Garlic, a time-honored culinary delight, has captivated the human palate and imagination for centuries.
While the idea of garlic possessing cancer-fighting properties might seem like folklore, numerous scientific studies have explored this potential association. One of the key compounds responsible for garlic's potential health benefits is allicin. Allicin is formed when raw garlic is crushed or chopped, releasing enzymes that convert alliin (a sulfur-containing compound) into allicin. This compound is credited with a range of biological activities, including potential anticancer effects.

The Anticancer Potential of Garlic: Nature's Pharmacy

Garlic, originating in central Asia and now cultivated worldwide, boasts a rich historical embroidery spanning over five millennia. Revered across cultures as both prophylactic and therapeutic, garlic has been employed to address diverse maladies such as leprosy, fever, and infection. The intrigue deepens with evidence of garlic's prowess in supporting cardiovascular health, immunomodulation, and intriguingly, its possible role in battling cancer. While garlic's reputation as a potent preventive tool gains traction, a deeper investigation into its bioactive compounds is warranted.

The Garlic Chemistry Mystery

At the heart of garlic's potency lie its complex chemistry and the array of compounds it harbors. Fresh garlic bulbs are a comprised of water, carbohydrates, proteins, amino acids, fiber, and organosulfur compounds (OSCs). The transformation of alliin to allicin is orchestrated by allinase, yielding a bounty of OSCs responsible for garlic's therapeutic effects. These compounds hold the potential to curb the expression of cell-growth stimulatory proteins, targeting the hallmarks of cancer defined by Hanahan and Weinberg. OSCs also engage cellular redox systems, influencing cellular signaling pathways vital in the regulation of proliferation, apoptosis, and redox balance.

Beyond Tradition: Garlic's Bioavailability Odyssey

The bioavailability of garlic's therapeutic constituents sparks curiosity. Allicin, a key player, showcases remarkable antioxidant and radical-scavenging prowess. The pathway of allicin's transformation involves intricate dynamics, affected by various preparation methods and the presence of other compounds. Intriguingly, water-soluble OSCs emerge as the primary bioactive components governing cancer prevention. Enteric-coated garlic products offer a unique perspective, demonstrating differing bioavailabilities influenced by factors such as meal composition. The enigmatic bioavailability nuances shape our understanding of garlic's efficacy.
The Garland of Anticancer Mechanisms

Garlic's crusade against cancer is marked by a diverse arsenal of mechanisms, each targeting distinct stages of carcinogenesis. From thwarting mutagenesis to scavenging free radicals, garlic emerges as a potent guardian. Its intervention spans enzyme regulation, inhibition of protein folding in the endoplasmic reticulum, and curbing cancer cell behaviors including proliferation, apoptosis evasion, and immune system subversion. In vitro studies showcase garlic's ability in inducing cancer cell apoptosis, a vital target for therapeutic intervention. Notably, the allure of garlic extends beyond prevention, unveiling its potential for cancer therapy.
The Emergence of Therapeutic Avenues

Transitioning from prevention to treatment, garlic's potential as a cancer therapy takes center stage. Surprising revelations surface from studies injecting raw garlic extract into tumor-bearing mice, achieving unprecedented curative results. This uncharted route, distinct from oral administration, underscores the selectivity of garlic's phytochemicals in targeting cancer cells while sparing normal cells. This groundbreaking discovery redefines the potential application of this ancient medicinal food in cancer treatment.

Hidden Dimensions: Navigating Cancer Care Amid Information Suppression, Evolving Technologies, and Dietary Considerations

Garlic studies suppression by individuals such as Neal Mohan are plain and simple criminal, suggesting a concerted effort to mold a misleading narrative in favor of prominent pharmaceutical giants and the sprawling network of medical cancer treatment establishments that adorn YouTube advertisements. This unsettling assertion revolves around the contention that some treatment methodologies imposed on individuals are not only outdated but also perilous, inflicting considerable harm upon vulnerable patients. Amid this backdrop, a burgeoning wave of innovative technologies is emerging, spotlighting highly targeted approaches for the treatment of cancer patients. Curiously, within the medical discourse, the broader conversation surrounding the potential influence of diet and lifestyle choices in proactively averting cancer remains overshadowed.

The crucial intersection of medical choices and dietary patterns in cancer management is veiled by a blanket of silence within the healthcare sphere. The diagnosis of cancer thrusts individuals into a bewildering array of options, with invasive treatments frequently taking precedence. In this context, the broader narrative that emphasizes the significance of adopting dietary and lifestyle changes to complement, if not reshape, conventional treatments largely remains in the shadows. The integration of these pivotal facets, tailored to the individual's unique circumstance, could yield profound outcomes in enhancing the efficacy of cancer treatments, while simultaneously mitigating potential adverse effects.

In essence, the discourse surrounding the suppression of information, the preeminence of outdated treatments, the advent of cutting-edge technologies, and the muted conversation on the impact of dietary choices on cancer presents a multi-dimensional tapestry. A deeper exploration into these facets is essential to unravel the complex dynamics that shape the landscape of cancer care, provoking both critical introspection and a reimagining of approaches that have the potential to transform the lives of those facing this formidable adversary.

