Cancer, a formidable disease with a significant mortality rate, continues to claim the lives of thousands of individuals annually in contemporary society. Conventional cancer therapies are notorious for their substantial adverse effects and lack of specificity. Within the context of neoplastic development, cancer hallmarks represent fundamental biological properties that cancer cells progressively acquire. A promising approach for combating cancer involves the simultaneous targeting of multiple cancer hallmarks. Plant-derived natural compounds stand out as a promising reservoir for the development of novel and more efficacious anticancer therapeutics due to their structural diversity and minimal toxicity profiles.

Garlic (Allium sativum) has garnered considerable attention for its established anti-cancer properties over the years. Within garlic, a myriad of bioactive constituents, including organosulfur compounds, flavonoids, and phenolic compounds, exhibit distinct effects on cancer cells.

The objective of this review paper is to furnish a comprehensive elucidation of the mechanisms underpinning the anticancer actions of garlic. The elucidated findings from the studies encompassed within this review not only contribute to a more profound comprehension of the anti-cancer properties of garlic but also serve as a robust foundation upon which researchers and healthcare practitioners can formulate enhanced anticancer pharmaceuticals grounded in natural garlic compounds.

allicin, anticancer, natural products, functional food, organosulfur campounds

Cancer stands as a highly fatal affliction in contemporary times, resulting in the loss of numerous lives on an annual basis (Chhikara and Parang 2023). In the year 2023, it is projected that the United States will witness the emergence of 1,958,310 fresh instances of cancer and the unfortunate demise of 609,820 individuals due to this disease (Siegel et al. 2023). The term “Hallmarks of Cancer” pertains to a set of functional capabilities that human cells acquire during their transition from typical growth phases to neoplastic growth states, particularly skills crucial for the formation of malignant tumors (Hanahan 2022). However, this concept was initially proposed in the year 2000 by Hanahan and Weinberg (Hanahan and Weinberg 2000). These same researchers originally identified six hallmarks, which were subsequently expanded to eight in the year 2011 (Hanahan and Weinberg 2011). The eight hallmarks encompass genomic instability, evasion of growth suppression, sustained proliferation, tissue invasion and metastasis, replicative immortality, altered cellular energetics, resistance to cell death, induction of angiogenesis, and evasion of the immune system (Hanahan and Weinberg 2011). These hallmarks collectively define the essential traits acquired by cells during their transformation from normal to neoplastic states, ultimately contributing to the development of malignant tumors (Hanahan and Weinberg 2011). Targeting several cancer hallmarks is a viable cancer treatment method (Talib et al. 2022). Conventional chemotherapy regimens are plagued by significant side effects arising from their lack of selectivity (Oliveri 2022). Consequently, in the pursuit of more sophisticated therapeutic approaches, a multitude of researchers are turning to nature as a source of novel materials. It is noteworthy that over 60% of contemporary anticancer drugs find their origins in natural products (Newman and Cragg 2012). Throughout history, natural products have served as effective treatments for various human ailments and have garnered considerable attention as potential reservoirs of innovative pharmaceutical agents (Jamshidi-Kia et al. 2017). This attraction is primarily attributed to their characteristic low toxicity and diverse chemical structures (Talib et al. 2022). According to the World Health Organization (WHO), in resource-limited regions, more than three-fourths of communities rely on medicinal plants for their fundamental healthcare needs, primarily due to the fact that over 60% of these populations lack access to and/or affordability of allopathic drugs (Organization 2008).

Among the early cultivated plants known for both culinary and therapeutic purposes, garlic (Allium sativum L.) occupies a prominent place. This remarkable plant exhibits a spectrum of pharmacological properties, including antibacterial, antithrombotic, anti-arthritic, hypolipidemic, hypoglycemic, and anti-tumor effects (Mondal et al. 2022). The beneficial effects attributed to Allium species are primarily attributed to their volatile organosulfur compounds (Corzo-Martínez et al. 2007). The Bulbs of A. sativum have found to contain a diverse array of phytochemicals, with sulfur-containing compounds such as ajones (E-ajoene, Z-ajoene), thiosulfinates (allicin), vinyldithiins (2-vinyl-(4H)-1,3-dithin, 3-vinyl-(4H)-1,2-dithiin), sulfides (diallyl disulfide (DADS), diallyl trisulfide (DATS)), thiacremonone, and others, collectively constituting 82% of the total sulfur content in garlic (Al-Snafi 2013).

Indeed, organosulfur compounds have been demonstrated to specifically induce redox stress in cancer cells, leading to apoptosis and cell death (Yu et al. 2012). Notably, Weisberger and Pensky observed in 1958 that diethyl thiosulfinate from garlic effectively inhibited the development of sarcomas in mice bearing S180 tumors (Weisberger and Pensky 1957). Subsequently, numerous studies have reaffirmed garlic’s efficacy in cancer treatment (Fleischauer and Arab 2001). This effectiveness can be attributed to its diverse mechanisms as an antineoplastic agent, including the inhibition of cell growth and proliferation, regulation of carcinogen metabolism, stimulation of apoptosis, and the prevention of angiogenesis, invasion, and migration (Liu et al. 2018).

