PLANT DERIVED ANTICANCER AGENTS FOR THE TREATMENT OF CANCER
HTML Full TextPLANT DERIVED ANTICANCER AGENTS FOR THE TREATMENT OF CANCER
Virender Kumar, Vandana Garg * and Harish Dureja
Faculty of Pharmaceutical Sciences, M. D. University, Rohtak, Haryana, India.
ABSTRACT: Cancer is defined as a condition where cancerous cells multiply out of control in the body. It severely affects the human population on a global basis. New therapies are constantly needed to prevent and treat this life-threatening disease. Natural-derived compounds are attracting scientific and research interest due to their substantially fewer side effects than the current cancer treatment. Plants produce secondary metabolites with anticancer properties and are being examined for their potential to be used as clinical drugs. Amazingly, antineoplastic activity has been reported even in most commonly found locally dwelling plants like ginger, turmeric, garlic, and Ashwagandha, besides their use in other illnesses by the local community. However, many medicinal plants are yet to be properly unveiled for their potential as anti-cancerous agents. They need extensive research and valuable resources for in-depth studies like identification, isolation, in-situ studies, bioequivalence studies, and in-vitro, ex-vivo, or in-vivo studies. This review summarizes the role of bioactive compounds in cancer, the mechanism by which compounds show anticancer activity, and the list of plants used for anticancer activity and clinical trials. The scientist will test plant-based anticancer agents and fill the research gap seeking chemopreventive substances.
Keywords: Phytoconstituents, Cancer, Bioactive compounds, Chemopreventive, Herbal drug
INTRODUCTION: Today's modern era has significantly improved people's quality of life with newer established technologies and utilities, especially in the healthcare sector, like developing new diagnostic techniques, medical devices, treatment strategies, and surgical procedures. However, there are certain deadly diseases for which no suitable and appropriate treatment is available, although immense research is already on them.
Cancer is a life-threatening disease that costs about 8 million out of 14 million people worldwide of every age group as per the world health organization, especially in developing and developed countries 1. Cancer increases the mortality rate every day, with an estimated 13.1 to 17 million fatalities by 2030 2. Cancer has been ranked second after cardiovascular diseases for morbidity and mortality in the general population 3.
Cancer is a situation in which the body's normal cells undergo uncontrolled division leading to tumor formation at the affected site, which damages and affects adjacent normal healthy tissues abnormally 4. The prime reason behind the cancer transformation of normal cells is a mutation in DNA and hence, in genes, leading to the development of oncogenes in them.
These can be caused by physical factors (X-rays), organic compounds, virus-infected pathogenic microorganisms, or behavioural and dietary variables such as a lack of physical activity, smoking, alcohol intake, and an unhealthy diet 5. The cancer cells can stimulate tumor growth at the local site (benign tumor) or can be significantly transmitted to various parts or organs of the body via the bloodstream (malignant tumor) 6. Cancer can be classified into various types based on affected sites like cells, tissues, or organs, as represented in Table 7.
TABLE 1: CLASSIFICATION OF CANCER
S. no. | Types of cancer | Affected / Associated part |
1 | Carcinoma | Skin, lungs, breast, pancreas, other organs & glands |
2 | Sarcoma | Bone, muscle, adipose tissue, blood vessels, cartilage or other soft, connective tissue |
3 | Melanoma | Melanocytes (pigmentation of the skin) |
4 | Lymphoma | Lymphocytes |
5 | Leukemia | Blood |
Various methods are used to treat cancer, including traditional drugs 8 as extract of plant 9, chemotherapy 1, radiotherapy, and surgery. Treatment of cancer using certain chemicals, i.e., chemotherapy, tends to cause side effects in cancer patients and severe adverse drug reactions like nausea, vomiting, hair loss, discomfort, and mental distress, simultaneously affecting other normal cells because of its non-selective approach and toxicity on slight over dosage 7.
Patient non-compliance overdosage is also a significant problem in chemotherapy treatment. Nevertheless, surgery needs to be performed on terminal cancer patients. In current years, there has been a substantial shift towards traditional natural herbal medicines and the active compounds obtained after extraction from plants for cancer treatment because of various shortcomings of chemotherapy, as mentioned above.