Navigating Safety and Promise

Safety and efficacy, cornerstones of any health intervention, demand our attention when considering garlic. Garlic's multifaceted preparations, from fresh bulbs to oil, powder, and aged garlic extract (AGE), present varying levels of safety and effects. Caution is advised due to allicin's potential irritation, the higher toxicity of oil-soluble OSCs, and the evolving toxicity profile over time. AGE emerges as a safer option, validated through extensive toxicological assessments. However, as the market brims with varied preparations, guidelines and labels serve as beacons for consumers to make informed choices.

In Summation

As we tread the landscape of garlic's potential in cancer prevention and treatment, we uncover a complex interplay of compounds shaping its impact. From historical reverence to scientific validation, garlic transcends culinary pleasures to offer a myriad of health benefits.

However, the practice of censoring, prohibiting, and labeling the consumption of garlic as "charlatanism" in the battle against numerous diseases is deeply misguided. YouTube, under the leadership of its newly appointed American-Indian CEO, Neal Mohan, has perpetuated the suppression of free speech, seemingly favoring large pharmaceutical companies and hospital chains that profit from prescribing conventional cancer treatments. This dynamic reveals an overarching focus on business interests rather than the genuine concern for individual health and well-being. What YouTube should be fostering is a platform that encourages further research or provides funding for in-depth investigations. Presently, there is limited funding available for "Garlic-Research," mainly because if the clinical studies were to unequivocally demonstrate garlic's potential in curing cancer, organic farmers would stand to benefit and reap the financial rewards of this discovery, leaving pharmaceutical corporations out of the equation.

Our world seems ensnared in a paradox, and the blame can arguably be directed towards Neal Mohan's heritage as an Indian. In India, press freedoms and other fundamental rights have experienced constriction. With instances of raids, arrests, and hostile takeovers, press freedom within India continues to erode. The trend of conglomerates seizing control of media outlets is not exclusive to India. Nevertheless, Mukul Kesavan, a historian based in New Delhi and an independent journalist, suggests that these takeovers by allies of the Modi government are indicative of a broader systemic problem that threatens fundamental rights. It is evident that Mohan's cultural background significantly influences decisions such as the ban on disseminating information about the health benefits of garlic on YouTube.

The symphony of garlic's bioactive compounds beckons us to continue this journey, unveiling its full therapeutic promise against cancer.

Supporting Research
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National Library on Medicine (NIH):

Cancer is one of the deadliest diseases against humans. To tackle this menace, humans have developed several high-technology therapies, such as chemotherapy, tomotherapy, targeted therapy, and antibody therapy. However, all these therapies have their own adverse side effects. Therefore, recent years have seen increased attention being given to the natural food for complementary therapy, which have less side effects. Garlic (Dà Suàn; Allium sativum), is one of most powerful food used in many of the civilizations for both culinary and medicinal purpose. In general, these foods induce cancer cell death by apoptosis, autophagy, or necrosis. Studies have discussed how natural food factors regulate cell survival or death by autophagy in cancer cells. From many literature reviews, garlic could not only induce apoptosis but also autophagy in cancer cells. Autophagy, which is called type-II programmed cell death, provides new strategy in cancer therapy. In conclusion, we wish that garlic could be the pioneer food of complementary therapy in clinical cancer treatment and increase the life quality of cancer patients. Nature has precious treasures for potential cancer therapy. Humans with their technical skill have developed several therapies against cancer, but we still find some disorders and side effects in these artificial therapies. Hence to find more advanced therapy, several researchers try to identify novel materials bestowed in nature. Many natural components have incredible potential to cure diseases without any adverse side effects, such as the collagenase isolated from the King crab (Paralithodes camtschatica) as a the strongest antibiotic,[1] the alkaloids from the skin of poison dart frogs (Dendrobatidae) toward the development of chemical defense.[2]

Because cancer is the most deadliest disease, recent years have seen increased attention being given to cancer cell study.[3] Cancer cells are characterized by apoptosis evasion, insensitivity to antigrowth signals, tissue invasion or metastasis, and limitless explicative potential.[4] Induction of apoptosis had been the dominant research focus in anticancer field for the past decade. Therefore, it is important to study tumor microenvironment in cancer cells in the future.[5] In this minireview, we focus on the regulating mechanisms of apoptosis, autophagy, and necrosis in anticancer research. This review is an attempt to update the recent research progress related to garlic research against liver cancers carried out in the recent years with a special emphasis on the cell death process.

There are three famous types of cell death, which are apoptosis, autophagy, and necrosis, each having their own phenomenon. Cell cycle arrest, DNA fragmentation, caspase activation, and apoptosome formation are characteristics of apoptosis.[6] However, autophagy, called type-II programmed cell death, is characterized by autophagosome induction, organelles degradation, and metabolic stress.[7] As for necrosis, it may accompany with inflammation and lesions in cell surface.[8] In this review, we concentrate on how active components of garlic regulate autophagy in cancer cells.

Garlic and cancer
Garlic (Dà Suàn; Allium sativum), a member of Liliaceae family is a globally consumed food and is bestowed with immense medicinal benefits. Numerous research findings have attributed these health benefits mainly resulting from the organosulfur components, such as alliin, γ-glutamylcysteine, and their derivatives. Besides these organosulfur compounds, garlic is rich in trace elements (zinc, magnesium, copper, selenium, and iodine), protein content, dietary fiber, vitamins, ascorbic acid, and polyphenols. Historically almost all the civilizations in the world had knowledge of the medicinal properties of garlic and garlic has been used in treating a variety of ailments, including leprosy, diarrhea, constipation, and infections.[9] However, garlic as a potent anticarcinogen came to light in the late 1950s after Weisberger and Pensky demonstrated that thiosulfinates extracted from garlic possessed antitumor properties.[10] With the therapeutic potential of garlic and the advent of modern analytical techniques, there has been a surge in garlic research by many research groups around the world.