The primary objective of this review article is to conduct a comprehensive analysis of the potential mechanisms through which garlic and its bioactive constituents manifest their anti-cancer properties by targeting multiple facets of cancer hallmarks.

Tumor cells are distinguished by their intrinsic capability for limitless replication, a hallmark feature that underpins their proliferative and invasive potential (Marques et al. 2018). Disrupting this perpetual replication constitutes a promising strategy to impede tumor initiation and progression. Of paramount importance in this context are telomerase and cyclin-dependent kinases (CDKs), both of which play pivotal roles in regulating cellular replication (Bodnar et al. 1998).

In this comprehensive review, our primary focus will be directed towards elucidating the impact of garlic on the process of replicative immortalization by its dual inhibitory effects on telomerase and CDKs.

Telomerase: Telomerase is an important enzyme in cell division. Its primary role lies in the elongation of the ends of chromosomes, which naturally undergo shortening during cell division (Talib 2018).

Henceforth, the activation of this enzyme, telomerase, assumes a pivotal role in facilitating uninterrupted cell division across diverse cancer types, as underscored by (Hanahan and Weinberg 2011). The regulation of replicative immortality is a multifaceted endeavor that encompasses the inhibition of various targets. These encompass not only telomerase but also a spectrum of key molecules, including mTOR, CDK4/6, CDK 1,2,5,9, Akt, and PI3K, as expounded upon by (Talib 2018).

Garlic’s Impact on Telomerase: A research study conducted on gastric cancer SGC-7901 cells unveiled a significant finding: allicin, a bioactive compound found in garlic, exhibited the ability to inhibit telomerase activity in a manner that is both time-dependent and dose-dependent. This discovery underscores the potential of allicin as a telomerase inhibitor with implications for the treatment of gastric cancer (Sun and Wang 2003). In another research investigation, the impact of Z-ajoene, an organosulfur compound derived from garlic, was assessed on the HL-60 cell line. The research findings revealed that a concentration of 10 µmol/L of Z-ajoene administered for a 24-hour period led to a noteworthy reduction in telomerase-associated human telomerase reverse transcriptase (hTRT) and telomerase associated protein 1 (TP1) mRNA levels. This observation highlights the potential of Z-ajoene as a telomerase-modulating agent with potential implications for therapeutic interventions (Ye et al. 2005).

Figure 1. 

Enhancement of DNA repair mechanisms by garlic compounds (created by BioRender.com). This diagram illustrates how garlic compounds enhance DNA repair mechanisms: DNA Damage: The process begins with DNA damage, represented as breaks and mutations in the DNA strands. Recognition: The damaged DNA is recognized by cellular repair machinery, signaling the need for repair. Garlic Compounds: Garlic compounds, highlighted in the diagram, play a crucial role at this stage. They are known for their Genoprotective properties. DNA Repair Mechanism: The diagram illustrates the sequential steps of DNA repair, including excision, polymerization, and ligation. Enhanced Repair: Garlic compounds facilitate and enhance the DNA repair process, as indicated by connecting lines and arrows.

Targeting CDKs in Cell Cycle Progression: Cancer cells employ a strategy of upregulating the expression of cyclin-dependent kinases (CDKs) to facilitate the progression of the cell cycle. These CDKs play a pivotal role in the process by orchestrating the phosphorylation of cyclins, thereby amplifying the momentum of the cell cycle’s forward progression (McTigue et al. 2022).

Garlic’s Impact on CDKs and Cell Cycle: S-allylcysteine (SAC), a compound derived from garlic, has been identified as an inhibitor of cell cycle progression. In a study conducted by Sengupta and colleagues, the cell cycle of HepG2 liver cancer cells was examined following treatment with SAC. The research outcomes demonstrated that the application of SAC to HepG2 cells led to an augmentation in the activity of Wee1, a kinase responsible for inhibiting mitosis. Additionally, SAC treatment resulted in the accumulation of cyclin-dependent kinase (CDK) inhibitors, specifically p15, p16, p21, and p27. These findings suggest that SAC exerts its cell cycle inhibitory effects by modulating key regulatory components involved in cell cycle control (Sengupta et al. 2017).

Cancer cells enact alterations in metabolic pathways to facilitate the generation of essential nutrients and enzymes necessary for their sustained proliferation and viability. These metabolic adaptations encompass processes such as aerobic glycolysis, diminished oxidative phosphorylation, and augmented synthesis of biosynthetic intermediates. To accommodate the heightened requirements associated with these metabolic transformations, cancer cells upregulate the expression of enzymes responsible for catalyzing these metabolic modifications, along with plasma membrane transporters that facilitate the uptake and transport of vital nutrients (Kalyanaraman 2017).

Cancer cells implement modifications in metabolic pathways to promote the production of vital nutrients and enzymes crucial for their ongoing growth and survival. These metabolic adjustments involve procedures like aerobic glycolysis, where cancer cells prioritize the utilization of glycolysis even when oxygen is available, resulting in elevated lactate synthesis. Moreover, there is a decline in oxidative phosphorylation, which leads to diminished energy generation via the mitochondrial electron transport chain (Schiliro and Firestein 2021).

