, the proportion of recombination in somatic cells of Drosophila melanogaster that were treated with the alkylating agent increased significantly.90 When applied in combination with ethyl methanesulfonate (EMS), N-methyl-N-nitrosourea (MNU) or bleomycin, 4-hydroxy-3-methoxybenzaldehyde prevented the cellular genotoxicity induced by these chemical substances.91, 92 Furthermore, measurements of DNA repair have shown the impact of vanillin on the repair of lethal damage induced by N-ethyl-N-nitrosourea (ENU) and EMS.93 Finally, studies on the anti-mutagenic effects of 4-hydroxy-3-methoxybenzaldehyde have shown its inhibitory potential and stimulating effects on detoxification enzymes.92, 93

In contrast to the research cited above, the following studies were conducted on mammalian ovary fibroblast CHO K-1 cells. Apart from overall antimutagenic effects of 4-hydroxy-3-methoxybenzaldehyde, the influence of the current phase of the cell cycle on these effects was examined. The results showed that vanillin caused significant growth in the incidence of sister chromatid exchange (SCE) induced in cells treated with N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) and methyl methanesulphonate (MMS), EMS and ENU. However, the effects obtained in cells treated with MMC were dependent on the cell cycle and occurred in the S phase.94 Also, vanillin treatment applied in the G2 phase in these cells decreased the frequency of breakage types of chromosome aberrations caused using X-ray radiation and ultraviolet (UV) light, whereas in phase G1, it suppressed both breakage and exchange types of aberrations induced with X-ray radiation.95 Even though the experiment was conducted successfully for several mutagens, in cells treated with N-ethyl-N′-nitro-N-nitrosoguanidine (ENNG) and mitomycin (MMC), the usage of vanillin did not produce significant changes. Cricetulus griseus lung fibroblast V79 cells have also been used to examine the suppressive properties of 4-hydroxy-3-methoxybenzaldehyde. Vanillin did not only minimize the incidence of 6-thioguanine-resistant mutations generated using ENU, X-ray radiation and UV light,96 but it also suppressed chromosomal aberrations evoked by hydrogen peroxide.97, 98

Human colon cancer HCT116 cells have also been used to study the antimutagenic capability of vanillin. The 4-hydroxy-3-methoxybenzaldehyde applied at antimutagenic concentrations caused DNA damage in mismatch-proficient (HCT116 + CHR3), as well as mismatch-deficient (HCT116) cells. In the end, the HCT116 cells treated with vanillin exhibited a change in the expression of 64 genes, mainly related to the DNA damage, oxidative damage, cell growth, and apoptosis.95 In addition, studies examining the effects of vanillin on DNA damage caused using UV light in human keratinocyte stem cells suggested that the ATM/p53 pathway relates to vanillin-induced protection of the cell.84

In vivo studies concerning
vanillin receptors

The first in vivo studies testing the anticancerogenic potential of vanillin were conducted in rats. These animal studies involved supplementing the diet with vanillin for 7 days and administering a hepatocarcinogen on the 6th day. Partial hepatectomy, as well as the application of phenobarbital and D-galactosamine, demonstrated antioxidant and inhibitory effects of vanillin on hepatocarcinogenesis initiation.99 Another study concerning medium-term multiorgan rat carcinogenesis used male F344 rats that were given vanillin in their diet, either from 1 day before and through the exposure to carcinogen, or afterwards. This study showed that 4-hydroxy-3-methoxybenzaldehyde suppressed the carcinogenesis of small intestine cancer and lung cancer, even though only for a week, whereas its effect on colon cancer cells in the initiation phase was strikingly different, and cancer cells progression was observed.100 Other studies have examined the effects of vanillin in rats with aberrant crypt foci (ACF) induced with azoxymethane.101 In these studies, the animals were given vanillin at either a low or a high dose, and several parameters, such as ACF density and distribution, as well as gene expression, were monitored. Although orally delivered 4-hydroxy-3-methoxybenzaldehyde did not yield any significant results, vanillin administered through intraperitoneal injection (at the higher concentration) was cancerogenic. However, the expression levels of many parameters were affected by the substance. For instance, the levels of the protooncogenes XRCC2, PMS2, p21, and cyclin B were increased.101 Both the cancerogenic and anticancerogenic effects of vanillin suggest that further studies are required in the field of vanillin-related changes in DNA.