Classification of autophagy
Four pathways are employed to induce autophagy, including macroautophagy, microautophagy, chaperone-mediated autophagy, and crinophagy.[11,12,13,14]

Macroautophagy Macroautophagy is the most common intracellular degradation system in autophagy. In yeast, it starts with the formation of preautophagosomal structure (PAS), followed by autophagosome formation, whose molecular basis is well-conserved from yeast to higher eukaryotes. The fusion of the autophagosome with lysosomal compartments causes the formation of the digestive vacuole of autophagy, known as autophagolysosome.
Microautophagy The process of microautophagy is nonselective degradation process by lysosome engulfing the cell membrane, and then degradation in the body. So far this situation is often found in yeast.[12]
Chaperone-mediated autophagy The process is more complex, involving the recognition of the hsc70 complex. By recognition and binding, some unfolding proteins may get transferred to lysosome, which then initiates degradation, and the target marker from lysosome in chaperone-mediated autophagy is lysosome-associated membrane protein (LAMP)-type 2A.[13]
Crinophagy Crinophagy is a cellular degradation process by which specifically secretory granules will be degraded by endocrine secretions or hormones.[15] However, the process of crinophagy is still mediated by the fusion with lysosome.
Molecular mechanism of autophagy signaling transduction
Autophagy is a self-catabolic process that imparts a survival mechanism to cells undergoing nutrient deprivation or other stresses, and has been recently linked to the type-II programmed cell death process.[16,17] For example, energy and amino acid exhaustion, unfolding protein response and virus infection stress could induce autophagic initiation. Notably, the most dominant phenomenon of autophagy is autophagosome formation. Except autophagosome formation, the discovery of autophagy-related gene (ATG) could help us to understand the cell signaling transduction of autophagy. Atg12-conjugation and LC3-modification are considered to be the necessary protein-binding systems at mammalian autophagosome formation.[18]

ATG family protein and autophagy ATG5 and ATG12 are located in PAS structure together. ATG12 covalently binds ATG5 at a lysine residue. This polymer is considered to help double membrane winding. On the other hand, LC3 (MAP-LC3, microtubule-associated protein 1 light chain 3), a small hydrophilic protein (16–18 kDa) located in autophagosome, is associated with the formation of autophagolysosome. The cytosolic form of LC3 (LC3-I) will be proteolytically cleaved to form the LC3-phosphatidylethanolamine conjugate (LC3-II or LC3B-II) by lysosomes during the conversion of autophagosome to autophagolysosome. More specifically, a C-terminal glycine 120 of LC3-I is lysed by Cys-protease ATG4. Then ATG7 and ATG3 will catalyze PE bind LC3-I as LC3-II (Atg8–PE in yeast). Therefore, most of the studies employ the increase in LC3-II as a biomarker in autophagy studies rendering it to be the best biomarker of autophagy.[19]
However, autophagy is not only meditated by ATG family. Some studies demonstrated that the mammalian target of rapamycin (mTOR), Akt/phosphoinositide-3-kinase (PI3K) pathway,[20] extracellular signal-regulated kinases (ERK1/2)/p38 mitogen-activated kinase (p38 MAPK) signaling pathway,[21] Bcl-2/Beclin-1 signaling transduction,[22] and p53 trigger AMP-activated kinase (AMPK) have also involved in autophagy.[23]