An additional characteristic of the metabolism of cancer cells is the increased synthesis of biosynthetic intermediates. This includes a rise in the production of the amino acids, lipids, and nucleotides necessary for the creation of membranes, the replication of DNA, and the synthesis of proteins, respectively. Together, these metabolic changes promote the quick division and development of cancer cells (Martínez-Reyes and Chandel 2021).

Cancer cells upregulate the production of the enzymes needed to catalyze these metabolic processes in order to meet the increased needs associated with them. Hexokinase 2 (HK2), for instance, is frequently overexpressed in cancer cells to promote glycolysis. Similar to this, transporters such as GLUT1 make it easier to absorb glucose, and monocarboxylate transporters (MCTs) help to export the lactate created during glycolysis (Elia and Haigis 2021).

These metabolic changes are essential for the development of cancer. In addition to giving cancer cells a quick source of energy, increased glycolysis also causes lactate to build up, which can provide an acidic microenvironment that encourages tumor spread and immune evasion. Furthermore, altered lipid and nucleotide synthesis pathways provide evidence for the increased demands for membrane synthesis and DNA replication seen in cancer cells that divide quickly (Hsu and Sabatini 2008).

Understanding the metabolic modifications made by cancer cells has important therapeutic ramifications. As a fresh approach to cancer treatment, researchers are actively investigating methods to disrupt these metabolic advantages. For instance, inhibitors aimed at important enzymes like hexokinase 2 (HK2) and transporters like GLUT1 seek to obstruct glucose absorption and glycolysis, hence limiting the availability of energy and metabolic intermediates and inhibiting the proliferation of cancer cells (Elia and Haigis 2021). These promising therapeutic modalities are now being investigated in preclinical and clinical settings.

It’s crucial to understand that tumor dysregulated metabolism does not function independently. It interacts with other characteristics of cancer, including DNA repair, immune evasion, and angiogenesis. For instance, enhanced glycolysis can encourage angiogenesis by supplying endothelial cell migration and proliferation with energy and metabolic intermediates (Semenza 2003). Creating comprehensive cancer therapy requires an understanding of these linkages.

In the last few years, there have been tremendous improvements in our knowledge of cancer metabolism, including the discovery of brand-new metabolic targets and the creation of ground-breaking treatments. The discipline is still being shaped by promising research on the use of metabolic inhibitors, immunotherapies, and combination medicines (Cantor and Sabatini 2012).

It is crucial to comprehend these metabolic modifications made by cancer cells because they have consequences for both understanding the biology of cancer and developing effective treatments. For the development of innovative anticancer therapies, targeting certain enzymes and transporters involved in these metabolic pathways is a current field of research. For example, inhibitors of HK2 or GLUT1 attempt to disrupt the metabolic advantage of cancer cells and prevent their proliferation (Kalyanaraman 2017).

By encouraging the synthesis of anti-apoptotic proteins and blocking or evading apoptosis through a variety of methods, cancer cells frequently display resistance to apoptosis, the normal process of programmed cell death. Changes to critical genes’ activity and crucial pathways may be involved in this resistance.

Although there are numerous ways for cancer cells to prevent apoptosis, one noteworthy pathway entails the alteration of the p53 tumor suppressor gene and the overexpression of antiapoptotic regulators including Bcl-2 and Bcl-xL. Additionally, they upregulate proapoptotic proteins like Bax, Bim, and Puma, downregulate survival signals like Igf1/2, and block signals in the extrinsic ligand-induced death pathway (Hanahan and Weinberg 2011).

Anti-growth signaling pathways can be disregarded by cancer cells, allowing for unchecked expansion. TP53 and RB1 are two examples of tumor suppressor genes that are crucial for controlling cell growth and avoiding unchecked proliferation. These genes’ normal function is disrupted by mutations or changes, allowing cancer cells to avoid anti-growth signals (Levine and Oren 2009).

Growth factor receptors or their production are frequently overexpressed in cancer cells. Due to this dysregulation, growth factor signaling pathways such as the PI3K/Akt and MAPK/ERK pathways are constantly stimulated, resulting in prolonged cell proliferation (Sliwkowski 2001).

According to research, garlic and its bioactive ingredients influence a number of these signaling pathways, which helps to reduce the growth and multiplication of cancer cells:

• diallyl trisulfide (DATS): Growth inhibition results from the diallyl trisulfide (DATS) treatment’s enhancement of p53 translocation into the nucleus via ROS (Jiang et al. 2017). It stimulates the SAPK/JNK and p38 pathways while inhibiting the stress-activated protein kinase extracellular signal-regulated kinase (ERK)/MAPK pathway. Additionally, it stops colorectal tumor growth by activating the NF-B signaling system (Saud et al. 2016). Aside from that, DADS inhibits Cdk1 activity during G2-M cell-cycle arrest, which is connected to a temporal rise in cyclin B1 protein levels, a decline in Cdk1-cyclin B1 complex formation, Cdk1 inactivation through hyperphosphorylation, and a drop in Cdc25C protein levels (Knowles and Milner 2000).
• S-allyl mercaptocysteine (SAMC): increases p53 and p21 expression and limits the development of breast cancer cells by causing apoptosis and G0/G1 phase cell cycle arrest (Zhang et al. 2014).
• Se-methyl-L-selenocysteine (MseC): a garlic organoselenium compound reduces the growth of colo205 cells by regulating the levels of the proteins ERK1/2 and PI3K/Akt and elevating the levels of p38 and JNK (Tung et al. 2015).
• Allicin: reduces the expression of heme oxygenase 1 and nuclear factor erythroid 2-related factor 2 (Nrf2), which inhibits the proliferation of cervical squamous cell carcinoma cells (SiHa). Additionally, it blocks the PI3K/Akt signaling pathway (phosphoinositide 3-kinase/protein kinase B)(Zhang and Yang 2019). In Hep 3B (p53 mutation) cell lines, allicin induces apoptosis through p53-mediated autophagy activation (Chu et al. 2013).
• Z-ajoene: By reducing the levels of catenin, c-Myc, and cyclin D1 expression in SW480 cells, another sulfur-containing component of garlic reduces the proliferation of colon cancer cells. Additionally, it raises catenin’s level of Ser45 phosphorylation, which affects casein kinase 1 (CK1) activity and blocks the Wnt/-catenin signaling pathway (Li et al. 2020).

These studies demonstrate the potential of garlic and its components in balancing proliferative and anti-growth signals in signaling pathways, ultimately suppressing the growth and proliferation of cancer cells. The influence of garlic on these pathways offers a promising direction for additional study and the creation of brand-new cancer therapies.

The creation of treatments that support the efficient destruction of cancer cells through apoptosis has been a cornerstone and objective of clinical oncology for more than three decades. The members of the Bcl-2 family are essential for controlling apoptosis. Cancer cells may have imbalances in the expression or activity of Bcl-2 family members that are pro- and anti-apoptotic, which can disturb the apoptotic equilibrium and encourage cell survival (Strasser et al. 2011).

Caspases are a prime example of a crucial apoptotic signaling pathway component that can become mutated or altered, preventing cancer cells from going through with cell death (Fulda and Debatin 2006). The diverse intracellular second messengers known as calcium ions (Ca2+) control a variety of intricate cellular processes, including cell death.

Ca2+/calpain activation happens, for instance, when chemicals derived from garlic, such as DAS, DADS, and DATS, cause apoptosis in glioblastoma and neuroblastoma cells. The release of pro-apoptotic molecules like cytochrome c and Apaf-1, which activate caspase-9 and then caspase-3 and ultimately lead to apoptosis, are all triggered by an increase in the concentration of Ca2+ in the mitochondria ([Ca2+] mit). Thus, caspase-dependent apoptosis takes place (Das et al. 2007; Nakagawa et al. 2020).

Additionally, chemicals derived from garlic have proven to be effective at triggering apoptosis. For instance, DADS reduced proliferation by triggering apoptosis through an intrinsic signaling mechanism linked to upregulated expression of Bax, Bad, caspase-3, and caspase-9 and downregulated expression of Bcl-2 (Talluri et al. 2017). By influencing NF-B, Thiacremonon decreased the expression of the anti-apoptotic proteins Bcl-2, cIAP1/2, XIAP, and the cell cycle-regulating gene cyclin D1, while increasing the expression of the apoptotic regulatory proteins Bax, cleaved caspases 3, and cleaved PARP (Ban et al. 2007).

Additionally, combination therapy using allicin and 5-fluorouracil (5-FU), two substances derived from garlic, have demonstrated encouraging anticancer efficacy. These therapies shown their potential for improved cancer therapy by increasing ROS levels, lowering mitochondrial membrane potential, activating caspase-3 and PARP, and decreasing Bcl-2 expression (Zou et al. 2016).

Their multimodal approach to treating cancer relies heavily on the facilitation of apoptosis by garlic components. Sustained proliferative signaling and angiogenesis are two additional cancer hallmarks that are closely related to this process. Understanding these links helps to clarify the broad significance of garlic components in the treatment of cancer (Xiao et al. 2003).

Cancer is characterized by replicative immortality, which is the unchecked capacity for cancer cells to divide endlessly. Due to the Hayflick limit, which restricts the number of times they may divide, normal human cells have a short lifespan. Cancerous cells can, however, get beyond this restriction and continue to multiply unabatedly. The preservation of telomeres, which are protective caps at the ends of chromosomes, is largely responsible for this ability. With each cell division, telomeres naturally shorten, which finally causes cellular senescence or death. Cancer cells turn on processes that either retain or lengthen their telomeres to combat this. This characteristic significantly contributes to the unchecked growth of malignancies and their ability to metastasize (Hanahan and Weinberg 2011).