Clinical trials involving vanillin

To date, several trials examining the use of vanillin in clinical practice have been conducted. Most of these studies have applied this natural compound for the treatment of hypoxic events102 or apneas103 in premature infants. In addition, the calming effects of vanilla odor have been tested for the potential induction of analgesia in preterm newborns.104 The repellent properties of vanillin have also been tested against flies, and thus its potential application for interrupting the transmission of trachoma has been examined.105 However, no trials have aimed to use vanillin as an anticancer therapy. Although vanillin has never been clinically applied in cancer patients, an extract from vanilla beans has been examined as a supportive/adjuvant therapy for cancer. Vanilla in nutraceuticals (especially flaxseed) has been tested for the prevention of doxorubicin- and trastuzumab-mediated cardiotoxicity.106 In the future, a registered clinical trial will evaluate its effects on the chemotherapy-induced nausea and vomiting (trial No. NCT04478630). The only study that concerned the standalone anticancer activity of vanilla was conducted on PSA-recurrent prostate cancer.107 This phase II clinical study revealed a decline in PSA slope after the administration of isoflavones (including vanilla).108 Although several studies aimed to evaluate the effects of whole food interventions (including vanilla) on mucositis in patients treated for thoracic109 and head and neck cancers,110 the studies were terminated early.

Conclusions

Substances of natural origin are effectively used in therapies, as these compounds tend to exhibit significantly less side effects. Even though our knowledge is still very limited, the anticancer potential of a widely accessible organic compound, vanillin, and the multitude of studies examining the role of vanilloid receptors in carcinogenesis, make the prospect of using vanillin and its derivatives in clinical trials very promising. The studies presented in this review reveal the antitumor activity of vanillin and its therapeutic potential in cancer treatment and prevention. The data reviewed above summarize the results of the most important research related to the role of 4-hydroxy-3-methoxybenzaldehyde and its derivatives as effective inhibitors of the pathophysiology of cancer. As it turns out, the described inconspicuous organic compound may be one of the substances that indirectly contributes to the inhibition of the tumor growth and it may become an effective treatment to combat the fatal consequences of carcinogenesis.

Figures


Fig. 1. Four vanilloid receptors play significant roles in the response of cancer cells to the natural compound. Each of the proteins is affected by vanillin in a different way; thus, the substance either leads to an inhibition of cell proliferation or to an increase in Ca2+ levels
Fig. 2. The TRPV1 receptor consists of 6 transmembrane segments (S1, S2, S3, S4, S5, and S6) with an amphipathic region between the 5th and 6th segment that forms the channel conductive pore

References (110)

  1. Gulsia O. Vanillin: One drug, many cures. Resonance. 2020;25(7):981–986. doi:10.1007/s12045-020-1013-z
  2. Walton NJ, Mayer MJ, Narbad A. Vanillin. Phytochemistry. 2003;63(5):505–515. doi:10.1016/S0031-9422(03)00149-3
  3. Sinha AK, Sharma UK, Sharma N. A comprehensive review on vanilla flavor: Extraction, isolation and quantification of vanillin and others constituents. Int J Food Sci Nutr. 2008;59(4):299–326. doi:10.1080/09687630701539350
  4. Santos Pedroso L, Marino Fávero G, Erzinger Alves de Camargo L, Mara Mainardes R, Maissar Khalil N. Effect of the o-methyl catechols apocynin, curcumin and vanillin on the cytotoxicity activity of tamoxifen. J Enzyme Inhib Med Chem. 2013;28(4):734–740. doi:10.3109/14756366.2012.680064
