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Anticancer properties

Anticancer properties

Green tea extract and sleep quality Us More Antifancer about contacting us Anticanfer receiving help with the Cancer. Isoquinoline alkaloids hydrastine, berberine, berberastine, candalineresin and lactone. Various natural extracts, obtained from medicinal plants grown in North America, have been found to induce apoptosis pathways at different levels Figure 4 and Table

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Best cancer fighting foods A varied diet rich in Anticancer properties Anticancet may help lower Antkcancer risk or developing cancer Blood sugar regulation decrease cancer growth. This propertiez include fatty Anticancer properties, vegetables, spices, and fruits like Antixancer. What you eat can drastically affect many aspects of your health, including your risk of developing chronic diseases like heart disease, diabetes and cancer. There are also several studies showing that a higher intake of certain foods could be associated with a lower risk of the disease. This article will delve into the research and look at 13 foods that may lower your risk of cancer. Broccoli contains sulforaphane, a plant compound found in cruciferous vegetables that may have potent anticancer properties.

Anticancer properties -

Quercetin decreases cell viability in PATU and PANC-1 pancreatic cancer cell line with the expression of neural cadherin N-cadherin , epithelial cadherin E-cadherin , vimentin, hinders migration and invasion, reverses interleukin 6 IL-6 -induced increase in malignant pancreatic cells by inhibiting the signaling pathway STAT3 The exposure to HUVEC human umbilical vein endothelial cell line and PC-3 human prostate cancer androgen-independent cell line cells to quercetin caused dose-dependent and time-dependent decrease in proliferation.

Further, quercetin inhibited the migration and invasion, angiogenesis, and tumor tissue in xenograft models Similarly, quercetin also reduced proliferation, migration, and invasion, induced apoptosis, and blocked angiogenesis by targeting vascular endothelial growth factor VEGF in Y79 cells human retinoblastoma cell line Apoptosis was induced in HT29 human colon adenocarcinoma cell line and CT26 mouse colon carcinoma cell line after quercetin treatment.

CT26 cells shown activated extracellular signal-regulated kinases ERK , c-Jun N-terminal kinases JNK , and p38 mitogen-activated protein kinases MAPK signaling pathways, inhibit migration and invasion by controlling the expression of E-cadherin, N-cadherin, β-catenin, snail, and in vivo metastasis These studies indicate that quercetin has profound anticancer effects, based on its ability to suppress proliferation, induce apoptosis, trigger cell cycle arrest in numerous cancer cell lines, and can be used as a potent anticancer agent.

Curcumin [1,7-bis 4-hydroxymethoxyphenyl -1,6-heptadiene-3,5-dione] is a hydrophobic polyphenol Figure 3 , bright-yellow, present in the rhizome of Curcuma longa, a perennial herb in the family Zingiberaceae Curcumin belongs to a chemical class of polyphenols has been shown to have therapeutic benefits in several chronic diseases including arthritis, neurodegenerative diseases, metabolic syndrome, liver disease, obesity, inflammation, and in several cancer types Curcumin shown to have significant anti-inflammatory, antioxidant, anticoagulant, antimutagenic, anticarcinogenic, and anti-infective effects.

Curcumin has also demonstrated significant healing properties for wounds 42 , Since then, the scientific interest in the use of curcumin for health benefits has increased. The recent study indicated that curcumin could suppress proliferation significantly and induce apoptosis in HT human colon cancer cell line cells through the mitochondrial cell death pathway.

Curcumin repressed proliferation of SK-OV-3 and A cells human ovarian cancer cell lines , stimulated apoptosis-induced autophagy with many autophagic vesicles and increased expression of Atg3, Beclin, and LC3B-II protein. Curcumin-treated HCT and SW cells human colon cancer cell lines showed growth inhibition followed by autophagy induction with LC3B, P protein regulation, yes-associated protein 1 YAP suppression and can reverse the effect of YAP on colon cancer cells DU cells human prostate cancer cell line exposed to curcumin reported growth inhibition in a dose-dependent manner.

Additionally, curcumin inhibited migration, matrix metalloproteinase MMP-2 expression, then inhibited metastasis in a prostate cancer cell line Likewise, Curcumin-treated D human lung cancer cell line cells suppressed cell growth and can effectively inhibit epidermal growth factor EGF or transforming growth factor TGF-β1 -induced migration, invasion, and the Rac1-dependent signaling pathway.

Curcumin also inhibited cell invasion through MMP-2 and MMP-9 expression in vivo RN5 cells murine malignant mesothelioma cell line exposed to curcumin cause growth inhibition in a concentration-dependent manner.