Since, the herbal medicines are naturally obtained, they have lesser toxic side effects on patient health, are easily affordable, are considered safe to use, and produce deemed positive results 10 Plants produce compounds like volatile oils, resins, gums, alkaloids, terpenoids, saponins, and secondary metabolites. The anti-cancerous evaluation and the efficacy have been determined with the help of various assays performed on several induced tumours as mentioned below:-
1. MTT (3 - (4, 5 - dimethylthiazol - 2 - yl) - 2, 5-Diphenyltetrazolium bromide) Colorimetric Assay: The extract mixed with DMSO is added to a diluted cell culture media (pure cell lines) and seeded for incubation in 96 well-microtiter plates along with the addition of MTT. Cell viability and absorbance were determined at definite time intervals 11.
2. WST - 1 (4 - [3 - (4 - iodophenyl) – 2 - (4 -nitrophenyl) - 2H – 5 - tetrazolio] - 1, 3 - benzene disulfonate) Colorimetric Assay: Firstly, pure cell lines are incubated in 96 well-microtiter plates with culture media. Later, definite concentrations of the extract are added and simultaneously dissolving the contents in DMSO. Finally, adding definite proportions of WST-1 to the above-solubilized mixture. The absorbance was determined at definite time intervals 12.
3. SRB (Sulforhodamine B) Method: Absorbance was determined for cultured RPMI 1640 medium of fetal bovine serum in which extract, TCA, and SRB solution were added simultaneously and kept for incubation 13.
4. Alamar Blue Resazurin Reduction Assay: Serial dilutions of plant extract are prepared with a medium containing pure cell lines suspended in DMEM and seeded for incubation in 96 well-microtiter plates. Afterward, culture media along with resazurin is added and kept for further incubation. The cytotoxic effect of the extract is determined by analyzing the resultant intensity of the fluorescent dye.
Various researchers proposed herbal extract, and the compound derived from the plants showed anticancer effects by numerous mechanisms. They have oxidation-resistant properties or act as antioxidants, resulting in an antiproliferative effect and inducing apoptosis through various subcellular metabolic pathways like decreasing the lipid peroxidation level, acid phosphatase activity, or inhibition of PI3K/Akt pathway 14 or repairing DNA and enhancing body immunity 15 Some of them are known to cause the arrest of the cell cycle at the metaphase stage by binding to tubulin protein, an essential constituent of microtubules that disrupts its functions and hence, mitotic spindle apparatus.
TABLE 2: FORMULATION OF ANTICANCER DRUG
S. no. | Active chemical constituent of plant | Formulated anticancer drug |
1 | Taxanes | Paclitaxel (taxol), docetaxel |
2 | Vinca alkaloids | Vinblastine, vindesine, vincristine |
3 | Camptothecin | Camptothecin derivatives like irinotecan |
4 | Epipodophyllotoxins | Etoposide, teniposide |
In this way, they prevent cancer cell proliferation and suppress tumor growth. Any plant part like stem, leaves, bark, flowers, shoot, roots, rhizomes, and fruits, which have anti-cancerous properties, can prepare extracts and derive novel compounds for treating cancer via various extraction methods 15 Although anti-cancerous activity has been detected in more than 3000 plants 16 till today, in the pharmaceutical market, only four major classes of drugs or medicinal agents obtained from plants 17 are available for cancer treatment with suitable approved formulations for patients which are mentioned in the table below:-
Mechanisms Involved in Anticancer Activity of Herbal Drugs: Numerous herbal drugs show anticancer potential used in cancer therapy. Various mechanisms responsible for the anticancer potential of the herbal medication are described below:
1. Apoptosis: Several cancers are therapeutically targeted by apoptosis, the most common process of programmed cell death. Apoptosis is characterized by morphological changes such as heterochromatin mass core, shrinkage of the cell membrane, and losing cytoplasmic organelles' position. Researchers found that several dietary compounds inhibited carcinogenesis via induction of apoptosis. These compounds include curcumin, resveratrol, apigenin, quercetin, and ellagic acid 18, 19. Apoptosis induction is the most significant marker of the anticancer herbal drug 20.
FIG. 1: HERBAL DRUG SHOWING ANTICANCER POTENTIAL VIA APOPTOSIS
2. Angiogenesis: It is the process which involves the development of new blood vessels from the old blood vessel resulting in increased blood flow 21. Angiogenesis plays an essential role in cancer pathogenesis, and targeting is necessary for treating the disease 22. A variety of natural compounds have been recently shown to modulate tumor angiogenesis by inhibiting angiogenesis-associated cytokines or other mechanisms 23. These compounds include Resveratrol, Epicatechin, Epigallocatechin, Genistein, Curcumin, Triphala churna, Red ginseng, and Sanguinarine 24. These plant-derived compounds act on various factors like pro-angiogenic (vascular growth endothelial factor), receptor-mediated signaling pathways (PI3K/Akt), matrix protein, and hypoxia-inducible factor. Different molecular mechanisms have been used to describe many plant-based compounds that exhibit antiangiogenic properties, shown in figure 2.