  5. Tai A, Sawano T, Yazama F, Ito H. Evaluation of antioxidant activity of vanillin by using multiple antioxidant assays. Biochim Biophys Acta. 2011;1810(2):170–177. doi:10.1016/j.bbagen.2010.11.004
  6. King AA, Shaughnessy DT, Mure K, et al. Antimutagenicity of cinnamaldehyde and vanillin in human cells: Global gene expression and possible role of DNA damage and repair. Mutat Res. 2007;616(1–2):60–69. doi:10.1016/j.mrfmmm.2006.11.022
  7. Shaughnessy DT, Setzer RW, DeMarini DM. The antimutagenic effect of vanillin and cinnamaldehyde on spontaneous mutation in Salmonella TA104 is due to a reduction in mutations at GC but not AT sites. Mutat Res. 2001;480–481:55–69. doi:10.1016/S0027-5107(01)00169-5
  8. Shaughnessy DT, Schaaper RM, Umbach DM, DeMarini DM. Inhibition of spontaneous mutagenesis by vanillin and cinnamaldehyde in Escherichia coli: Dependence on recombinational repair. Mutat Res. 2006;602(1–2):54–64. doi:10.1016/j.mrfmmm.2006.08.006
  9. Kumar SS, Priyadarsini KI, Sainis KB. Inhibition of peroxynitrite–mediated reactions by vanillin. J Agric Food Chem. 2004;52(1):139–145. doi:10.1021/jf030319d
  10. Chou TH, Ding HY, Hung WJ, Liang CH. Antioxidative characteristics and inhibition of α-melanocyte-stimulating hormone-stimulated melanogenesis of vanillin and vanillic acid from Origanum vulgare. Exp Dermatol. 2010;19(8):742–750. doi:10.1111/j.1600-0625.2010.01091.x
  11. Fitzgerald DJ, Stratford M, Gasson MJ, Ueckert J, Bos A, Narbad A. Mode of antimicrobial of vanillin against Escherichia coli, Lactobacillus plantarum and Listeria innocua. J Appl Microbiol. 2004;97(1):104–113. doi:10.1111/j.1365-2672.2004.02275.x
  12. Park SH, Sim YB, Choi SM, et al. Antinociceptive profiles and mechanisms of orally administered vanillin in the mice. Arch Pharm Res. 2009;32(11):1643–1649. doi:10.1007/s12272-009-2119-8
  13. Beaudry F, Ross A, Lema PP, Vachon P. Pharmacokinetics of vanillin and its effects on mechanical hypersensitivity in a rat model of neuropathic pain. Phyther Res. 2010;24(4):525–530. doi:10.1002/ptr.2975
  14. Abraham DJ, Mehanna AS, Wireko FC, Whitney J, Thomas RP, Orringer EP. Vanillin, a potential agent for the treatment of sickle cell anemia. Blood. 1991;77(6):1334–1341. doi:10.1182/blood.v77.6.1334.bloodjournal7761334
  15. Clapham DE. TRP channels as cellular sensors. Nature. 2003;426(6966):517–524. doi:10.1038/nature02196
  16. Montell C, Birnbaumer L, Flockerzi V. The TRP channels, a remarkably functional family. Cell. 2002;108(5):595–598. doi:10.1016/S0092-8674(02)00670-0
  17. Moran MM, Xu H, Clapham DE. TRP ion channels in the nervous system. Curr Opin Neurobiol. 2004;14(3):362–369. doi:10.1016/j.conb.2004.05.003
  18. Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature. 2001;413(6852):203–210. doi:10.1038/35093019
  19. Minke B, Cook B. TRP channel proteins and signal transduction. Physiol Rev. 2002;82(2):429–472. doi:10.1152/physrev.00001.2002
  20. Montell C. Thermosensation: Hot findings make TRPNs very cool. Curr Biol. 2003;13(12):R476–R478. doi:10.1016/S0960-9822(03)00406-8
  21. Caterina MJ, Julius D. The vanilloid receptor: A molecular gateway to the pain pathway. Annu Rev Neurosci. 2001;24:487–517. doi:10.1146/annurev.neuro.24.1.487
  22. Jordt SE, Bautista DM, Chuang H, et al. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature. 2004;427(6971):260–265. doi:10.1038/nature02282
  23. McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature. 2002;416(6876):52–58. doi:10.1038/nature719
  24. Moqrich A, Hwang SW, Earley TJ, et al. Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science. 2005;307(5714):1468–1472. doi:10.1126/science.1108609