Further, it decreases tumor growth in vivo , and then angiogenesis was confirmed by immunostaining On the other hand, NCI-H and NCI human lung cancer cell lines treated with curcumin exhibited cell proliferation. Curcumin also inhibited the expression of MMP-2, MMP-7, VEGF, Bcl-XL, Survivin, and ICAM-1 in cells confirming the inhibition migration, angiogenesis, and invasion through suppression of the STAT3 Comparative study of BDMC-A an analog of curcumin and curcumin-treated MCF-7 human breast cancer cell line cells shown significant downregulation of marker genes related to angiogenesis, metastasis, and invasiveness In vivo experiments have shown that curcumin sensitizes TRAIL-resistant LNCaP cells human prostate cancer cell line through various mechanisms.

It stimulates death receptors, upregulates proapoptotic Bax members, Bak, suppresses antiapoptotic Bcl-xL proteins, and further inhibits VEGF, MMP-2, MMP-9 activation, which plays a vital role in metastasis, invasion, and angiogenesis These research studies confirm that curcumin has a strong anticancer effect on the diverse cancer cell lines, and it can be considered in drug development for cancer treatment.

Resveratrol 3,5,4'-trihydroxystilbene; Figure 4 , a polyphenolic compound which occurs naturally, is a stilbene found in berries, grapes, peanuts, and other plant sources This compound is also well known for its anticancer effects.

Resveratrol has shown protective effects on a variety of cancers such as breast, prostate, colorectal, lung, ovarian, cervical, hepatic, and gastric cancer Resveratrol suppresses the dose-dependent growth of cells with SGC human gastric adenocarcinoma cell line and induces apoptosis with increased reactive oxygen species ROS levels.

Resveratrol treatment to SGC cells caused DNA damage with higher γ-H2AX levels and reduced ku70 in western blot analysis TRAMP-C1, TRAMP-C2, and TRAMP-C3 murine prostate cancer cell lines cells treated with resveratrol caused mitochondrial-mediated caspase-dependent apoptosis and increased expression of γ-H2AX by sensitizing DNA damage Likewise, BF10 murine melanoma cell line and A human melanoma cell line cells treated with resveratrol showed reduced cell viability, induce apoptosis, and inhibits invasion and migration with increased cleaved caspase-9 levels in A cells.

The cytotoxic effect of resveratrol evaluated on Huh7 human hepatocellular cancer cell line cells revealed reduced migration, invasion, and protein levels of urokinase plasminogen activator receptor u-PA in a concentration-dependent manner.

Resveratrol exhibited an inhibitory effect on many essential metastasis stages Resveratrol exhibits a concentration-dependent inhibitory effect on HCT and Caco2 human colorectal carcinoma cell lines cells.

Further, it induces insulin expression, intrinsic and extrinsic apoptotic pathway decreases VEGF levels in treated cells. The enhancement of hypoxia-inducible factor HIF-1α protein expression resulted in the inhibition of VEGF expression Likewise, B16 murine melanoma cell line cell treated with resveratrol together with antineoplastic drug fluorouracil inhibits migration, reduce VEGF levels, and angiogenesis MDA-MB human breast adenocarcinoma cell line tumors treated with resveratrol induces apoptosis and inhibits xenografts angiogenesis in vivo In general, these studies indicate that resveratrol has anticancer properties that could be used as an effective anticancer agent.

Kaempferol [3,5,7-trihydroxy 4-hydroxyphenyl -4Hbenzopyranone; Figure 5 ], is extracted from tea and found in various widely known vegetables and fruits, including broccoli, beans, gooseberries, kale, strawberries, grapes, citrus fruits, brussel sprouts, tomatoes, grapefruits and apples It has also been recognized in various medicinal plants as Acacia nilotica L.

Kaempferol and its glycosylated derivatives are neuro-protective, cardio-protective, antidiabetic, anti-inflammatory, antitumor, antioxidant, antimicrobial, and have anticancer functions Kaempferol triggers antiproliferative effects on OVACAR-3 cells human ovarian cancer cell line and affects cell viability.

Further, apoptosis percentage also increased in a concentration-dependently supported by the regulation of apoptotic proteins like cleaved caspase-3 and cleaved caspase Similarly, kaempferol treatment triggers apoptosis in HT cells human colon cancer cell line through both extrinsic and intrinsic pathways, changes the expression Bcl-2 family proteins that lead to mitochondrial membrane depolarization and release cytochrome c from the mitochondria.

In cytosol cytochrome c activates caspase-9, further allows caspase-3 activation Research has found that eating nuts may be linked to a lower risk of certain types of cancer.

For instance, a study looked at the diets of 19, people and found that eating a greater amount of nuts was associated with a decreased risk of dying from cancer Another study followed 30, participants for up to 30 years and found that eating nuts regularly was associated with a decreased risk of colorectal, pancreatic and endometrial cancers For example, Brazil nuts are high in selenium, which may help protect against lung cancer in those with a low selenium status These results suggest that adding a serving of nuts to your diet each day may reduce your risk of developing cancer in the future.