FIG. 2: HERBAL DRUG SHOWING ANTICANCER POTENTIAL VIA ANGIOGENESIS
3. Cell Cycle Arrest: In the cell cycle series of events occurs at the macromolecular level, i.e., cell division and formation of two daughter cells 25. In a cell cycle process, a new piece of DNA is produced, chromosomes must be segregated, cells undergo mitosis, and then they begin to divide 26. A cell's ability to adapt to a constantly changing microenvironment relies on regulating cell cycle progression 27, 28.
FIG. 3: HERBAL DRUG SHOWING ANTICANCER POTENTIAL VIA CELL CYCLE ARREST
Understanding how uncontrolled and rapid cell division contributes to cancer development is the key factor in selecting the anticancer drug. It has been shown in-vivo, in-vitro and in clinical studies that it is possible to kill cancer cells with natural compounds that inhibit the cell cycle arrest.
Various natural compounds berberine, quercetin, apigenin, chebulagic acid, squamocin, rosamultic acid, silibinin, bufotalin palmatine, paclitaxel, rhizoxin, and tryprostatin acting on the cell cycle at different checks point of the cell cycle. Different checkpoints are affected by various herbal drugs, as shown in diagram.
4. Autophagy: Autophagy is a catabolic process that evolved and delivered cytoplasmic components to the lysosome for degradation in lysosomes 29. The main objective of autophagy is to maintain cell vitality by eliminating damaged proteins 30, 31. There has been evidence that natural products play an essential role in modulating autophagy, co-related to pro-survival autophagy or autophagic cell death 32, 33.
These compounds include Quercetin, Kaempferol, Genistein, Resveratrol, Rottlerin, Ursolic Acid, Camptothecin, Neferine, and Thymoquinone 34.
To develop novel therapeutic approaches, autophagy targets must be identified. Several natural products can induce or inhibit autophagy and target various stages of autophagy, as shown in the figure.
FIG. 4: HERBAL DRUG SHOWING ANTICANCER POTENTIAL VIA AUTOPHAGY
Phytochemicals and the active constituents derived from different plant parts, i.e., leaf, stem, rhizome, fruit, seed, root, pericarps, and fruit, show different pharmacological properties and therapeutic potential.
The different experimental studies found that plant extracts and their isolated phytoconstituents can exert chemopreventive actions 35.
These herbal drugs act by different approaches, i.e., made more responsive cancer cells to herbal chemotherapeutic drugs, increase the accumulation of herbal drugs in cancerous cells, and reduce the adverse effects of chemotherapeutic agents 36.
Herbal drugs from natural sources are excellent candidates for cancer treatment because of their capacity to affect different targets such as migration and growth of cells and numerous molecular pathways.
Updated information about plant binomial name, common name, family name, part of the plant used, active constituents, and the mechanism responsible for anticancer activity are given in Table 3.
TABLE 3: MEDICINAL PLANT USED AS ANTICANCER DRUG
S. no. | Plant binomial name | Common name | Family | Plant part used | Effective against specific cancer type | Active chemical constituent | Mechanism of action | Ref. |
1. | Zingiber officinale | Ginger, inguru | Zingiberaceae | Rhizome | Gastrointestinal, esophageal, liver | Gingerols converted to shogaols, paradols, zingerone | Suppresses TNFα & reduces the expression of NFkB | 37 |
2. | Curcuma longa | Turmeric, kaha | Zingiberaceae | Rhizome | Colon, hepatocellular, MCF-7 & ZR-75 breast type, renal, prostate, T-cell leukemia, B cell lymphoma | Curcumin | Downregulation of COX-2 enzyme, apoptosis via caspase-3 activity & increasing level of ROS, Ca2+ | 38 |