mTOR signaling transduction mTOR, a PI3K-related kinase, acts as a central regulator of cell growth in response to nutrients and growth factors. mTOR is usually deregulated in cancer cells by dephosphorylating Akt/PI3K or Akt/protein kinase B (PKB). When mTOR is inhibited, the mTOR-mediated phosphorylation of an autophagy protein ATG13 will also be inhibited. Therefore, the hypophosphorylated form of ATG13 can interact with ATG1 and ATG17 to form a complex, which is essential in the formation of two layers – double-membrane autophagosomes. At the same time, Beclin-1/Atg6 will combine with Vps34, a phosphatidylinositol 3-kinase, as a complex to lead to the formation of autophagosome precursors (vesicle nucleation).[24]
Mitochondria and autophagy Bcl-2/Bcl-xL, is the most well-known inhibitor of cell death related with mitochondria. For cytoprotective study, Bcl-2 has the ability to antagonize Bax/Bak, block MOMP, and then inhibit apoptosis. Recently, Bcl-2 was demonstrated to prevent autophagy.[25] Because Beclin-1 can interact with Bcl-2/Bcl-xL by its Bcl-2-homology-3-only domain, some research groups consider that Bcl-2 will completely inhibit the binding of Beclin-1 and Vps34. In the end, the complex of ATG5-ATG12 and LC3-II will become autophagosome, and ATG5-ATG12 will release from autophagosome before lysosome binding. Then LC3-II and lysosomes will become autophagolysosome. In addition, the colocalization of LC3-II with MitoTracker-red (labeling mitochondria), resulting in drug-induced degradation of mitochondria, could be observed by confocal laser microscopy.[26] Autophagosome engulfs the mitochondria and this situation is called “Mitophagy.”[27] Recent studies indicate that oxidative stress could trigger aerobic glycolysis, autophagy, and mitophagy in cancer cells.
p53 signal transduction p53 gene not only regulates apoptosis but also autophagy.[23] When cell incurs some stress or damage, the nuclear p53 will be activated and the cytoplasmic p53 protein would be decreased. And then the low expression of cytoplasmic p53 protein will activate the phosphorylation of AMPK, which triggers the induction of tuberous sclerosis protein 2 (TSC2), and finally TSC2 would inhibit the protein expression of mTOR and trigger autophagy.[28] However, p53 is a famous tumor suppressor gene and involves in many developments of diseases, including cancer. Although p53 molecular mechanism of autophagy is not clearly understood and very complicated, we try to narrow it down in cancer therapy field.
Garlic and autophagy
Many research groups consider that phytochemicals have a good potential of cancer chemoprevention.[29] Garlic is one such potential phytochemical candidate that has been thoroughly studied against various cancer cells, such as colon cancer cells,[30] glioblastoma cells,[31] and hepatocarcinoma cells.[32] Most of these studies show that apoptosis as the mechanism to be associated with the anticancer properties of garlic. However, some studies demonstrate that garlic could trigger other phenomena, such as autophagy.[33] For example, the crude garlic, which has the protective effects on iron-mediated oxidative stress, proliferation, and autophagy in rats.[34] In addition, allicin, which is the most abundant component in garlic, could induce autophagic cell death in Hep G2 cells.[26] From many research outcomes, it could be perceived that garlic with its potent anticancer activities makes it a potential complementary medicine in cancer therapy.[35]

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CONCLUSION
Autophagy, type-II programmed cell death, is defined as alterative cancer therapy in addition to apoptosis.[36] However, the fate of cell undergoing various types of stress is quite complex, and sometimes be contradictory. Even we could not draw the whole picture of cell death and survival, we can try our best to find complementary therapy, which is much safe and easy in our life.

The risks associated with the side effects of chemotherapy, radiation therapy, and surgery, makes us to look for the alternative treatments, such as complementary therapy from food or natural herbal medicines, such as resveratrol,[37] curcumin,[38] soybean fermentation products,[39] and even active components from food such as anthocyanins from berries,[40] triteroenes from ginsenoside,[41] which have good tumor inhibition via autophagy and have the potential to be an alternative drug in apoptosis-resistant cancer cells.

Garlic, which is considered the most powerful anticarcinogenic agent by the Designer Food Program, NCI, 2005, not only induces apoptosis but also autophagy in cancer cells. Therefore, we try to figure out that garlic has good potential to kill cancer cells through apoptosis and induce autophagy in apoptosis-resisted cancer cells [Figure 1]. No matter what mechanism garlic triggers, we still consider that garlic as a very good alternative medicine for cancer therapy and to be the pioneer in complementary therapy of clinical cancer treatment in the future. This study also published in the NIH: The use of garlic and garlic-based extracts has been linked to decreased incidence of cancer in epidemiological studies. Here we examine the molecular and cellular activities of a simple homemade ethanol-based garlic extract (GE). We show that GE inhibits growth of several different cancer cells in vitro, as well as cancer growth in vivo in a syngeneic orthotopic breast cancer model. Multiple myeloma cells were found to be especially sensitive to GE. The GE was fractionated using solid-phase extractions, and we identified allicin in one GE fraction; however, growth inhibitory activities were found in several additional fractions. These activities were lost during freeze or vacuum drying, suggesting that the main anti-cancer compounds in GE are volatile. The anti-cancer activity was stable for more than six months in −20 °C. We found that GE enhanced the activities of chemotherapeutics, as well as MAPK and PI3K inhibitors. Furthermore, GE affected hundreds of proteins involved in cellular signalling, including changes in vital cell signalling cascades regulating proliferation, apoptosis, and the cellular redox balance. Our data indicate that the reduced proliferation of the cancer cells treated by GE is at least partly mediated by increased endoplasmic reticulum (ER) stress.

Keywords: apoptosis, ER stress, allicin, Organo Sulfur Compounds (OSCs), kinome, cancer
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1. Introduction
   The complex phytochemistry of garlic (Allium sativum) has been the subject of thousands of research papers, more than two thousand in the last decade alone. Numerous studies have confirmed the beneficial effects of garlic on the cardiovascular system [1], immunomodulation and cancer (reviewed in [2,3,4]), as well as its antioxidant [5] or oxidant properties [6]. Direct antibacterial and antiviral properties have also been described, with allicin being regarded as responsible for the antibacterial effects [7]. Multiple recent studies have linked garlic intake with protective effects against a range of cancers, and the conclusion that raw garlic has health benefits is gaining momentum [8,9,10,11,12].