Still, more studies in humans are needed to determine whether nuts are responsible for this association, or whether other factors are involved.

Summary Some studies have found that an increased intake of nuts may decrease the risk of cancer. Research shows that some specific types like Brazil nuts and walnuts may also be linked to a lower risk of cancer. Several studies have even found that a higher intake of olive oil may help protect against cancer.

One massive review made up of 19 studies showed that people who consumed the greatest amount of olive oil had a lower risk of developing breast cancer and cancer of the digestive system than those with the lowest intake Another study looked at the cancer rates in 28 countries around the world and found that areas with a higher intake of olive oil had decreased rates of colorectal cancer Swapping out other oils in your diet for olive oil is a simple way to take advantage of its health benefits.

You can drizzle it over salads and cooked vegetables, or try using it in your marinades for meat, fish or poultry. Though these studies show that there may be an association between olive oil intake and cancer, there are likely other factors involved as well.

More studies are needed to look at the direct effects of olive oil on cancer in people. Summary Several studies have shown that a higher intake of olive oil may be associated with a reduced risk of certain types of cancer. Turmeric is a spice well-known for its health-promoting properties.

Curcumin, its active ingredient, is a chemical with anti-inflammatory, antioxidant and even anticancer effects. One study looked at the effects of curcumin on 44 patients with lesions in the colon that could have become cancerous. In a test-tube study, curcumin was also found to decrease the spread of colon cancer cells by targeting a specific enzyme related to cancer growth Another test-tube study showed that curcumin helped kill off head and neck cancer cells Curcumin has also been shown to be effective in slowing the growth of lung, breast and prostate cancer cells in other test-tube studies 30 , 31 , Use it as a ground spice to add flavor to foods, and pair it with black pepper to help boost its absorption.

Summary Turmeric contains curcumin, a chemical that has been shown to reduce the growth of many types of cancer and lesions in test-tube and human studies. Eating citrus fruits such as lemons, limes, grapefruits and oranges has been associated with a lower risk of cancer in some studies.

One large study found that participants who ate a higher amount of citrus fruits had a lower risk of developing cancers of the digestive and upper respiratory tracts A review looking at nine studies also found that a greater intake of citrus fruits was linked to a reduced risk of pancreatic cancer These studies suggest that including a few servings of citrus fruits in your diet each week may lower your risk of developing certain types of cancer.

More studies are needed on how citrus fruits specifically affect cancer development. Summary Studies have found that a higher intake of citrus fruits could decrease the risk of certain types of cancers, including pancreatic and stomach cancers, along with cancers of the digestive and upper respiratory tracts.

Some research has shown that it may even help decrease cancer growth and help kill off cancer cells. In one study, 32 women with breast cancer received either a flaxseed muffin daily or a placebo for over a month.

At the end of the study, the flaxseed group had decreased levels of specific markers that measure tumor growth, as well as an increase in cancer cell death In another study, men with prostate cancer were treated with flaxseed, which was found to reduce the growth and spread of cancer cells Flaxseed is high in fiber, which other studies have found to be protective against colorectal cancer 7 , 8 , 9.

Try adding one tablespoon 10 grams of ground flaxseed into your diet each day by mixing it into smoothies, sprinkling it over cereal and yogurt, or adding it to your favorite baked goods. Summary Some studies have found that flaxseed may reduce cancer growth in breast and prostate cancers.

It is also high in fiber, which may decrease the risk of colorectal cancer. Lycopene is a compound found in tomatoes that is responsible for its vibrant red color as well as its anticancer properties.

Several studies have found that an increased intake of lycopene and tomatoes could lead to a reduced risk of prostate cancer. A review of 17 studies also found that a higher intake of raw tomatoes, cooked tomatoes and lycopene were all associated with a reduced risk of prostate cancer Another study of 47, people found that a greater intake of tomato sauce, in particular, was linked to a lower risk of developing prostate cancer To help increase your intake, include a serving or two of tomatoes in your diet each day by adding them to sandwiches, salads, sauces or pasta dishes.

Summary Some studies have found that a higher intake of tomatoes and lycopene could reduce the risk of prostate cancer. However, more studies are needed. The active component in garlic is allicin, a compound that has been shown to kill off cancer cells in multiple test-tube studies 40 , 41 , Several studies have found an association between garlic intake and a lower risk of certain types of cancer.

One study of , participants found that those who ate lots of Allium vegetables, such as garlic, onions, leeks and shallots, had a lower risk of stomach cancer than those who rarely consumed them A study of men showed that a higher intake of garlic was associated with a reduced risk of prostate cancer Another study found that participants who ate lots of garlic, as well as fruit, deep yellow vegetables, dark green vegetables and onions, were less likely to develop colorectal tumors.