3. | Hemidesmus
indicus |
Indian sarsaparilla | Apocynaceae | Root , leaves | Leukemia, liver, uterine breast, HepG2 | Ledol, nerolidol, caryophyllene, camphor, borneol, lupeol, dodecanoic acid | Upregulation of CD83 and activation of caspases 3&9, inhibition of glutathione S- transferseP expression | 39-42 |
4. | Munronia
pinnata |
Bin kohomba | Meliaceae | Leaves, root & even whole plant | Lung, brain, LLC, T47D, S-180, MethA, PANC-1 | Β-caryophyllene, caryophyllene oxide ganoderiol F | Inhibits PI3K, AKT, Mtor, stat3 responsible for cell proliferation | 43-44 |
5. | Smilax zeylanica | Kumarika, kabarossa | Smilacaceae | Root, stem | Lung cancer, Breast cancer (MDA-MB 231, MCF-7) | Diosgenin, smilagenin, β-sitosterol, phenolics, flavonoids, tannins | Antioxidant activity, upregulation of p53 tumor suppressor gene, downregulation of Bcl2 | 45 |
6. | Tinospora cordifolia | Heart-leaved moonseed | Menispermaceae | Stem | Leukemia, Hela | Berberine, choline, tembetarine, tetrahydropalmatine, β-sitosterol, cordiofolioside A,giloinsterol, furanolactone, palmatine. | Inhibit cell cycle at G1 & G2 by suppression of cyclin D1, anti-apoptotic protein Bcl-xL | 46-47 |
7. | Adenantherapavonina | Red lucky seed, madatiya | Leguminosae | Bark | Leukemia (HL-60), lymphoma, Hela cells, HCT-116 cells | β-sitosterol, arginine, cysteine, arachidonic acid, dulcitol, lignoceric acid, malonic acid | Free radical scavenger activity, antioxidant effect, arrest of G2 phase (prevents cell proliferation) | 48 |
8. | Thespesiapopulnea | Malvaceae | Tulip tree, gansuriya | Leaves | Leukemia, lymphoma, B16-F10 melanoma | ,Lupeol, β-sitosterol,
Kaempferol. |
Reduction of glutathione level, apoptosis, antioxidant activity by quenching free radicals | 49-50 |
9. | Phyllanthus emblica | Phyllanthaceae | Gooseberry, nelli | Fruit or fruit juice | Throat, lung cancers, A549 (lung), HepG2, Hela, SW620 (colon) | Pyrogallol, quercetin, Kaempferol,geraniin. | Induces caspase 3/7 & upregulated Fas protein, inhibiting NFkB | 51-52 |
10. | Boerhavia diffusa | Nyctaginaceae | Hog weed, karichcharani | leaves | Gastric, liver, MCF-7 cells | Rhamnoside,quercetin, borhaavone. | Inhibits S, G1 phase of cell cycle, apoptosis Inducement | 53 |
11. | Ziziphusnum mulariawight | Rhamnaceae | Harbor, wild jujube | Root, bark, stem, flowers, seeds | p53 mutant cells | Botulin, betulinic acid | Generation of ROS, Topoisomerase-I inhibited, MAP kinase activated | 54-55 |
12. | Andrographispaniculata | Acanthaceae | The king of bitters, kiryat | Roots, leaves | KB, P388, MCF7, HCT-116, HT29 | Diterpenes, flavonoids, stigmasterols, andrographolide | Alterations in the levels of glutathione,
Glutathione-S-transferase activity increased |
56-59 |
13. | Centella asiatica | Apiaceae
(umbelliferae) |
Brahmamanduki, Asiatic pennywort, gotu kola | Leaves, whole plant | Ehrlich ascites cells | Vallerine, pectic acid, sterol, flavonoids, ascorbic acid,asiaticoside, | DNA synthesis inhibition, increase the level of Ca2+ ATPase | 60-61 |
14. | Annona atemoya | Annonaceae | Sour-sop of America, mamaphal | Root, bark, leaf, fruit | A-549, MCF-7, HT-29, HepG2 | Bullatacin, annomuricin A&B, | Induces apoptosis via antitoxidant activity | 62-64 |
15. | Mappia foetida | Icacinaceae | Amruta, kalgur, narkya | Whole plant, leaves | Hela cells, L-120 cells, breast carcinoma | Camptothecin | Inhibits nucleic acid synthesis, DNA topoisomerase-I | 65-68 |
16. | Withania somnifera | Solanaceae | Ashwagandha, winter cherry | Roots, leaves | HL-60, sarcoma | Withanolide A, withaferin A | Apoptosis activated