  25. Story GM, Peier AM, Reeve AJ, et al. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell. 2003;112(6):819–829. doi:10.1016/S0092-8674(03)00158-2
  26. Smith GD, Gunthorpe MJ, Kelsell RE, et al. TRPV3 is a temperature-sensitive vanilloid receptor-like protein. Nature. 2002;418(6894):186–190. doi:10.1038/nature00894
  27. García-Sanz N, Fernández-Carvajal A, Morenilla-Palao C, et al. Identification of a tetramerization domain in the C terminus of the vanilloid receptor. J Neurosci. 2004;24(23):5307–5314. doi:10.1523/JNEUROSCI.0202-04.2004
  28. Ghilardi JR, Röhrich H, Lindsay TH, et al. Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain. J Neurosci. 2005;25(12):3126–3131. doi:10.1523/JNEUROSCI.3815-04.2005
  29. Messeguer A, Planells-Cases R, Ferrer-Montiel A. Physiology and pharmacology of the vanilloid receptor. Curr Neuropharmacol. 2005;4(1):1–15. doi:10.2174/157015906775202995
  30. Bujak JK, Kosmala D, Szopa IM, Majchrzak K, Bednarczyk P. Inflammation, cancer and immunity: Implication of TRPV1 channel. Front Oncol. 2019;9:1087. doi:10.3389/fonc.2019.01087
  31. Pecze L, Jósvay K, Blum W, et al. Activation of endogenous TRPV1 fails to induce overstimulation-based cytotoxicity in breast and prostate cancer cells but not in pain-sensing neurons. Biochim Biophys Acta. 2016;1863(8):2054–2064. doi:10.1016/j.bbamcr.2016.05.007
  32. Ortega-Guerrero A, Espinosa-Duran JM, Velasco-Medina J. TRPV1 channel as a target for cancer therapy using CNT-based drug delivery systems. Eur Biophys J. 2016;45(5):423–433. doi:10.1007/s00249-016-1111-8
  33. Hofmann NA, Barth S, Waldeck-Weiermair M, et al. TRPV1 mediates cellular uptake of anandamide and thus promotes endothelial cell proliferation and network-formation. Biol Open. 2014;3(12):1164–1172. doi:10.1242/bio.20149571
  34. Nabissi M, Morelli MB, Santoni M, Santoni G. Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents. Carcinogenesis. 2013;34(1):48–57. doi:10.1093/carcin/bgs328
  35. Liddle RA. The role of transient receptor potential vanilloid 1 (TRPV1) channels in pancreatitis. Biochim Biophys Acta. 2007;1772(8):869–878. doi:10.1016/j.bbadis.2007.02.012
  36. Meng J, Ovsepian SV, Wang J, et al. Activation of TRPV1 mediates calcitonin gene-related peptide release, which excites trigeminal sensory neurons and is attenuated by a retargeted botulinum toxin with anti-nociceptive potential. J Neurosci. 2009;29(15):4981–4992. doi:10.1523/JNEUROSCI.5490-08.2009
  37. Feng J, Yang P, Mack MR, et al. Sensory TRP channels contribute differentially to skin inflammation and persistent itch. Nat Commun. 2017;8(1):980. doi:10.1038/s41467-017-01056-8
  38. Park M, Naidoo AA, Burns A, et al. Do TRPV1 antagonists increase the risk for skin tumorigenesis? A collaborative in vitro and in vivo assessment. Cell Biol Toxicol. 2018;34(2):143–162. doi:10.1007/s10565-017-9407-8
  39. Hwang MK, Bode AM, Byun S, et al. Cocarcinogenic effect of capsaicin involves activation of EGFR signaling but not TRPV1. Cancer Res. 2010;70(17):6859–6869. doi:10.1158/0008-5472.CAN-09-4393
  40. Gonzales CB, Kirma NB, De La Chapa JJ, et al. Vanilloids induce oral cancer apoptosis independent of TRPV1. Oral Oncol. 2014;50(5):437–447. doi:10.1016/j.oraloncology.2013.12.023
  41. Kiełbik A, Szlasa W, Michel O, et al. In vitro study of calcium microsecond electroporation of prostate adenocarcinoma cells. Molecules. 2020;25(22):5406. doi:10.3390/molecules25225406
  42. Staruschenko A, Jeske NA, Akopian AN. Contribution of TRPV1–TRPA1 interaction to the single channel properties of the TRPA1 channel. J Biol Chem. 2010;285(20):15167–15177. doi:10.1074/jbc.M110.106153
  43. Nur G, Nazıroğlu M, Deveci HA. Synergic prooxidant, apoptotic and TRPV1 channel activator effects of alpha-lipoic acid and cisplatin in MCF-7 breast cancer cells. J Recept Signal Transduct Res. 2017;37(6):569–577. doi:10.1080/10799893.2017.1369121