According to research, garlic and its bioactive components may help fight cancer cells’ ability to replicate indefinitely. It has been discovered that garlic extracts, such as diallyl trisulfide (DATS), affect telomerase activity. Telomerase is an enzyme that increases the length of telomeres by attaching repeating DNA sequences to the ends of chromosomes. A potential method to reduce cancer cells’ capacity for replicative immortality is to inhibit the activity of the enzyme telomerase (Zeng et al. 2012).

Garlic components have also been related to the control of several pathways involved in replicative immortality. For example, some research indicates that garlic may affect the expression of crucial genes involved in telomere maintenance (Mármol et al. 2017).

Research on garlic’s impact on replicative immortality is ongoing, and while the precise mechanisms are not yet fully understood, it provides encouraging insights into the potential of garlic to combat this characteristic of cancer. To develop tailored therapeutics using this knowledge, more research is required to better understand how garlic components affect replicative immortality.

One of the main characteristics of cancer is tumor dysregulated metabolism, in which cancer cells alter metabolic pathways to create the nutrients and enzymes necessary for their unabated proliferation and survival. Changes in procedures like aerobic glycolysis, the Krebs cycle, and oxidative phosphorylation are examples of this characteristic (Kalyanaraman 2017). Dialyl disulfide (DADS), one of the bioactive components of garlic, has been researched for its potential to inhibit aerobic glycolysis in cancer cells. Research on DADS-treated MGC-803 human gastric cancer cells produced several interesting findings. The therapy reduced lactate production, upregulated AMP-activated protein kinase alpha1 (AMPK) expression and increased the amount of glucose in the medium. Since AMPK1 is frequently overexpressed in many cancer cells, inhibiting it causes apoptosis, which makes DADS a possible choice for addressing abnormal glucose metabolism in cancer cells (Zhang et al. 2020).

Additionally, the effects of DADS on the glucose metabolism of breast cancer stem cells (BCSCs) have been investigated. It was shown that DADS preferentially targets pyruvate kinase isoform M2 (PKM2), a crucial enzyme involved in glycolysis, to block glucose metabolism in BCSCs. This inhibition demonstrates the ability of garlic components to interfere with the metabolic processes of cancer cells (Zhang et al. 2020).

The effects of allicin, a different sulfur-containing component of garlic, on post-translational thiol-modification in human Jurkat T-cells have been studied. Enolase-1 (ENO1), an enzyme in the glycolytic pathway that changes 2-phosphoglycerate into phosphoenolpyruvate, was S-thioallylated by allicin. Enolase activity was reduced as a result of this change, suggesting that allicin, a chemical found in garlic, may interfere with important enzymes involved in the metabolism of cancer cells (Martin C. H. Gruhlke et al. 2019).

Research is currently being done to determine the precise processes by which garlic components interfere with cancer cell proliferation and dysregulated metabolism in tumors. However, a few proposed pathways and ways that garlic compounds might function include as follows:

• Key enzyme inhibition: It has been demonstrated that chemicals in garlic, such as diallyl disulfide (DADS) and allicin, inhibit the activity of important enzymes in metabolic pathways. For instance, AMP-activated protein kinase alpha1 (AMPK1), which is involved in glycolysis, has been discovered to be inhibited by DADS. Garlic chemicals can interfere with the metabolic processes that cancer cells rely on to produce energy by blocking these enzymes (Song et al. 2021).
• Changes in glucose metabolism: According to certain research, garlic components may influence how cancer cells use glucose. For instance, it has been demonstrated that DADS increases the medium’s glucose concentration while reducing lactate generation. The Warburg effect, a metabolic change frequently seen in cancer cells that depend on glycolysis for energy production, is interfered with by this change in glucose metabolism (Liberti and Locasale 2016).
• Targeting cancer stem cells: The effects of garlic components, such as DADS, on cancer stem cells have also been studied. These cells frequently play a role in the development and upkeep of tumors. DADS has been reported to block pyruvate kinase isoform M2 (PKM2), which in turn prevents glucose metabolism in breast cancer stem cells. Garlic chemicals have the ability to slow tumor development and progression by interfering with the metabolic processes in cancer stem cells (Mitra et al. 2022).
• Modification of enzyme activity: Allicin, another component of garlic, has been found to alter the activity of glycolysis-related enzymes. Enolase-1 (ENO1) was specifically S-thioallylated by allicin, which reduced the enzyme’s activity. The ability of the cancer cell to efficiently digest glucose is compromised by this interference with crucial glycolysis enzymes (M. C. H. Gruhlke et al. 2019).

Reduction of Survival Signals: Garlic chemicals may also block insulin-like growth factor 1 and 2 (Igf1/2), which are survival signals in cancer cells. Garlic components can encourage apoptosis (programmed cell death) and prevent unchecked cell development by decreasing these signals (Chen et al. 2017).

Rudolf Virchow made the first allusion to a potential link between inflammation and tumor in the 19^th century after observing inflammatory mediators (leukocytes) in the tumor microenvironment (Coussens and Werb 2002). Before or after tumor initiation, inflammation can take place in the tumor microenvironment. Inflammation supports all stages of tumor growth and aids in the development of cancer in tumor-promoting inflammation. Early stages of tumor formation may see the effects of inflammation, or later phases such as metastasis or late stages may not see any effects (Greten and Grivennikov 2019).