and generation of NO, increase in production of inflammatory mediators (CD4+, IFN-ϒ, IL-2) |
69-73 |
17. | Cedrus deodara | Pinaceae | Devdar (timber of gods), Himalayan cedar | bark | HL-60 cells, leukemia | Oleo-resin, wikstromal, matairesinol, dibenzylbutyrolactol | Activation of caspase 3,8,9, increase in level of NO, sub G0 cells concentration and formation of apoptotic body. | 74-75 |
18. | Boswellia serrata | Burseraceae | Indian oli-banum, salaiguggul | Stem, bark, | Hela cells, carcinoma | Oleo gum resin, boswellic acid | Excessive OS, NO formation, increased sub G0 fraction, Bcl-2 cleavage, expression of CDR4, apoptosis | 76-80 |
19. | Aloe barbadensis | Cape aloe, mussabar | Asphodelaceae (liliaceae) | Whole plant | HepG2, breast and cervical cancer | Aloin, emodin, volatile oil, barbaloin, chrysophanic acid, β-barbaloin, isobarbaloin | Downregulation of cyclin D1, CYP1A1, CYP1A2 | 81 |
20. | Arbutus andrachne | Greek strawberry tree | Ericaceae | Leaves,aerial parts | MCF-7 cell line, CACO-2 and HRT18 cell line | Arbutin, flavanoids, polyphenols | Antioxidant activity, antiproliferative and lipid peroxidation | 82 |
21. | Aristolochia longa | Barraztam | Aristolochiaceae | Roots | VCREMS, breast cancer | Aristolochic acid, aristolctams, aporphines, isoquinolones, flavanoids, coumarins, terpenoids | Induced apoptosis | 83 |
22. | Asplenium nidus | Bird’s nest fern, langsuyar | Aspleniaceae | Whole plant | HepG2, HeLa | Gliciridin-7-O-hexoside, phenols, flavanoids, quercetin, kaempferol, myricetin-3-O-rhamnoside | Atiproliferative effect | 84 |
23. | Averrhoa bilimbi | Star fruit, carambola | Oxalidaceae | Fruit, leaves | MCF-7 | Β-sitosterol, apigenin, fucopyranoside, flavanoids | Induced apoptosis via antioxidation and inhibits DNA replication | 85-86 |
24. | Azadira chtaindica | Neem, idian lilac, margosa | Meliaceae | Leaves, seeds | EACC, HBP carcinoma | Nimbin, nimbolide, nimbidin,limonoids, β-sitosterol, quercetin, ascorbic acid, polyphenolic compounds, azadirachtin | Antioxidant activity,
Modulated the activity of VEGF, p53 and NF-kB
|
87-88 |
25. | Barleria grandiflora | Devkaranti, shemmuli | Acanthaceae | Leaves | A-549, DLA | Alkaloidal, phenolics, flavanoidsbalarenone, barlerinoside, lupulinoside, lupeol, β-sitosterol | Antioxidant activity leading to induced cell death via ROS generation, decline in tumor growth by antiproliferative effect | 89 |
26. | Berberis aristata | Indian barberry, daruhaldi, tree urmeric | Berberidaceae | Root, stem | Colo205, Hop62, HT29, SiHa, MIA-PA-CIA-2, DWD, T24, PC3, A549, ZR75-I, A2780, DU145, MCF7, K562 | Alkaloidal, flavanoids, berberine, berbamine, columbamine, oxyacanthine, chelidonic acid | Influencing the mitochondrial Transmembranepotential, MMP regulation, p53 activation, NF-kB signal activated , inhibition of telomerase. | 90 |
27. | Caesalpinia sappan | Sappan wood, brazil wood | Caesalpiniaceae (fabaceae) | Heartwood, leaves | MCF7, A549 cell lines | Ombuin, quercetin, rhamnetin, sappanchalcone, sappanol, 8-methoxy bonducellin, chromanomones, brazilein, brazilin | Induced S phase & G2/M phase accumulation, acts on p53 independent pathway & induce apoptosis | 91-92 |
28. | Calligonum camosum | Fire bush, arta | Polygonaceae | Whole plant | HepG2 | Catechin, dehydrocatechin, kaempferol, quercetin, isoquercetrin, mequilianin, β-sitosterol, lauric acid, myristic acid, palmitic acid | Apoptosis induced via ROS generation, induced G0/G1 , antioxidant enzyme catalase | 93-95 |
29. | Cenchrus
ciliaris |
African foxtail grass | Poaceae | Aerial parts, roots | HepG2, CACO, A-549 | Glycosides, flavanoids, steols, triterpenes, anthraquinones | Antioxidant and antiproliferative activity | 96-97 |