  44. Deveci HA, Nazıroğlu M, Nur G. 5-Fluorouracil-induced mitochondrial oxidative cytotoxicity and apoptosis are increased in MCF-7 human breast cancer cells by TRPV1 channel activation but not Hypericum perforatum treatment. Mol Cell Biochem. 2018;439(1–2):189–198. doi:10.1007/s11010-017-3147-1
  45. Zheng L, Chen J, Ma Z, et al. Capsaicin enhances anti-proliferation efficacy of pirarubicin via activating TRPV1 and inhibiting PCNA nuclear translocation in 5637 cells. Mol Med Rep. 2016;13(1):881–887. doi:10.3892/mmr.2015.4623
  46. Xu S, Zhang L, Cheng X, Yu H, Bao J, Lu R. Capsaicin inhibits the metastasis of human papillary thyroid carcinoma BCPAP cells through the modulation of the TRPV1 channel. Food Funct. 2018;9(1):344–354. doi:10.1039/c7fo01295k
  47. Gowda C, Soliman M, Kapadia M, Ding Y, Payne K, Dovat S. Casein kinase II (CK2), glycogen synthase kinase-3 (GSK-3) and Ikaros mediated regulation of leukemia. Adv Biol Regul. 2017;65:16–25. doi:10.1016/j.jbior.2017.06.001
  48. Piazza F, Manni S, Ruzzene M, Pinna LA, Gurrieri C, Semenzato G. Protein kinase CK2 in hematologic malignancies: Reliance on a pivotal cell survival regulator by oncogenic signaling pathways. Leukemia. 2012;26(6):1174–1179. doi:10.1038/leu.2011.385
  49. Buontempo F, McCubrey JA, Orsini E, et al. Therapeutic targeting of CK2 in acute and chronic leukemias. Leukemia. 2018;32(1):1–10. doi:10.1038/leu.2017.301
  50. Lirdprapamongkol K, Sakurai H, Suzuki S, et al. Vanillin enhances TRAIL-induced apoptosis in cancer cells through inhibition of NF-κB activation. In Vivo. 2010;24(4):501–506. PMID:20668316
  51. Cozza G, Zonta F, Dalle Vedove A, et al. Biochemical and cellular mechanism of protein kinase CK2 inhibition by deceptive curcumin. FEBS J. 2020;287(9):1850–1864. doi:10.1111/febs.15111
  52. Trembley JH, Wang G, Unger G, Slaton J, Ahmed K. CK2: A key player in cancer biology. Cell Mol Life Sci. 2009;66(11–12):1858–1867. doi:10.1007/s00018-009-9154-y
  53. Faust RA, Niehans G, Gapany M, et al. Subcellular immunolocalization of protein kinase CK2 in normal and carcinoma cells. Int J Biochem Cell Biol. 1999;31(9):941–949. doi:10.1016/S1357-2725(99)00050-3
  54. Kato T, Delhase M, Hoffmann A, Karin M. CK2 is a C-terminal IκB kinase responsible for NF-κB activation during the UV response. Mol Cell. 2003;12(4):829–839. doi:10.1016/S1097-2765(03)00358-7
  55. Borgo C, Ruzzene M. Role of protein kinase CK2 in antitumor drug resistance. J Exp Clin Cancer Res. 2019;38(1):1–15. doi:10.1186/s13046-019-1292-y
  56. Ljubimov AV, Caballero S, Aoki AM, Pinna LA, Grant MB, Castellon R. Involvement of protein kinase CK2 in angiogenesis and retinal neovascularization. Investig Ophthalmol Vis Sci. 2004;45(12):4583–4591. doi:10.1167/iovs.04-0686
  57. Silva-Pavez E, Tapia J. Protein kinase CK2 in cancer energetics. Front Oncol. 2020;10:893. doi:10.3389/fonc.2020.00893
  58. Lian H, Su M, Zhu Y, Zhou Y, Soomro SH, Fu H. Protein kinase CK2, a potential therapeutic target in carcinoma management. Asian Pacific J Cancer Prev. 2019;20(1):23–32. doi:10.31557/APJCP.2019.20.1.23
  59. D’Amore C, Borgo C, Sarno S, Salvi M. Role of CK2 inhibitor CX-4945 in anti-cancer combination therapy: Potential clinical relevance. Cell Oncol. 2020;43(6):1003–1016. doi:10.1007/s13402-020-00566-w
  60. Beg A, Khan FI, Lobb KA, Islam A, Ahmad F, Hassan MI. High throughput screening, docking, and molecular dynamics studies to identify potential inhibitors of human calcium/calmodulin-dependent protein kinase IV. J Biomol Struct Dyn. 2019;37(8):2179–2192. doi:10.1080/07391102.2018.1479310
  61. Lin F, Marcelo KL, Rajapakshe K, et al. The CaMKK2/CaMKIV relay is an essential regulator of hepatic cancer. Hepatology. 2015;62(2):505–520. doi:10.1002/hep.27832