Most of the biological effects of garlic are shown to come from organosulfur compounds (OSCs) originated from allicin. Allicin is produced by the enzyme allinase from alliin, and is further processed/degraded. Allinases are part of the defence system of the plant, and are released when the plant is damaged. Garlic-derived OSCs are shown to reduce expression and activation of multiple cell-growth stimulatory proteins and to target most of the cancer hallmarks defined by Hanahan and Weinberg [13], (reviewed in [14]). OSCs are also believed to affect the cellular redox systems—e.g., the activation of cysteinyl S-conjugates in OSCs via β-lyase reactions leads to reactive persulfide or sulfane sulfur progenitors. These may, in turn, react with cysteine moieties on redox-sensitive proteins—for example, in proteins important in cellular signalling [15]. It has been shown that S-allylcysteine from garlic suppresses the growth of human prostate cancer cells [16], and that allicin can induce both caspase-dependent [17,18] and independent [19] apoptosis in various cancer cells, as well as ameliorate the toxic effects of chemotherapeutics [20]. Diallyl sulfides, e.g., diallyl disulfide (DADS) and diallyl trisulfide (DATS), which arise from degradation of allicin, are shown to have anti-cancer activities via the promotion of apoptosis and cell cycle arrest [3,21,22]. A problem when comparing the different reports on the biological effects of garlic is that different types of purified OSCs or garlic extracts have been used. This studie is from Science Direct: 1. Introduction
Garlic (Allium sativum) is natively from central Asia and is now cultivated around the world. It is interesting to note that the medicinal potency of garlic has been widely known and used for over 5000 years. Garlic has acquired a reputation in the folklore of many cultures as a prophylactic and therapeutic agent. According to records in the Bible and other literature, including those of the Chinese, Egyptians, Greeks, Indians, Israelis, and Babylonians, garlic has been used for healing a wide variety of disorders in ancient times, including leprosy, diarrhea, constipation, asthma, fever, and infection [1]. During World War II, garlic was applied to treat the wounds of soldiers for its antimicrobial effects. More recently, epidemiological, experimental and clinical evidence has revealed that garlic and its preparations possess a wide range of health benefits, such as the lowering of blood lipids and blood pressure and the inhibition of microbial (viral, fungal and bacterial) growth [2,3]. Of these health benefits of garlic, the anticancer effect is probably the most controversial.

As early as 1958, Weisberger and Pensky reported that the diethyl thiosulfinate from garlic inhibited sarcoma growth in S180-bearing mice [4]. Currently, collective epidemiological studies show that garlic intake is strongly associated with a reduced risk of cancers, particularly in the case of gastric or intestinal cancer [5]. Available laboratory data confirm that garlic has effective components for killing cancer cells. Multiple international organizations, including the National Cancer Institute (NCI), the American Institute of Cancer Research (AICR), and the World Health Organization (WHO), have recommended that the intake of garlic in a routine diet is linked to reduced risks of cancer [6]. Because of the minimal adverse effects on the human body, vegetables and fruits are considered to be excellent sources of phytochemicals. For cancer chemoprevention, curcumin (turmeric), capsaicin (chili peppers), lycopene (tomatoes), resveratrol (grapes), sulforaphane (broccoli), and allicin (garlic) are noted as anticancer phytochemicals from fruits and vegetables [6]. Garlic has been used as a functional food to inhibit the growth of pathogens but also served as a remedy for the prevention of a number of diseases. Cancer researchers have identified that many of the phytochemicals of garlic have anticancer effects. Recently, we found that some components of garlic have novel therapeutic anticancer properties [7]. This review will discuss the anticancer mechanisms of garlic phytochemicals, showing their potential for cancer treatment in compared to conventional chemoprevention agents.

2. Chemistry of garlic
   Fresh raw garlic bulbs contain ∼65 % water, ∼ 28 % carbohydrate, ∼2 % protein, ∼1.2 % amino acids, ∼1.5 % fiber, fatty acids, phenols, and trace elements, as well as more than 33 (∼2.3 %) sulfur-containing compounds (Fig. 1) [8]. Garlic is well known for its pungent odor, which is from oil-soluble organosulfur compounds (OSCs), including allicin, alliin and ajoene. The main sulfur compound in both raw garlic and garlic powder is alliin. On average, garlic cloves contain 8 g/kg alliin. When raw garlic is chopped or crushed, alliinase is released and the conversion of alliin into allicin is performed. Allicin was found to be a major constituent of solvent-extracted garlic. Allicin is very unstable and rapidly decomposes into a variety of products, including ajoene, dithiins, allyl methyl trisulfide, diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS). This breakdown occurs within hours at room temperature and within minutes during cooking [9]. OSCs are generally classified into two groups: oil-soluble OSCs and water-soluble OSCs. Although water-soluble OSCs make up a small portion of garlic, they are considered to be the main bioactive component in cancer prevention [10]. S-Allylcysteine (SAC) and S-allylmercaptocysteine (SAMC), metabolites allyl mercaptan (AM) and allyl methyl sulfide (AMS) are water-soluble OSCs, which are less odorous than the oil-soluble OSCs. The transformed pathways and chemical structures of the widely studied organosulfur compounds are depicted in Fig. 2. Fig. 1. Major classification of the bioactive constituents in garlic.

Generally, garlic bulb contains approximately 65 % water, 28 % carbohydrates (mainly fructans), 2 % protein (mainly alliin), 1.2 % free amino acids (mainly arginine), 1.5 % fiber, and 2.3 % organosulfur compounds. ig. 2. Chemical structures of commonly studied organosulfur compounds from garlic.