However, this study did not isolate the effects of garlic Based on these findings, including 2—5 grams approximately one clove of fresh garlic into your diet per day can help you take advantage of its health-promoting properties.

In colorectal cancer cells, it has been shown an increased level 2 to 3 times of autophagy with the creation of lysosomes in the cells treated with bromelain. The immunomodulatory effects of bromelain have been studied extensively, showing that it can activate or suppress the mammalian immune system One of the first researches was conducted on human T cells from bromelain-treated PBMC stimulated by mitogenic CD2 mAb to explore the migration and activation of lymphocytes The continuation of the research expanded the use of bromelain in monocytes and granulocytes and extended the surface molecules affected by the enzyme, again remarking on the promoting effects on adhesion and activation of immune cells Also, human peripheral blood lymphocytes were pretreated with bromelain to study the anti-proliferative activity in different cancer cell lines The authors reported that lymphocytes were boosted by the enzyme and could enhance the immune system response to the fight against cancer at least in vitro experiments.

More strictly to human studies, in 16 breast cancer patients treated for 10 days, bromelain could reduce CD44 expression similar to above , while augmenting CD11a and CD62L expression The inhibition was probably unspecific, as it acted on ERK-2 and p21ras of T cells, however proteolytic-dependent, evoked by selective cysteine protease inhibitor in further experiments.

In addition, the work showed that Ag-specific B cell antibody response was expanded in bromelain-treated mice, though IL-2 mRNA expression was simultaneously blocked. The authors remarked as bromelain could concurrently boost and inhibit T cell responses, depending on the immune environment and consequently, the enzyme could be potentially implicated in T cell autoimmunity.

Bromelain was also studied in the innate immune system, where it could enhance and sustain the process. In a recent study, murine macrophages RAW In addition, in murine natural killer, bromelain was able to augment IL and ILmediated IFN- γ production, IL-6, and Gm-CSF, while reducing T helper cells activation.

One important property of bromelain is its anti-inflammatory action. Since ancient times, pineapple as the main source of bromelain has been widely applied against inflammation disorders The main applications of bromelain concern the edema processes of an inflammatory nature in the medical and surgical fields.

Bromelain administered i. At the level of inflammatory tissue, bromelain reduces vasodilation, and increased capillary permeability, leukocyte migration and local pain by inhibiting the formation of bradykinin and serotonin. In addition to these, bromelain exhibited anticancer activity and the ability to induce apoptotic, necrotic and autophagic mechanisms.

More recently, the inflamed colon tissue was used as a model to evaluate the bromelain anti-inflammatory role. The research was expanded with the use of pineapple juice or purified bromelain in the same animal model, showing that both treatments could lessen colon inflammation and neoplastic lesions Moreover, in the murine inflammatory bowel disease model, a reduction in neutrophil migration was demonstrated through the blockade of the CD chemokine receptor In another inflammatory disorder, bromelain has notably been shown to reduce inflammation in the gastro-enteric environment In particular, using 3 different cell lines as digestion simulated models AGS, Caco-2, and SW cells , the authors demonstrated that a proprietary bromelain extract could decrease IL-8, COX-2, iNOS, and TNF-α without affecting cell viability.

In addition, bromelain inhibited the iNOS and COX-2 expression in LPS-stimulated RAW Zhou and co-authors have reported that purified fruit bromelain could stop epithelial TNF-α receptors in rat colitis models and intestinal cell line IEC-6 and Caco-2 cells The work reported that colitis symptoms were ameliorated, together with reduced macroscopic damage, decreased mucosal inflammation, and tight junction barrier recovery.

Bromelain can accelerate tissue repair processes as a result of the depolymerization of intercellular structures and modification of vascular permeability The biological effects of bromelain have been partially associated with the modulation of the arachidonic acid cascade , similar to another study that showed the alteration of arachidonic acid metabolism with anti-inflammatory and antiplatelet effects of bromelain Bromelain therapy resulted in platelet formation reduction with increased resistance to aggregation It experimentally induced inflammatory reactions in the rat with the interference of eicosanoid formation in the arachidonic acid cascade and could modulate the immune system as an anti-inflammatory factor Habashi and co-authors have also reported that bromelain potentially exerted anti-inflammatory effects by reducing nitric oxide synthesis in vitro without cytotoxicity Bromelain downregulated COX-2 and PGE-2 prostaglandin E2 expression levels in cells Bhui and co-authors explored that bromelain inhibits COX-2 expression by blocking the activation of MAPK-regulated NF-kappa B against skin tumor initiation triggering the mitochondrial death pathway Bromelain was able to inhibit PGE2 production Similarly, another work suggested that bromelain could regulate inflammatory cytokines and growth factors, including TNF-α, IL-1β, IL-6, and IFNγ Moreover, 2.