  62. Naz H, Tarique M, Khan P, et al. Evidence of vanillin binding to CAMKIV explains the anti-cancer mechanism in human hepatic carcinoma and neuroblastoma cells. Mol Cell Biochem. 2018;438(1–2):35–45. doi:10.1007/s11010-017-3111-0
  63. Gupta P, Khan S, Fakhar Z, et al. Identification of potential inhibitors of calcium/calmodulin-dependent protein kinase IV from bioactive phytoconstituents. Oxid Med Cell Longev. 2020;8:1–14. doi:10.1155/2020/2094635
  64. Takai N, Miyazaki T, Nishida M, Nasu K, Miyakawa I. Ca2+/calmodulin-dependent protein kinase IV expression in epithelial ovarian cancer. Cancer Lett. 2002;183(2):185–193. doi:10.1016/S0304-3835(02)00107-6
  65. Naz H, Tarique M, Suhail M, et al. Calcium-/calmodulin-dependent protein kinase IV (CAMKIV): A multifunctional enzyme and its role in various cancers. An update. Curr Mol Biol Rep. 2020;6(3):139–147. doi:10.1007/s40610-020-00138-9
  66. Li Z, Lu J, Zeng G, et al. MiR-129-5p inhibits liver cancer growth by targeting calcium calmodulin-dependent protein kinase IV (CAMK4). Cell Death Dis. 2019;10(11):1–14. doi:10.1038/s41419-019-1923-4
  67. Heidary Arash E, Shiban A, Song S, Attisano L. MARK4 inhibits Hippo signaling to promote proliferation and migration of breast cancer cells. EMBO Rep. 2017;18(3):420–436. doi:10.15252/embr.201642455
  68. Sun W, Lee S, Huang X, et al. Attenuation of synaptic toxicity and MARK4/PAR1-mediated Tau phosphorylation by methylene blue for Alzheimer’s disease treatment. Sci Rep. 2016;6:34784. doi:10.1038/srep34784
  69. Rovina D, Fontana L, Monti L, et al. Microtubule-associated protein/microtubule affinity-regulating kinase 4 (MARK4) plays a role in cell cycle progression and cytoskeletal dynamics. Eur J Cell Biol. 2014;93(8–9):355–365. doi:10.1016/j.ejcb.2014.07.004
  70. Marx A, Nugoor C, Panneerselvam S, Mandelkow E. Structure and function of polarity‐inducing kinase family MARK/Par‐1 within the branch of AMPK/Snf1‐related kinases. FASEB J. 2010;24(6):1637–1648. doi:10.1096/fj.09-148064
  71. Trinczek B, Brajenovic M, Ebneth A, Drewes G. MARK4 is a novel microtubule-associated proteins/microtubule affinity-regulating kinase that binds to the cellular microtubule network and to centrosomes. J Biol Chem. 2004;279(7):5915–5923. doi:10.1074/jbc.M304528200
  72. Tang EI, Xiao X, Mruk DD, et al. Microtubule affinity-regulating kinase 4 (MARK4) is a component of the ectoplasmic specialization in the rat testis. Spermatogenesis. 2012;2(2):117–126. doi:10.4161/spmg.20724
  73. Liu Z, Gan L, Chen Y, et al. Mark4 promotes oxidative stress and inflammation via binding to PPARγ and activating NF-κB pathway in mice adipocytes. Sci Rep. 2016;6:21382. doi:10.1038/srep21382
  74. Li L, Guan KL. Microtubule-associated protein/microtubule affinity-regulating kinase 4 (MARK4) is a negative regulator of the mammalian target of rapamycin complex 1 (mTORC1). J Biol Chem. 2013;288(1):703–708. doi:10.1074/jbc.C112.396903
  75. Naz F, Sami N, Naqvi AT, Islam A, Ahmad F, Imtaiyaz Hassan M. Evaluation of human microtubule affinity-regulating kinase 4 inhibitors: Fluorescence binding studies, enzyme, and cell assays. J Biomol Struct Dyn. 2017;35(14):3194–3203. doi:10.1080/07391102.2016.1249958
  76. Naz F, Sami N, Islam A, Ahmad F, Hassan MI. Ubiquitin-associated domain of MARK4 provides stability at physiological pH. Int J Biol Macromol. 2016;93(Pt A):1147–1154. doi:10.1016/j.ijbiomac.2016.09.087
  77. Jenardhanan P, Mannu J, Mathur PP. The structural analysis of MARK4 and the exploration of specific inhibitors for the MARK family: A computational approach to obstruct the role of MARK4 in prostate cancer progression. Mol Biosyst. 2014;10(7):1845–1868. doi:10.1039/c3mb70591a