DNA damage is one possible factor that connects cancer and inflammation. Numerous mechanisms, including DNA repair and tolerance pathways, cell cycle arrest mechanisms, as well as intra- and extracellular signaling pathways, may mediate the relationship between DNA damage and inflammation. DNA repair and the response to oxidative stress are highly coordinated in healthy cells. DNA repair mechanisms are crucial for cellular survival because they prevent mutations by repairing DNA damage (Kay et al. 2019).

Tumorigenesis, proliferation, and migration may be influenced by factors that interfere with these systems by preventing repair or initiating the damage. Oxygen and nitrogen species (RONS) are produced during inflammation to combat infections and support tissue repair. On the other hand, these organisms have the ability to interact with DNA bases, damage them, interfere with repair processes, and reduce the efficiency of those processes. Nitric oxide has a function in repair disruption as it has the potential to disrupt DNA repair processes and result in mistakes (Kay et al. 2019).

Additionally, some cytokines, such as IL-22, activate the DNA damage response (DDR) gene to reduce genotoxicity, which is a contributing factor in inflammation (Gronke et al. 2019). Since inflammation and the development of tumors are strongly correlated, inflammation is being examined as a potential target for improving anti-cancer treatment (Zhao et al. 2021).

A study comparing the chemoprotective properties of spirulina and garlic against hepatocellular cancer was carried out in 2022 on male rats. This study demonstrated that garlic has a hepatoprotective effect due to its antioxidant activity, as it caused a significant decrease in the activity of malondialdehyde (MDA), an oxidative stress marker, compared to that in the HCC group, and as it sequenced elevated levels of superoxide dismutase (SOD) and catalase (CAT)(Zhao et al. 2021).

SOD catalyzes the disproportionation of two superoxide species to yield H₂O and O₂, and CAT enhances the conversion of H₂O₂ to H₂O by assisting antioxidant enzymes (Vásquez-Garzón et al. 2009). Garlic’s ability to reduce the expression of genes linked to cancer growth and inflammation is the second component that contributes to its hepatoprotective effects. According to their findings, garlic has the ability to reduce the production of the genes for TGF-1, nitric oxide synthase, tumor necrosis factor, and interleukin-6 (Abouzed et al. 2022).

Another study examined the effects of the organic sulfides contained in garlic—DADS, DATS, and DTS—on the gene expression profiling of human hepatocellular carcinoma cells (HepG2), which are cells that produce liver tumors. This study found that DTS decreased the expression of pro-inflammatory cytokines in macrophages, and among 33 inflammatory markers, IL-1, IL-2, IL-6, IL-12, TNF-, and Eotaxin were six that underwent significant alteration. We may argue that garlic administration may be helpful in controlling liver cell cancer based on the two studies stated above and the evidence that shows the majority of HCC cases are caused by liver inflammation (Lv et al. 2021). A randomized study on breast cancer-bearing female mice was carried out in 2022 to demonstrate the effects of garlic consumption and endurance training on the levels of pro- and anti-inflammatory cytokines in the serum. The results showed that eight weeks of garlic administration and endurance training decreased serum levels of IL-6, IL-8, and IL-17, increased levels of IL-10, and inhibited NF-B, which prevented the transcription of the genes for TNF-, IL-12, IL-8, IL-6, IL-1B, and IL-17 cytokines, which are essential pro-inflammatory mediators. The effect of allicin, a garlic extract, on glioblastoma multiforme (GBM) with human cytomegalovirus (HCMV) infection was demonstrated in a separate investigation. The release of IL-6 and IFN- was found to have significantly decreased. They recommend allicin as a cutting-edge treatment option for GBM (Enayatjazi et al. 2022).

Garlic and its bioactive components, such as allicin and diallyl trisulfide (DATS), work through complex pathways to reduce inflammation. For instance, allicin can prevent nuclear factor-kappa B (NF-B), a crucial regulator of inflammatory reactions, from becoming activated. Allicin dampens the entire inflammatory cascade by inhibiting NF-B activation, which in turn decreases the expression of pro-inflammatory cytokines, chemokines, and adhesion molecules (Shang et al. 2019).

DATS, a different component of garlic, affects mitogen-activated protein kinases (MAPKs) like p38, JNK, and ERK1/2 to target inflammatory mediators. This interference disrupts the inflammatory signaling pathways and prevents the generation of inflammatory cytokines (You et al. 2013).

The anti-inflammatory effects of garlic have significant clinical significance, particularly when it comes to cancer. Tumor genesis and progression are intimately linked to inflammation. Garlic may affect cancer formation, progression, and therapeutic response by reducing inflammation. The use of garlic or garlic supplements in cancer treatment plans to control the inflammatory tumor microenvironment is gaining popularity (Schäfer and Kaschula 2014).