In addition, CL-bromelain was reported for its suppression of ERK, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase Kalra and others have reported that bromelain regulates p53, NF-kB, and COX-2 expression by targeting the mitogen-activated protein kinase pathway in mouse skin Another hypothetic role of bromelain is in the inflammation caused by advanced glycation end-products AGEs.

It has been shown that the enzyme could increase the soluble form of receptor for advanced glycation end products sRAGE in 11 patients affected by chronic kidney disease CDK.

It is known that kidneys are implicated in the removal of sRAGE and circulating AGEs and non-AGE ligands are present in CKD Bromelain delivery in association with other molecules is often used to obtain a synergistic effect.

Although bromelain alone has shown apoptotic effects in cancer cell lines, other studies combining this enzyme with other compounds or extracts have been developed. An example is the combination of this enzyme with peroxidase, indeed their association produced additive effects with an intensification of intracellular ROS level and disruption of mitochondrial membrane potential, leading to acute myeloid cells K growth inhibition.

In addition, they participated in the regulation of the expression of Bax, Bcl2, caspase-3, and cytochrome, which are highly related to apoptosis, as well as promoting a positive regulation of p53, a key molecule involved in cell death In another study, the combination of olive leaf extract Olea europaea L.

and bromelain could have promising effects against lung cancer Combining ethanolic olive leaf extract EOLE with bromelain increased Nrf2 translocation from the cytoplasm to the nucleus and terminated the translocation of NF-κB from the cytoplasm to the nucleus.

Furthermore, the levels of IL-6 and TNF-α, as well as some metalloproteinases, decreased, suggesting that this association could reduce lung carcinogenesis through the regulation of inflammation and oxidative stress The combination of curcumin, harpagophytum and bromelain has been shown to reduce inflammation and pain in osteoarthritic human synovial cells, through the decrease of prostaglandin E2, Nerve Growth Factor NGF , IL-6 Similarly to the previous study, the combination treatment of bromelain, trypsin, and rutin resulted in a significant reduction in pain and inflammation in patients with osteoarthritis of the knee This randomized double-blind study demonstrated that the combination regimen was efficacy in Bromelain may increase the cytotoxicity of cisplatin in the treatment of breast cancer as reported in 2 studies with MDA-MB and 4T1 Breast Tumor cell lines 78 , Besides the use of bromelain as a single drug, there are studies in which the effect of bromelain has been combined with other molecules, such as N-acetylcysteine.

The combination of the two compounds in different gastrointestinal cancer cell lines showed significant inhibition of cell proliferation, with an increase in autophagosomal markers such as LC3-II In another study, malignant peritoneal mesothelioma MPM cells were exposed to the combination of bromelain with cisplatin and fluorouracil, showing cytotoxic effects against these cells in the mixture between bromelain and cisplatin Bromelain and N-acetylcysteine NAC constitute two active ingredients capable of inhibiting the growth and proliferation of induced peritoneal tumors in mice as model animals.

This activity can be traced back to the proteolytic activity of bromelain and the mucolytic activity of NAC. It is known that some mucins, highly glycosylated high molecular weight proteins i. MUC2 and MUC5AC , are involved in the pathogenesis of cancer.

Besides, extracellular mucus presents a clinically relevant barrier to effective therapy in mucinous cancers. Thus, extracellular mucolytic would decrease compressive effects from bulky mucinous tumor burden. Bromelain is made up of a mixture of hydrolytic enzymes, not only with endopeptidase activity, hydrolyzes esters, amides and glycosidic bonds, while NAC can reduce disulfide bridges.

Such a combination impaired the complex lattice framework of mucus thus improving drug delivery and increasing cytotoxic effects Bromelain-based mucus-disrupting strategies are also gaining much attention as an effective tool in decreasing the mucus barrier.

However, this effect of bromelain may be ineffective, if not harmful, in some circumstances. Non-Small Cell Lung Cancer NSCLC is any type of epithelial lung cancer other than small cell lung cancer SCLC. A significant percentage of these NSCLC cases are characterized by the expression of the anaplastic lymphoma kinase ALK protein.

Inhibition of ALK is a target for slowing proliferation in NSCLC. Commercial bromelain was tested to evaluate efficacy during the administration of certain ALK inhibitor drugs such as alectinib ALC , ceritinib CER , and crizotinib CRZ. Interestingly, bromelain administration in male Wistar rats caused a significant decrease in plasma levels of CER and CRZ along with an increase in the apparent clearance.

However, no significant effect was noticed with ALC Thus, the well-known bromelain muco-permeation enhancing effect can sometimes have unwanted effects.