30. | Cenchrus antiochia | Sand burs, sand spur | Asteraceae | Aerial parts | Vero , HeLa | Alkaloidal, phenolics, sterols, anthraquinones | Antioxidant activity and altering the caspase enzyme avtivation | 98 |
31. | Vitexagnus castus | Monk’s pepper, abrahm’s balm | Lamiaceae | Fruits, leaves | MCF-7 breast cancer | 1,8- cineole, phenolic compounds, sabinene, β-caryophyllene, flavanoids (vitexin, casticin), iridoid glycoside (agnuside, aucubin) | Potent antioxidant, cytotoxic & apoptotic activity | 99-100 |
32. | Chrysanthemumcoronarium | Chop-suey greens | Asteraceae | All parts | T47D, HRT18, CACO-2, A375.MCF-7 | Camphor, α-pinene, lyratyl acetate, β-pinene, chrysanthenylactetae, β-farnesene, germacrene, camphor, perillaldehyde, isoitalicene | Radical scavenging activityrelative to the strong antioxidant effect, also exhibits antiproliferative effect | 101-102 |
33. | Cocculus hirsutus | Broom creeper, patalgarudi | Menispermaceae | Aerial parts | MCF-7, Dalton’s lymphoma ascites | Flavanoids rutin, liquiritin, quercetin, hirsudioltrilobine, magnofluorine, ginnol, β-sitosterol | Endogenous antioxidant mechanism | 103 |
34. | Cordadic hotoma | Indian cherry, bird lime tree | Boraginaceae | Leaves | PC3, MCF-7 | Stearic acid, betulin, octacosanol, oleic acid, α-amyrins, lupeol-3rhamnoside. | Antioxidant activity leading tot decrease in cell viability | 104 |
35. | Cotynuscog gygria | Smoke tree | Anacardiaceae | Leaves | Vero , HeLa | Quercetin, gallic acid, disulfuretin, myricetin, taxifolin, phenolics, flavanoids, tannins, limonene, α-pinene | Lipid peroxidation inhibition | 105 |
36. | Crataegus microphylla | Hawthorn | Rosaceae | Leaves | Vero , HeLa | phenolic compounds, chlorogenic acid, hyperoside and epicatechin | Potent antioxidant effect leading to apoptosis | 106 |
37. | Croton caudatus | Scandent shrub | Euphorbiaceae | Leaves | DL, MCF7, HeLa | ethyl hexatriacontanoate, palmic acid, stearic acid, zheberiesinol, vanillin, vanillic acid, syringic acid, octacosanoic acid, succinic acid, inosine, isosinensetin | Antioxidant effect, free radical scavanging activity leading to cellular toxicity | 106 |
38. | Delphinium staphisagaria | Stavesacre | Ranunculaceae | Seeds | H56, N2A | Isoazitine, azitine,19-oxodihydroatisine, dihydroatisine, 22-O-acetyl-19-oxodihydroatisine.
|
Used for hair loss treatment in cancer patients and have cytotoxic and angiogenic potential | 107- 108 |
39. | Dillenia pentagyna | Dog teak | Dillenaceae | Stem, bark | DL, MCF7, HeLa | phenolics, flavonoids, tannin, saponin, alkaloid, and terpenoids | apoptosis via NF-Kb pathway through the increase of the bax to Bcl2 ratio, leading to fall of MMP & subsequently induced release of cytC , activation of caspase-3 followed by nuclear fragmentation in A549 cells | 109 |
40. | Euphorbia tirucalli | Indian tree spurge, pencil tree, finger tree, petroleum plant | Euphorbiaceae | Leaves, stem | MiPaCa2 | Terpenes, sterols, taraxasterol, tirucallol, euphol, α-euphorbol, tigliane, ingenane | Inhibition of protein kinase activity, induce genotoxicity, and changes in antioxidant gene expression | 110- 111 |
41. | Ficus racemosa | Goolar, cluster fig | Moraceae | Roots, bark | HL60 | α-amyrin acetate , tannin, wax, cerylbehenate,saponingluanol acetate, β-sitosterol (A). | Antioxidant effect observed in-vitro | 112- 113 |
42. | Helicteres isora | Enthaniavartani, marodphali, | Sterculiaceae | Plant
(Whole) |
H60, PN-15,HeLa-B75. | Cucurbitacin b ,gallic acid, vanillin. | Induced apoptosis, generation of ROS & antioxidation activity | 114- 115 |
43. | Hibiscus micranthus | Tiny flower hibiscus, rose mallow