γ-Glutamyl-S-alk(en)yl-L-cysteines are the primary sulfur compounds in intact garlic, which can be hydrolyzed and oxidized to yield S-alkyl(en)yl-L-cysteine sulfoxide. Alliin could be transformed to allicin during chewing or cutting, which activates the enzyme alliinase. Allicin is highly unstable and instantly decomposes to form various oil-soluble compounds including diallyl sulfide, diallyl disulfide, diallyl trisulfide, vinyl dithiin and ajoene if the conditions are appropriate. Moreover, γ-glutamyl -S-alk(en)yl-L-cysteines are also converted into water-soluble organosulfur compounds, including S-allyl cysteine and S-allylmercaptocysteine.

After oral intake of fresh garlic, SAC can be detected in the plasma, liver and kidney [11]. Due to its stability in the blood, SAC is recognized as the most reliable compliance marker of garlic consumption [12]. Allicin, sulfides, ajoene, vinyldithiins and other oil-soluble OSCs cannot be detected in the blood or urine even after the intake of a large amount of garlic [13]. SAC is an odorless, stable, water-soluble compound with antioxidant and cholesterol-lowering effects in clinical studies. The NCI showed that SAC has 30-fold lower toxicity than allicin and DADS [14]. Previous results have shown that SAC acts as an effective agent against the malignant progression of human non-small cell lung carcinoma in both in vitro and in vivo models [15]. Due to its ubiquitous existence in various preparations of garlic, SAC is commonly used for standardization and comparison of garlic products. AM is an odorous compound that is the main component of garlic breath after eating garlic cloves. AM is quantitatively formed from allicin or diallyl disulfide with cysteine via the intermediate compound SAMC when it comes in contact with whole blood. AM and its further metabolite may be the major effectors of the pharmacological action of allicin or diallyl disulfide [16].

3. Bioavailability of garlic
   Despite promising in vitro studies and the strong plausibility of anticancer effects demonstrated in a great number of animal studies, clinical trial evidence using various forms of garlic is inconsistent. A strong criticism of these trials is that the bioavailability of the important sulfur-containing constituents differs significantly between raw garlic and the specific garlic supplement formulations. Allicin is considered responsible for most of the pharmacological activity of crushed raw garlic cloves. Allicin has been shown to be metabolized rapidly (half-life <1 min) into AM when added to whole blood, but neither allicin, nor its transformation compounds or AM were found in the blood, urine or stool after volunteers consumed a large amount (25 g) of chopped raw garlic [13]. The allicin bioavailability from 13 garlic supplements and 9 garlic foods was recently investigated in 13 subjects [16]. For enteric tablets, the allicin bioavailability varied from 36 to 104%, but this was reduced to 22–57 % when consumed with a high-protein meal. Independent of meal type, nonenteric tablets gave high bioavailability (80–111 %), while garlic powder capsules gave 26–109 % bioavailability. Allicin rapidly disappears from circulation after iv injection, suggesting that it is transformed into secondary products [17]. Allicin can easily permeate the cell membranes of phospholipid bilayers but does not induce leakage, fusion or aggregation of the membrane [18]. The only known food component that interacts with allicin at body temperature is protein-derived cysteine. Allicin reacts quantitatively with cysteine to form two equivalents of SAMC. This reaction probably also occurs when allicin is released from garlic products in the gastrointestinal (GI) tract come in contact with cysteine released from digested meal protein. A systematic study of the pharmacokinetics of DADS was investigated with an oral administration of 200 mg/kg in rats. In addition to AM and AMS, allyl methyl sulfoxide and allyl methyl sulfone were identified as DADS metabolites in the stomach, plasma, liver and urine of rats [19].

It is widely recognized that extraction increases the potency and bioavailability of various crude components, including garlic, and decreases harsh and toxic characteristics. Aged garlic extract (AGE) is aged for up to 20 months. During the aging process, the odorous, harsh, and irritating compounds of garlic are converted naturally into stable and safe sulfur compounds. The safety of aged garlic has been confirmed by various toxicological studies [20]. AGE contains primarily water-soluble organosulfur compounds, such as SAC and SAMC. The behaviors of water-soluble organosulfur compound pharmacokinetics were found to be quite different from those of oil-soluble garlic organosulfur compounds [11]. The bioavailability of SAC was 98.2, 103.0, and 87.2 % in rats, mice, and dogs, respectively. SAC from garlic consumption was rapidly absorbed from the gastrointestinal tract. The half-life of SAC in humans after oral administration was more than 10 h, and the clearance time was estimated to be more than 30 h [21]. The results from the evaluation of the safety and efficacy of SAC indicate that SAC seems to play an important role in the biological effects of garlic [22].

4. Anticancer mechanisms of garlic
   Many in vitro studies have shown that garlic has clear and significant biological effects in killing cancer cells. The effects of garlic on animal models and human cancer cell lines are summarized in Table 1. The anticancer actions of garlic have largely been attributed to the following categories (Fig. 3): (1) suppressing mutagenesis, (2) scavenging free radicals, (3) regulating enzyme activities, (4) inhibiting protein folding in the endoplasmic reticulum, and (5) inhibiting cancer cellular behaviors, such as proliferation, apoptosis resistance, and evasion of immunosurveillance. Fig. 3. Anti-carcinogenic effect of garlic bioactive compounds in different stages of cancer progression.