  78. Khan P, Rahman S, Queen A, et al. Elucidation of dietary polyphenolics as potential inhibitor of microtubule affinity regulating kinase 4: In silico and in vitro studies. Sci Rep. 2017;7(1):9470. doi:10.1038/s41598-017-09941-4
  79. Anwar S, Shamsi A, Shahbaaz M, et al. Rosmarinic acid exhibits anticancer effects via MARK4 inhibition. Sci Rep. 2020;10(1):10300. doi:10.1038/s41598-020-65648-z
  80. Voura M, Khan P, Thysiadis S, et al. Probing the inhibition of microtubule affinity regulating kinase 4 by N-substituted acridones. Sci Rep. 2019;9(1):1676. doi:10.1038/s41598-018-38217-8
  81. Durant S, Karran P. Vanillins: A novel family of DNA-PK inhibitors. Nucleic Acids Res. 2003;31(19):5501–5512. doi:10.1093/nar/gkg753
  82. Gustafson DL, Franz HR, Ueno AM, Smith CJ, Doolittle DJ, Waldren CA. Vanillin (3-methoxy-4-hydroxybenzaldehyde) inhibits mutation induced by hydrogen peroxide, N-methyl-N-nitrosoguanidine and mitomycin C but not 137Cs-γ-radiation at the CD59 locus in human-hamster hybrid A(L) cells. Mutagenesis. 2000;15(3):207–213. doi:10.1093/mutage/15.3.207
  83. Marton A, Kúsz E, Kolozsi C, et al. Vanillin analogues o-vanillin and 2,4,6-trihydroxybenzaldehyde inhibit NFκB activation and suppress growth of A375 human melanoma. Anticancer Res. 2016;36(11):5743–5750. doi:10.21873/anticanres.11157
  84. Lirdprapamongkol K, Kramb JP, Suthiphongchai T, et al. Vanillin suppresses metastatic potential of human cancer cells through PI3K inhibition and decreases angiogenesis in vivo. J Agric Food Chem. 2009;57(8):3055–3063. doi:10.1021/jf803366f
  85. Wu SL, Chen JC, Li CC, Lo HY, Ho TY, Hsiang CY. Vanillin improves and prevents trinitrobenzene sulfonic acid-induced colitis in mice. J Pharmacol Exp Ther. 2009;330(2):370–376. doi:10.1124/jpet.109.152835
  86. Liang JA, Wu SL, Lo HY, Hsiang CY, Ho TY. Vanillin inhibits matrix metalloproteinase-9 expression through down-regulation of nuclear factor-κB signaling pathway in human hepatocellular carcinoma cells. Mol Pharmacol. 2009;75(1):151–157. doi:10.1124/mol.108.049502
  87. Lirdprapamongkol K, Sakurai H, Kawasaki N, et al. Vanillin suppresses in vitro invasion and in vivo metastasis of mouse breast cancer cells. Eur J Pharm Sci. 2005;25(1):57–65. doi:10.1016/j.ejps.2005.01.015
  88. Kada T, Shimoi K. Desmutagens and bio‐antimutagens: Their modes of action. BioEssays. 1987;7(3):113–116. doi:10.1002/bies.950070305
  89. Rodrigues de Andrade HH, Santos JH, Gimmler-Luz MC, Correa MJF, Lehmann M, Reguly ML. Suppressing effect of vanillin on chromosome aberrations that occur spontaneously or are induced by mitomycin C in the germ cell line of Drosophila melanogaster. Mutat Res. 1992;279(4):281–287. doi:10.1016/0165-1218(92)90245-U
  90. Santos JH, Graf U, Reguly ML, Rodrigues de Andrade HH. The synergistic effects of vanillin on recombination predominate over its antimutagenic action in relation to MMC-induced lesions in somatic cells of Drosophila melanogaster. Mutat Res. 1999;444(2):355–365. doi:10.1016/S1383-5718(99)00101-1
  91. Sinigaglia M, Reguly ML, Rodrigues de Andrade HH. Effect of vanillin on toxicant-induced mutation and mitotic recombination in proliferating somatic cells of Drosophila melanogaster. Environ Mol Mutagen. 2004;44(5):394–400. doi:10.1002/em.20067
  92. Sinigaglia M, Lehmann M, Baumgardt P, et al. Vanillin as a modulator agent in SMART test: Inhibition in the steps that precede N-methyl-N-nitrosourea-, N-ethyl-N-nitrosourea-, ethylmethanesulphonate- and bleomycin-genotoxicity. Mutat Res. 2006;607(2):225–230. doi:10.1016/j.mrgentox.2006.04.012
  93. Furlanetto MP, Sinigaglia M, do Amaral VS, Dihl RR, Rodrigues de Andrade HH. Effect of vanillin on toxicant-induced lethality in the Drosophila melanogaster DNA repair test. Environ Mol Mutagen. 2007;48(1):67–70. doi:10.1002/em.20275