|
Malvaceae | Aerial parts | HepG2, MCF-7 | β-sitosterol, phenolic acids, fatty alcohols and acids | Increase oxidative stress, decrease MMP, selectively induced apoptosis via ROS production, though the exact mechanism is not known | 116 |
44. | Hypericiumkotshcyanum | St. john’s wort, goat weed | Hypericaceae | Aerial parts | Vero , HeLa | Hypericin | Apoptosis Induce | 117- 118 |
45. | Inulavis cosa | False yellowhead, woody fleabane | Compositae | Flowers | MCF-7, Hep-2 | Sesquiterpene lactones (tomentosin, inuviscolide)
|
Inhibition of cell proliferation | 119-121 |
46. | Jasmium sambac | Arabian jasmine | Oleaceae | Flowers | MCF-7, Hep-2 | benzyl acetate, benzyl alcohol, linalool, geraniol. | Dose dependent tumor cell proliferation inhibition activity | 122- 123 |
47. | Lavandulaangustifolia | True lavender, narrow-leaved lavender, garden lavender | Lamiaceae | Flowers | MCF-7, Hep-2 | Camphor,linalool,
terpine-4-ol, |
Antiproliferative effect as the main mechanism | 124 |
48. | Leea indica | Bandicoot berry | Vitaceae | Leaves | DU-145, PC-3 | Phthalic acid, palmitic acid, ursolic acid, gallic acid, β-sitosterol | Augmentation of bax/Bcl2 ratio, induced mitochondrial-mediated apoptosis | 125 |
49. | Limonium densiflorium | Sea-lavender, marsh-rosemary | Plumbaginaceae | Shoots | A549, DLD-1 | 3-hydroxycinnamic acid, myricetin, isorhamnetin | Highest antioxidant effect recorded | 126 |
50. | Luffa cylindrica | Sponge guard | Araceae | Aerial parts | MCF-7, Hep-2 | Lucyosides C,
Lucyosides F, Lucyosides H |
Minimise recurrence and metastasis through antiproliferative effect | 126–130 |
51. | Manilkara zapota | Chiku, sapodilla, naseberry, chicle gum | Sapotaceae | Flower, leaves | MCF-7 | Lupeol acetate,
caffeic acid oleanolic acid |
Induce apoptosis via antioxidant effect | 131 |
52. | Mirabilis jalapa | Marvel of peru, four o’çlock flower | Nyctaginaceae | Roots, stem | Hep-2,
MCF-7 |
Phytosterols, β-sitosterols, stigmasterol, brassicasterol, ursolic, oleanolic acid, betulinic acid, Miraxanthin-III,II,V, vulgaxanthin-I | LDHA inhibition activity in silico | 132 |
53. | Morus nigra | Black mulberry, blackberry | Moraceae | Leaves | HeLa, MCF-7 | β-Sitosterol, flavanoids | Antioxidant & cytoprotective effect, decrease tumor growth via antiproliferative effect | 132 |
54. | Narcissus tazetta | Daffodil, Chinese sacred lily | Amaryllidaceae | Aerial parts, flowers | MCF-7, Hep-2 | Heptanal, myrcene, cineole, ocimene, linalool, nonanal, benzyl acetate, terpineol | Antioxidant as the major mechanism | 133 |
55. | Nepetaita lica | True catnip | Laminaceae | Aerial parts | Vero , HeLa | α-Pinene, 4αβ,7α,7αβ-nepetalactone, 4αα,7α,7αβ-nepetalactone, α-amorphene, ϒ-cadinene, cis-calamenene, β-pinene, β-caryophyllene | Effect on lipid peroxidation, functions of oxidative enzymes | 134- 135 |
56. | Ocimum sanctum | Tulsi, holy basil | Laminaceae | Leaves | HFS-1080 | Oleanolic acid, ursolic acid, linalool, carvacrol, eugenol | Cytotoxic effect on leukemia cell lines | 136-138 |
57. | Oldenlandia corymbosa | Flat-top mille grains, dimond flower | Rubiaceae | Leaves | K562 | Geniposide, 6-α-hydroxygeniposide | Significant cytotoxic effect with Parthenium hysterophorus on cancer cell lines | 139 |
58. | Olea europea | Common olive, Indian olive | Oleaceae | Leaves | MCF-7, B16F10, HeLa | Secoiridoids such as oleuropein, ligstroside, methyloleuropein, flavanoids | Antiproliferative effect leading to decrease in tumor growth | 140- 141 |
59. | Ononis hirta | Restharrows | Fabaceae | Parts
(Aerial) |
Breast cancer cell line MCF-7
|
Flavanoids, terpenoids, phenolic compounds, alkaloidal | Solid tumor necrosis on combination with Bifiridobacteriumlongum | 142 |