According to Adair and Montani (2010), angiogenisis is a difficult process that creates new blood vessels from preexisting ones in order to provide the tissues with enough oxygen and blood (Adair and Montani 2010). It is regarded as an essential mechanism for the development and spread of tumors (Carmeliet and Jain 2011). Additionally, because it serves as a pathway for metastatic cells to travel to other organs, neovascularization is a necessary condition for the spread of cancer cells (Aventurado et al. 2020). Tumors can only grow to a maximum size of 1–2 mm without being stimulated to generate new blood vessels, and they are unable to metastasize (Dijkgraaf and Boerman 2009).

One important regulator of this biological process is VEGF.

Angiogenesis takes an appealing emphasis in cancer therapy because of its critical role in tumor growth (Yang et al. 2020). Veterini et al. found that allicin, a chemical found in garlic, had anti-angiogenic properties through their computer investigation. This is explained by its capacity to inhibit breast cancer cells’ production of vascular endothelial growth factor receptor-2 (VEGFR-2)(Veterini et al. 2021). Additionally, through preventing VEGF and subsequently angiogenesis, the combination of garlic and lemon aqueous extracts had a suppressive effect on EMT6/P breast cancer cells in BALB/c mice (Talib 2017).

In a 2015 in vivo investigation, it was found that Diallyl trisulfide, a component of garlic, inhibits the migration, invasion, and angiogenesis of human colon cancer HT-29 cells as well as the formation of mice xenograft tumors. DATS was found to dramatically reduce VEGF in HT29 cells and human umbilical vein endothelial cells (HUVEC) in this study. Which suggests that VEGF is crucial to DATS’s anti-angiogenic impact. Additionally, the chorioallantois membrane (CAM) tests showed that DATS decreased the number of blood vessels and hindered tubule formation in HUVEC. Additionally, it was shown that HT-29 cell tumor xenografts had far less blood vessels than normal, which explains how DATS’s ability to block angiogenesis may have contributed to the reduction in proliferation. They came to the conclusion that DATS is a strong angiogenesis inhibitor and is thought to have promise for the treatment of human colon cancer and other conditions dependent on angiogenesis (Lai et al. 2015).

Organosulfur compounds found in garlic, especially diallyl disulfide (DADS), are the main compounds responsible for its carcinogenic activity. The exact molecular mechanism of cell migration inhibition is not completely understood yet. The inhibition of metalloproteinases expression in the extracellular matrix is supposed to be a mechanism of cell migration inhibition (Lin et al. 2002), the down-regulation of the expression of PI3K, Ras, MEKK3, MKK7, ERK1/2, JNK1/2, and p38, are thought to inhibit the expression of MMP-2, -7, and -9 which are involved in the metastasis and invasion of cancer. In addition, the inhibition of proteins found in tight junctions can be a way of cell motility and invasion inhibition.

The DADS compounds found in garlic can lower the levels of claudin proteins which are an important elements in tight junctions responsible for paracellular transport, this lowering can increase the tightness of junctions that inhibit motility and invasion (Shin et al. 2010). The up-regulation of transcription factor 3 (ATF3) mRNA is thought to have a role in metastasis inhibition, where it can induce genes responsible for some proteins like maspin and plasminogen activator inhibitor (PAI-1), and repress genes responsible for metastatic elements like metastasis-associated protein MTA-1 and b-catenin(Bottone Jr et al. 2005).

Figure 2. 

Angiogenesis processes and garlic compound interference (created by: BioRender.com). Fig. 2 provides an overview of the intricate process of angiogenesis within the tumor microenvironment and demonstrates how garlic compounds interfere with this critical pathway. Tumor Microenvironment: On the left, the tumor microenvironment is depicted as the origin of angiogenesis.

Diallyl trisulfide (DATS) compounds also have an inhibitory effect of metastasis through modulation of MMP9 and E-cadherin protein expressions. DATS showed an increment in E-cadherin expression level and a decrement in MMP-9 expression level, which will modulate the cell migration.(Jiang et al. 2017)

Allicin was thought to prevent metastasis in MCF-7 (an ER-α positive breast cancer cell line) through altering the function of vascular cell adhesion molecule-1 (VCAM-1), that has an important role in cell migration and metastasis. Allicin has inhibited TNF-α-induced VCAM-1 protein expression and the suggested mechanism is that allicin strongly suppressed TNF-α-induced activation of ERK½ and NF-κB signaling pathways(Lee et al. 2015).

Angiogenesis Pathway: A branching pathway illustrates the sequential steps in angiogenesis. It starts with the release of angiogenic factors from cells within the tumor microenvironment. These factors trigger endothelial cell activation, leading to the formation of new blood vessels, a process facilitated by VEGF.

Garlic Compound Interference: Running alongside the angiogenesis pathway, garlic compounds intervene in the process. They disrupt angiogenesis at various stages, ultimately inhibiting the formation of new blood vessels.

Inhibition of Angiogenesis: Garlic compounds interfere with the angiogenesis process, making it a potential therapeutic approach to hinder tumor growth and metastasis.

Tumor cells use a variety of techniques to elude immune monitoring, which might hinder the body’s built-in cancer protection. These evasion strategies involve modifying immune checkpoint pathways, producing immunosuppressive cells, and preventing the invasion of essential immune components (Talib et al. 2022).