  94. Sasaki YF, Imanishi H, Ohta T, Shirasu Y. Effects of vanillin on sister-chromatid exchanges and chromosome aberrations induced by mitomycin C in cultured Chinese hamster ovary cells. Mutat Res. 1987;191(3–4):193–200. doi:10.1016/0165-7992(87)90153-9
  95. Sasaki YF, Imanishi H, Watanabe M, Ohta T, Shirasu Y. Suppressing effect of antimutagenic flavorings on chromosome aberrations induced by UV-light or X-rays in cultured Chinese hamster cells. Mutat Res. 1990;229(1):1–10. doi:10.1016/0027-5107(90)90002-L
  96. Imanishi H, Sasaki YF, Matsumoto K, et al. Suppression of 6-TG-resistant mutations in V79 cells and recessive spot formations in mice by vanillin. Mutat Res. 1990;243(2):151–158. doi:10.1016/0165-7992(90)90038-L
  97. Tamai K, Tezuka H, Kuroda Y. Different modifications by vanillin in cytotoxicity and genetic changes induced by EMS and H2O2 in cultured Chinese hamster cells. Mutat Res. 1992;268(2):231–237. doi:10.1016/0027-5107(92)90229-U
  98. Keshava C, Keshava N, Ong T, Nath J. Protective effect of vanillin on radiation-induced micronuclei and chromosomal aberrations in V79 cells. Mutat Res. 1998;397(2):149–159. doi:10.1016/S0027-5107(97)00203-0
  99. Tsuda H, Uehara N, Iwahori Y, et al. Chemopreventive effects of β‐carotene, α‐tocopherol and five naturally occurring antioxidants on initiation of hepatocarcinogenesis by 2‐amino‐3‐methylimidazo[4,5‐f] qumoline in the rat. Jpn J Cancer Res. 1994;85(12):1214–1219. doi:10.1111/j.1349-7006.1994.tb02932.x
  100. Akagi K, Hirose M, Hoshiya T, Mizoguchi Y, Ito N, Shirai T. Modulating effects of ellagic acid, vanillin and quercetin in a rat medium term multi-organ carcinogenesis model. Cancer Lett. 1995;94(1):113–121. doi:10.1016/0304-3835(95)03833-I
  101. Ho KL, Chong PP, Yazan LS, Ismail M. Vanillin differentially affects azoxymethane-injected rat colon carcinogenesis and gene expression. J Med Food. 2012;15(12):1096–1102. doi:10.1089/jmf.2012.2245
  102. Praud JP. Effects of vanilla on hypoxic intermittent events in premature infants. ClinicalTrials.gov. Accessed March 19, 2021. https://clinicaltrials.gov/ct2/show/NCT02630147
  103. Hospices Civils de Lyon. Odors to insufflate life. ClinicalTrials.gov. Accessed March 19, 2021. https://clinicaltrials.gov/ct2/show/results/NCT02851979
  104. Assistance Publique Hopitaux De Marseille. The calming effect of vanilla odor on preterm infant without mother’s breast milk feeding. ClinicalTrials.gov. Accessed March 19, 2021. https://clinicaltrials.gov/ct2/show/NCT03626974
  105. London School of Hygiene and Tropical Medicine. Testing insect repellents against Musca sorbens, the vector of trachoma. ClinicalTrials.gov. Accessed March 19, 2021. https://clinicaltrials.gov/ct2/show/NCT03813069
  106. Davinder S. Jassal SBH. Can flaxseed prevent broken hearts in women with breast cancer study? ClinicalTrials.gov. Accessed March 19, 2021. https://clinicaltrials.gov/ct2/show/NCT04632407
  107. University of Florida. Isoflavone in prostate-specific antigen recurrent prostate cancer. ClinicalTrials.gov. Accessed March 19, 2021. https://clinicaltrials.gov/ct2/show/NCT00596895
  108. Pendleton JM, Tan WW, Anai S, et al. Phase II trial of isoflavone in prostate-specific antigen recurrent prostate cancer after previous local therapy. BMC Cancer. 2008;8:132. doi:10.1186/1471-2407-8-132
  109. Providence Health & Services. The effects of whole food intervention on mucositis in patients treated for thoracic cancer. ClinicalTrials.gov. Accessed March 19, 2021. https://clinicaltrials.gov/ct2/show/NCT02575391
  110. Providence Health & Services. The effects of whole food intervention on mucositis in patients treated for head and neck cancer. ClinicalTrials.gov. Accessed March 19, 2021. https://clinicaltrials.gov/ct2/show/NCT02575313
© Wroclaw Medical University