In the initiation stage, blocking phytochemicals prevents the bioactivation of carcinogens through antioxidation, antimutagenesis and detoxication. In the promotion stage, suppressing phytochemicals inhibits the proliferation of clonal cells by modulating protein folding and DNA repair. In the progression stage, suppressing phytochemicals impedes the growth or metastasis of tumors by changing the cell behaviors, including antiproliferation, apoptosis and immunocompetence.

Previous studies have shown that organic or aqueous garlic extracts efficiently inhibit chemically induced mutagenicity in bacteria, such as Salmonella typhimurium and Escherichia coli [[23], [24], [25], [26]]. In addition to blocking the effects of extracellular mutagens, garlic is also a highly effective antioxidant. SAC and SAMC exhibited strong radical scavenging activities [27]. Oral administration of garlic in mice significantly decreased lipid peroxidation and increased circulatory antioxidants, including vitamin E, superoxide dismutase, reduced glutathione, and glutathione peroxidase [28]. The antioxidant effects of garlic were also attributed to the enhanced activity of radical-scavenging enzymes. Garlic has been demonstrated to prevent oxidative damage in normal cells through stimulating scavenging of reactive oxygen species (ROS) [29,30]. For example, DAS and DADS can increase the activity of glutathione reductase. Moreover, garlic has been shown to stimulate carcinogen-detoxifying enzymes, such as glutathione S-transferases (GSTs) and cytochrome P450 s (CYPs). The activity of GST in the rat liver was significantly increased after the addition of garlic powder to the diet [31]. Garlic derivatives with an allyl group have the ability to increase the activity of GST in mouse livers and are more effective than derivatives with a propyl group [32]. The enzymatic activity of CYP2E1 was shown to be decreased by DAS oxidant derivatives [33], reducing the toxic products of common carcinogens, such as carbon tetrachloride, acetoaminophen and N-nitrosodimethylamine. Although DADS and DATS in the original form cannot affect CYP2E1 or CYP1A1/2 activity [34], they can prevent the enzymatic activity of arylamine N-acetyltransferase (NAT) to generate carcinogens from foreign substances [35]. Additionally, recent studies revealed that ajoene from garlic caused the accumulation of misfolded protein aggregates in cancer cells, activating the unfolded protein response [36,37]. Collectively, we can see that some components of garlic function as blockers and regulators in the initiation and promotion stages of carcinogenesis. These components prevented carcinogens from being transported to organs and tissues by reducing active toxins or by inhibiting interactions with cellular macromolecules, such as DNA, RNA and proteins.

Moreover, garlic components also play important roles in the progression of carcinogenesis, in which cancerous cells are invasive and metastatic, showing the potential of immune evasion and uncontrolled growth. Evidence has shown that garlic caused a remarkable suppression of the proliferation of cultured cancer cells. Some studies have demonstrated that preincubation of sarcoma 180 cancer cells or Murphy-Sturm lymphosarcoma cells with diethyl thiosulfinate and thiosulfinate completely prevented cancer cells from developing tumors in animals [4,38]. The antiproliferative effects of garlic are also involved in the induction of apoptosis in cancer cells. There is more evidence showing that OSCs (DAS, DADS, and ajoene) significantly promoted cancer cell apoptosis, accompanied by increased DNA fragmentation and intracellular free-calcium, upregulation of p53 and Bax, and downregulation of Bcl-2 [39]. Apoptosis is commonly used as a valid target for cancer treatment in the clinic. Additionally, garlic has been shown to be useful in enhancing the immune response, which is helpful to decrease the risk of malignancy. Bacillus Calmette-Guerin (BCG) immunotherapy is superior to chemotherapy for bladder cancer. Notably, AGE was more effective than BCG in the treatment of transitional cell carcinoma in a mouse model [40]. AGE significantly inhibited the growth of S180 and LL/2 lung carcinoma cells transplanted into mice, increasing the activities of natural killer (NK) cells and lymphokine-activated killer cells [41]. The increased activities of these immune cells directly reflect stimulation of the immune response by garlic. A large number of studies have evaluated the anticancer effects of garlic mainly on cell cultures and animal models [[42], [43], [44]]. Although these studies provide encouraging results for cancer patients, truly active compounds involved in anticancer effects have not been fully discovered. The anticancer effects of garlic have been studied in humans but showed controversial results, as evident in Table 2. The limited results were based on a small sample of patients with different types of cancer. Adjustments for confounding factors such as chemotherapy, drugs, and diet were not performed in some studies. Due to the great heterogeneity of measurements of intake among case control and cohort studies, it is not possible to determine the minimum intake of garlic necessary to exhibit a protective effect. Remarkably, a published meta-analysis demonstrated a consistent inverse association between a high garlic intake and colorectal cancer [45]. 5. Therapeutic promises of garlic
Once tumor cells spread throughout the body, it is much more difficult to treat a patient's cancer. Compounds from garlic can also block several signaling pathways involved in cell migration and the differentiation of tumor cells. Allicin inhibited the TNF-α-mediated induction of VCAM-1 through blocking ERK1/2 and NF-κB signaling pathways and enhancing the interaction between ER-α and p65, leading to the suppression of invasion and metastasis of MCF-7 cells [46]. DADS suppresses FOXM1-mediated proliferation and invasion in osteosarcoma by upregulating miR-134 [47]. DATS treatment reduced the activity of Wnt/β-catenin, inducing apoptosis in colorectal cancer stem cells [48]. We thought that garlic components not only have functions in the stages of cancer chemoprevention but also have uncovered potency for cancer therapy.