Even the simple administration of bromelain in mice challenged with 4T1 triple-negative breast cancer cells can increase the effectiveness of anticancer drugs with severe side effects. Animals receiving cisplatin and bromelain jointly showed more significant effects in tumor shrinkage than those receiving bromelain and cisplatin separately by modulating the tumor environmental inflammation Significant benefits could be obtained if the administration of bromelain allowed the total elimination of synthetic drugs with anticancer activity, which often cause severe side effects.

When bromelain was used in association with peroxidase, the two enzymatic systems were able to counteract some of the typical effects of lymphoma. In fact, during the progression of the tumor the white blood cell count was increased as well as the number of abnormal leukocytes, while the red blood cell count decreased.

These negative effects were mitigated following the administration of bromelain and peroxidase, both enzymatic systems found in some pineapple extracts.

This may be due to the increase in tumor cell apoptosis 92 resulting from the increase of pro-apoptotic protein factors and the restoration of ROS levels by controlling the activity of antioxidant enzymes.

A similar approach aims to replace drugs with antioxidant substances extracted from plants rich in phenolic compounds. For this purpose, ethanol extract of Olea europaea leaves EOLE in combination with bromelain was used to evaluate the amelioration of various hallmarks associated with benzo a pyrene-induced lung carcinogenesis in male Swiss albino mice Majumder et al.

The same kind of antioxidant protection can explain the observed general improvement in lung tissue architecture. Hydroxytyrosol and oleuropein are the main components of the polyphenolic fraction of Olea europaea , and their antioxidant potential has long been recognized.

On the other side, inflammation provides various molecules essential to the formation of a microenvironment suitable for tumor development. Such molecules include growth factors, survival factors, proangiogenic factors and extracellular matrix-modifying enzymes Ben-Baruch, Treatment with bromelain-EOLE reduced some crucial proinflammatory cytokines TNF-α and IL-6 , and also interrupted the NF-kB translocation.

Altogether, a combination of EOLE and bromelain alleviated the benzo a pyrene-induced lung carcinogenesis associated with pulmonary oxidative stress and inflammation Majumder et al. The various strategies for the fight against cancer include also radiotherapy, the effectiveness of which can be limited by the radioresistance of some tumors as well as by the undesirable effects affecting normal tissues.

The development of radiosensitizing drugs has therefore found application in the treatment of tumors by radiotherapy. Radiosensitizers are intended to enhance tumor cell killing while having much less effect on normal surrounding tissues. Some drugs target different physiological characteristics of the tumor, particularly hypoxia of the solid tumor tissue which is considered a major cause associated with radioresistance.

From this perspective, the hypothesis that bromelain acts as a radiosensitizer and radioprotector becomes suggestive.

Mekkawy and coworkers make this hypothesis their own through in vivo studies in Ehrlich solid tumor EST bearing mice The size and weight of tumors in gamma-irradiated EST-bearing mice treated with bromelain decreased significantly with a significant amelioration in the histopathological examination Mekkawy et al.

The benefits could be linked to the gene expression of some nuclear factors poly ADP ribose polymerase-I, NF-κB , and peroxisome proliferator-activated receptor α together with restored liver function. Besides, bromelain radiosensitizing action could be expressed through increasing lipid peroxidation and ROS production in tumor tissue, inhibition of repair of DNA strand breaks and inhibition of proliferation The administration of bromelain in tumor patients has been also tested in a few numbers of clinical studies and could represent an adjuvant treatment in cancer care.

The immunotoxicity effect of monocytes and lymphocytes against target cells of mammary carcinoma K and MDA-MB was tested in vitro after 10 days of oral bromelain administration in breast cancer patients daily up to a dose of mg as above mentioned paragraph 4.

Eckert and coworkers found that the intake of the bromelain increases the activity b-MAk and MAK of patient monocytes about 2-fold; in the responder patients, it was recorded an increase in cytotoxicity of b-MAK and MK cells respectively from 7. No detectable IL-1β from monocyte was found in patients before, during and after the treatment in contrast with what was recorded in healthy blood donors, and no effects were observed in NK and LAK-cell activity in the patient cohort.

Moreover, the oral intake of bromelain reduced the expression of the cell surface markers CD44 but poorly increased the expression of CD11a and CD62L without changing the level of CD These effects were observed also in vitro with a higher decrease in the expression of CD16 and CD The anti-cancer properties of bromelain, in combination with N-acetylcysteine, were used also to produce a new drug BromAc ® which has been recently proved effective in the recurrent thoracic pseudomyxoma peritonei PMP treatment According to the bromelain-based mucus-disrupting activity see above , the mucolytic properties of BromAc ® help the tumor dissolution when it was injected directly into mucinous disease.