• Cancer cells’ immunosuppressive mechanisms

Cancer cells use a variety of strategies to evade the immune system’s close attention. These tactics involve modifying immunological checkpoint pathways, creating immunosuppressive cells, and weakening the immune components required for a successful antitumor response. For instance, cancer cells might hinder essential immune cells from penetrating the tumor microenvironment, which would decrease the immune system’s capacity to identify and eradicate cancerous cells (Talib et al. 2022).

• The Immunomodulatory Potential of Garlic

Numerous studies demonstrating garlic’s capacity to elicit immunological responses have established its immunomodulatory potential. It increases the production of cytokines including interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) as well as T-lymphocyte blastogenesis, natural killer (NK) cells, dendritic cell activity, phagocytosis, and cytokines like tumor necrosis factor-alpha and interferon-gamma. According to Venkatesh (2018), the organosulfur compounds, immunomodulatory proteins (mainly lectins), other water-soluble fructans, and fructosyl arginine present in garlic are responsible for these immunomodulatory effects (Venkatesh 2018).

• Impact on T-Lymphocytes and Infiltration

Garlic is effective at increasing the infiltration of T-lymphocytes into the tumor microenvironment, with a focus on CD8+ cytolytic T-cells, according to studies (Ebrahimi et al. 2013). The increased presence of these CD8+ cells within tumors has a promising immunomodulatory effect as they play a crucial role in tumor rejection. Additionally, altering the CD4/CD8 ratio can be a successful immunomodulatory approach for malignancies (Hilders et al. 1994).

• Stimulation of IFN-γ Production

Garlic’s immunomodulatory effects include a notable rise in splenocyte IFN- production in addition to boosting lymphocyte infiltration (Tabari and Ebrahimpour 2014). IFN- is an important cytokine that is involved in immune responses and has been linked to anticancer properties. Garlic may have an anticancer effect via increasing IFN- production, which can counteract immune system dysfunction and tumor resistance.

T-cell levels reduce during tumor progression, which assures that these cells contribute to tumor rejection, studies showed that the presence of T-helper (CD4+) and cytolytic (CD8+) cells are required for tumor rejection. Lymphocytes that migrate into the tumor site (tumor infiltrating lymphocytes) represent an enriched group of cells having a specific effect to the tumor (Hilders et al. 1994).Then, any treatment that can modulate the infiltrating T-lymphocytes, as well as the CD4/CD8 ratio assumed to be a good immunomodulatory agents in tumors.

As a result, garlic is a good candidate for preventing tumor-associated immune evasion due to its immunomodulatory effects. It has the potential to improve the results of cancer therapy and strengthen the immune response against cancer due to its capacity to increase lymphocyte infiltration and activate IFN-production.

A traditional food and medicine for millennia, garlic presents a potential approach to the treatment of several cancers. Garlic’s varied role in cancer prevention has been thoroughly examined, indicating its potential as a potent anticancer agent.

Phytoconstituents with anti-cancer properties: Among the many phytochemicals found in garlic, allicin, SAC, SAMC, DAS, DADS, and DATS have all shown significant anti-cancer effects in a variety of cancer models. Their mechanisms of action include angiogenic pathway modulation, cell cycle arrest, and induction of cancer cell death.

Breast and colon cancer prevention: By preventing angiogenesis and inflammation, garlic shows noteworthy effectiveness in the treatment of breast and colon cancer. Garlic chemicals interfere with the mechanisms that promote cancer progression by blocking VEGF and important inflammatory mediators. Garlic components also control proteins involved in cell motility, tight junctions, and transcription factors, which reduce metastasis and cell migration. Garlic also increases CD8+ lymphocyte intra-tumor infiltration and stimulates splenic IFN- production, which reduces its potential for tumor immune evasion.

Replicative immortality is prevented: The ability of garlic to suppress telomerase and cyclin-dependent kinases (CDKs) has been demonstrated. Garlic is an attractive possibility for obstructing this essential characteristic of cancer because these enzymes play critical roles in the replicative immortality of cancer cells.

Molecular protection and metabolic dysregulation: Compounds produced from garlic have been found to be powerful regulators of the metabolism of cancer cells. Garlic also has Genoprotective qualities since it reduces DNA damage brought on by genotoxic substances. Garlic demonstrates its capacity to repair DNA damage when combined with vitamin E.

Changing important genes and signaling networks: The anticancer effects of garlic and its active metabolites are mediated through modulation of multiple genes and existing signaling networks. These include the Wnt/-catenin signaling network, the JNK signaling pathway, the PI3K/Akt and p38 MAPK signaling pathways, the Chk1/CDC25C/cyclin B1 signaling pathway, p53-mediated autophagy, the ERK signaling pathway, the NF-B signaling pathway, and the NF-B signaling pathway.

In conclusion, garlic’s diverse range of cancer-management potential makes it an important natural resource in the fight against cancer. It holds significant promise for improved cancer treatment tactics thanks to its variety of modes of action, making it a promising choice for future study and therapeutic development.