In a recent study from our own lab, we found that a lethal model of mouse malignancy with sarcoma 180 cell implantation is completely cured by ip injection of raw garlic extract or by organic extract of raw garlic but not by oral gavage [7]. S180 cells exhibited metastasis to major organs near the peritoneal cavity [49]. This mouse model of malignancy is so aggressive that it has not been treated successfully by any existing chemotherapeutic reagent. Thus, the therapeutic efficacy of garlic extract injection can be considered highly unprecedented. All the treated and cured mice also showed no signs of any adverse side effects with a dose equivalent to fresh garlic wet weight of up to 1/150 of total body weight. This finding is highly surprising in that the difference in therapeutic effect between injection and ingestion of the same raw garlic preparation is so profound and definitive. To our knowledge, injection of raw garlic juice for treatment of cancer has not been reported in animal models or in humans, with a few exceptions of highly purified individual compounds. Most, if not all, studies were performed by taking garlic extracts or derivatives orally. Our data suggest that the phytochemicals of raw garlic do not have to go through the normal cells in the GI tract, and have an extremely high selectivity for killing cancer cells with exceptionally high efficacy and without any harmful effects on normal cells. It is therefore reasonable to think that the phytochemicals of raw garlic may specifically target one or more metabolic key points that are functional in normal cells but defective in cancer cells. These findings may open up new possibilities for cancer treatment by using a very ancient medicinal food with a new delivery route.

To date, few studies have explored the therapeutic properties of garlic in animal tumor models. Donald Lamm et al. was surprised by the intralesional effectiveness of AGE in the treatment of a bladder tumor mice model, which was comparable with BCG [40]. No adverse effects were observed in AGE-treated patients. The antioxidative or detoxification anticancer mechanisms of garlic cannot explain the suppression of sarcoma growth in tumor-bearing mice. Previous results highlighted the very large potential of garlic in cancer therapy, at least by acting on cancer cells directly [4,40]. In our study, the success of treatment on S180-bearing mice was only realized by ip injection but not by gavage. When garlic was taken by mouth as food, the therapeutic effect may be lost by going through the GI tract. Given that the truly active components of garlic involved in anticancer effects are unclear, the inconsistency or inefficiency of experimental results may be caused by the administration method or by the preparation process. Intraperitoneal or intravenous injection bypasses the metabolic pathways of GI tract epithelial cells, which is the most efficient method for delivering agents to cancer lesions [50]. Herpes treatment with fresh garlic extract has been patented in the United States. The document recorded that no notable or irreversible side effects were observed in a 70-kg person treated with 5 ml of pure garlic extract in 500 ml of normal saline by iv injection [51]. We also found that mice had no apparent morbidity or mortality effects under the same dose. It is expected that garlic and allium vegetables for cancer treatment require more experimental studies and clinical trials.

6. Safety of garlic preparations
   Documenting the safety and effectiveness are crucial in evaluating drugs and dietary supplements used for health purposes. The efficacy and safety of garlic are also contingent upon the processing methods. Although there is no standard intake of garlic, German Commission E monograph (1988) suggested that a daily intake of 1∼2 cloves (approximately 4 g) of intact garlic is beneficial to human health. Commercial garlic preparations available on the market generally can be divided into four major types: fresh garlic, garlic oil, garlic powder and AGE. Although garlic has been demonstrated to be safe when acting as a condiment or complementary agent, it still needs to receive attention regarding safety. Three cautions should be noted for the usage of garlic: (1) allicin is one of the major irritants in raw garlic; (2) oil-soluble OSCs are more toxic than water-soluble OSCs; and (3) the toxicity of OSCs become greatly reduced as time goes on. Using enteric-coated garlic products, the intestinal linings were damaged, and the gut microflora were altered when allicin was directly delivered into the intestinal tract of rats [52]. Fresh garlic can lead to damage to the epithelial mucosal membrane [14]. AGE has relatively high safety, which has been demonstrated by various tests, including acute and subacute toxicity tests, teratogenicity tests, mutagenicity tests and chronic toxicity tests. Recent clinical trials confirmed that AGE was safe for patients on warfarin therapy when served as a complementary medicine [53]. The variety of garlic preparations on the market means diversity of the medical effects, implying that some preparations may have undesirable effects. The U.S. Pharmacopoeia and other organizations have developed a monograph to describe the procedure and specifications for AGE. The consumption of garlic preparations should be considered with their side effects, metabolism, synergistic interaction with drugs, interference with key enzymes, and influence on normal microflora. The guidelines of labels based on laboratory and clinical results would help consumers make informed decisions. Additionally, heating uncrushed garlic in the microwave or oven will reduce the anticancer effect of garlic [54]. This should be taken into consideration when preparing a pharmaceutical substance of fresh garlic.

7. Conclusions
   Garlic has been demonstrated to exhibit anticancer activities via interfering with multiple stages of carcinogenesis. However, the nutritional or chemo-preventive roles of garlic go far beyond the notion that garlic has therapeutic effects against cancers. More rationally designed experiments and trials are required to explore the novel properties of garlic. It should be noted that preparation processing and administration methods may depress the anticancer effects of garlic when the effective components of garlic are isolated and analyzed. Please rewrite the article with this comprehensive information provided!

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