However, its effectiveness is related to neoplastic characteristics. In the first two cases reported, effectively, large response differences were reported, possibly due to the tumor consistency Lam et al. The safety profile was however good as also the objective response.

In a phase I study, the safety of bromelain treatment was tested on 20 patients affected by inoperable mucinous cancer. Among the patients, 13 had intra-tumoral treatment and 7 had intraperitoneal treatment Valle et al. Intra-tumoral doses consisted of mg of bromelain and 1. The volume of the fluidized tumor removed was measured and collected for laboratory analysis.

The side effects of treatment were recorded after 24 h. No death or anaphylactic reactions were recorded. BromAc ® safety was investigated also using blood parameters in 25 patients mean age 64 with inoperable PMP pre and post-treatment administration Ke et al.

Patients received bromelain mean dosage of mg and 4. An increase in CRP values and WBC, neutrophils and monocytes in both high and low-dose subgroups was found, with a concomitant decrease in albumin and lymphocyte levels suggesting an inflammatory reaction.

The other blood parameters, including liver enzymes or coagulation parameters, have not undergone any alteration. This aspect is important in the evaluation of BromAc ® safety, that have not shown liver or kidney toxicity.

The role of bromelain in combination with papain, sodium selenite and Lens culinaris lectin has been also tested as a complementary medicine on more than breast cancer patients to reduce the side effects caused by the administration of the adjuvant hormone therapy.

On the whole, these results support further studies on the role of bromelain in the treatment of tumors possibly representing a non-invasive treatment for people suffering from cancer.

Despite these promising effects, the number of clinical trials is low and limited to early stages. More efforts are thus desirable to validate a promising new strategy for inoperable neoplastic cases.

The recent studies underline its safety and easy of administration with sufficient bioavailability and tolerability both in animal and human studies. Other recent studies have shown few side effects arising as a result of taking bromelain in both animals and humans, thus bromelain is considered relatively safe.

The main side effects are attributable to the gastrointestinal system stomach pain and diarrhea , although allergic reactions are always possible in predisposed individuals Bromelain is considered to be safe and it is an effective agent in burn debridement.

In Europe, bromelain is approved as a non-steroidal anti-inflammatory agent for oral and topical use for surgical wounds, inflammation, and debridement of deep burns , A single 4-hour application of the bromelain-based agent completely debrides deep partial-thickness burns in a validated porcine model Numerous studies in the literature were focused on the anti-cancer role of bromelain, highlighting its importance in cell processes such as apoptosis and necrosis Available data on bromelain also suggested that the enzyme possesses anti-inflammatory activity in acute and chronic inflammation which are associated with cancer.

Bromelain can modulate the metabolism of arachidonic acid affecting the production or activity of cytokines and growth factors involved in the inflammatory process. There are numerous published data on the potential mechanism of action of bromelain in anti-inflammatory activity.

Nonetheless, they are not exhaustive and leave many questions unanswered: additional anti-inflammatory works are necessary for a better understanding of its mechanism of action. Many preclinical pharmacological studies showed that Bromelain affected cell viability of cancer cells, however, the exact mechanisms of action produced by bromelain are rarely explored.

Nonetheless, it is reported that bromelain could act as an immunomodulator by improving the weakened immunocytotoxicity. Other recent studies showed that bromelain stimulates autophagy which is involved in cancer progression and drug resistance.

The activation of autophagosome and lysosome formation by bromelain induces cancer cell death, a key factor that should be more profitably exploited in future research. A complex picture of the effects of bromelain on the immune system is also perceived. Indeed, most of the published papers reported an immunomodulatory activity of bromelain, with a different behavior based on a specific tissue or cell type.

Preclinical pharmacological experiments represent the vast majority of research on the effects of bromelain on the immune system, from which it appears that in the future it is necessary to test bromelain in larger clinical studies in humans.

Moreover, its cytotoxic effects in cancer cells could be triggered by proteolytic activity, or by platelet aggregation-inhibitory activity or anti-inflammatory properties Tumour cells with such compromised processes are potential targets of bromelain.

In addition, it is known that cancer cell death can be induced in different ways, such as via apoptosis, necrosis, and autophagy. The lack of wide clinical trials leaves the opportunity to further test bromelain in humans, giving the possibility to clinicians to lay clear indications of its use.

Another issue to be expanded in future research will be bromelain association with other compounds, as above mentioned in some successful works 78 , 82 , 84 , 92 — 94 , — The possibilities are enormous, and should not be limited to chemotherapeutic drugs 78 , 84 , — , but expanded to other drug categories, such as anti-hypertensives, hypoglycemics, anti-asthmatics, anti-microbials, immunomodulators, etc.

Moreover, it should be kept in mind that bromelain is highly attractive for the industry, given its indispensable nature in foods, cosmetics, pharmaceuticals, and textiles. A key limitation factor for the successful use of bromelain as a potential anticancer agent is its production and method of extraction: the more these are reduced and the more the market expands.

Indeed, more economical but equally effective bromelain will be highly competitive with other products or other sources and will facilitate its use among both the population and industry. This could in turn generate a scientific relapse with the initiation and extension of new and old research in this field.

It is expected that in the next future bromelain will be deeply studied and explored, especially focusing on its anti-cancer activity, as this kind of disease is considered the second leading cause of death all over the world New perspectives and strategies have been proposed to increase the anti-cancer effects of Bromelain from the bench to bedside.

The most promising approach is to enhance the bioavailability of bioactive compounds using new pharmaceutical nanoformulations Thus and simple bromelain delivery may require high doses of the active principle also due to the characteristics of the extracellular matrix ECM which constitutes a barrier that slows down or prevents the spread of drugs in the parenchyma of the tumor.

For this reason, other delivery methods have been investigated. NPs-based delivery systems can offer an effective alternative. The proteolytic activity of bromelain can pave the way for these antitumor drug delivery systems by increasing their penetration into the cell, weakening the resistance of ECM proteins.

Thus, doxorubicin, a potent anticancer drug, but with heavy side effects, was delivered in association with chemically immobilized bromelain, by lactobionic acid-modified chitosan NPs. In vivo drug biodistribution and antitumor activity in ICR, male mice model lead to higher drug concentration in tumor area and superior antitumor effect Wang et al.

Pancreatic cancer is one of the most difficult cancers to treat largely because of the inability of anticancer drugs to penetrate the malignant tissue as a result of the dense ECM This can limit the effect of bromelain in degrading the tumor ECM due to the short half-life of bromelain in the blood.

This technology based on reversible poly ethylene glycol PEG modification was applied to stabilization of bromelain in vivo , thus enhancing antitumor activities of doxorubicin and doxorubicin encapsulated in PEGylated liposomes DOXIL in tumour-bearing mice. The release rate of doxorubicin can be increased by using nanocarriers prepared by crosslinking bromelain with an ortho-ester-based crosslink agent.

The release of bromelain in tumour-bearing mice by pH-sensitive NPs increased the hydrolysis of the ECM favoring the penetration of the anticancer drug Bromelain can also be uploaded to obtain poly lactic-co-glycolic acid NPs bromelain-PLGA NPs.

Such a delivery system was evaluated for its anti-cancer efficacy in 7,dimethylbenz[a]anthracene DMBA -induced and O-tetradecanoylphorbolacetate TPA promoted 2-stage skin tumorigenesis model in Swiss albino mice.

Bromelain-PLGA NPs showed the most significant chemopreventive and chemotherapeutic effects when compared with free bromelain Bhatnagar et al. Bromelain-NPs possibly acted by maintaining a balance between the positive and negative regulators of apoptosis and triggering more cells to apoptosis than free bromelain.

Bromelain, the main medicinal component of pineapple, was discovered in the late s and since that time research continues to increase available data on its potential benefits. Bromelain is an enzyme with numerous pharmacological properties, as it can act on different health disorders, including osteoporosis and osteoarthritis, diarrhea, chronic wounds, surgical debridement, edema, inflammation, and cancer.

Nonetheless, clinical uses of bromelain are limited and poorly representative. The anticancer properties of bromelain are extensively documented in vitro experiments, but such demonstrations in vivo animal models are far less. Modalities were tested that involved both the administration of bromelain alone, and in association with other molecules, but the most promising use was the formulation of nanoparticles.

Novel approaches to cancer chemotherapy are warmly urgent and bromelain could be regarded as an important tool in the cancer fight. Several clinical properties have been ascribed to bromelain vide supra including anticancer activity.

Besides, the utility of these proteins also comprises the cosmetic field, food and beverage production and textile industries as a consequence, the industrial demand in the last few years increased. This phenomenon further affected the final price of the product.

However, the protein isolation and purification costs are responsible for more than half of the final commercial price. All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or in all these areas - that is, revising or critically reviewing the article; giving final approval of the version to be published; agreeing on the journal to which the article has been submitted; and confirming to be accountable for all aspects of the work.

All authors have read and agreed to the published version of the manuscript. MM wants to thank ANID FONDECYT Iniciación and ANID CENTROS BASALES ACE The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Open access. Submitted: 23 Propertiess Published: 19 June com Green tea extract and sleep quality cbspd. Cancer Anticahcer one of the most severe health Shortness of breath in both developing and developed countries, worldwide. Among the most common lung, stomach, colorectal, liver, breast types of cancers, lung cancer has continued to be the most common cancer diagnosed in men and breast cancer is the most common cancer diagnosed in women. Anticancer properties

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