60. | Origanum sipyleum | Amaracusgled, Turkish oregano | Laminaceae | Aerial parts | Vero , HeLa | ϒ-Terpinene, pcymene | Inhibition of cancer cell migration, proapoptotic activity, inhibit tumor growth | 143 |
61. | Parthenium hysterophorus | Santa-maria, white top weed, famine weed, congress grass | Asteraceae | Leaves | K562 | Germacrene- D, trans-β-ocimene | Considerable potential effect as cytotoxic & antioxidant action, inhibits lipid peroxidation, increase activity of caspase-3,6,9. | 144 |
62. | Phagna lonrupstre | Gnaphalonlowe | Asteraceae | Aerial parts | MCF-7, Hep-2 | Dimethylallyl-hydroquinone glucoside, | Antioxidation effect leading to generation of ROS, induces apoptosis | 145 |
63. | Picrorhiza kurroa | Kutki, katuka, picrorhiza | Plantaginaceae | Root | Colo205, Hop62, HT29, SiHa, MIA-PA-CIA-2, DWD, T24, PC3, A549, ZR75-I, A2780, DU145, MCF7, K562 | Picoside I, II, d-mannitol, kutkiol, kutkisterol, apocynin, androsin | Regulate the expression of cyclinD1 &CDKs help protect cells against carcinogenesis, inhibition of NF-Kb | 146 |
64. | Piper longum | Pipli, Indian long pepper | Piperaceae | Fruit | Colo205, Hop62, HT29, SiHa, MIA-PA-CIA-2, DWD, T24, PC3, A549, ZR75-I, A2780, DU145, MCF7, K562 | α-pinene, caryophyllene,Limonene, α-copaene, | Selectively induced caspase independent apoptosis | 147 |
65. | Plectranthus stocksii | Spur-flower | lamiaceae | Stempart and leaves, | MCF-7,
RAW 264.7, Caco cell line |
Ferulic acid, caffeic acid, catechin | Antioxidant effect as the major mechanism | |
66. | Populous alba | Silver poplar, white poplar | salicaceae | Flowers | MCF-7, Hep-2 | Tremuloidin, populin, chaenomeloidin, salicin, tremulacin, catechol, benzoic acid, salicylol | Strong antiproliferative, cytotoxic & potent antioxidant properties | 148 |
67. | Pterocephaluspulverulentus | Wing head shaped | Dipsacaceae | Aerial parts | MCF-7, Hep-2 | Flavanoids, alkaloidal, polyphenols, quercetin | Antioxidant effect and antimigratory effect shown against cancer cell lines | 149 |
68. | Rosa damascena | Damask rose, bulgarian rose | Rosaceae | Flowers | Vero , HeLa | Flavanoids, carboxylic acid, glycosides, quercetin | Cell viability decreased | 150 |
69. | Diplotaxis harra | Middle east harra, forssk. | Brassicaceae | Whole plant, aerial parts | HCT116, HepG2, MCF7 | Quercetin | Antioxidant effect | 151 |
70. | Salvia officinalis | Culinary sage, garden sage | Lamiaceae | Aerial parts | MCF-7, B1610, HeLa | Thujone, β-caryophyllene, cineole, α-humulene, β-pinene, β-thujone, camphor, allo-aromadendrene, borneol, α-pinene | Regulates p53 signalling, cell cycle regulation by G1/S phase arrest | 152- 153 |
71. | Saururus chinensis | Lizard’s tail | Saururaceae | Roots | MCF-7 | Glucosides, hydrolyzable tannins, indolealkaloidal, sitosterols, aristolactam A, ellagic acid, corilagin, lyoniside, neolignans | Antiproliferative activity and antiangiogenetic action | 154- 155 |
72. | Scorzoneratomentosa | Scorzonera | Asteraceae | Aerial parts | Vero, HeLa | Flavanoidaglycones, glycosides, phenolic acids, triterpenoids, bibenzyl derivatives | Antioxidant activity leading to apoptosis | 156-158 |
73. | Senecio scandens | Climbing senecio, sai-ek-hlo | Asteraceae | Leaves | MCF-7, DL, HeLa | Senecainin A, 3-methoxyisonicotinic acid, monoepoxylignanolide, pinoresinol | High ration of Bax/Bcl-2 promotes apoptosis activity, upregulation of capase-3,9 proteins | 159-160 |
74. | Solanum khasianum | Nightshade | Solanaceae | Fruit | MCF-7, DL, HeLa | Dillapiole, α-cardinol, para-cymene, β-damascenone, α-phellandrene, β-pinene, α-bisabololactate | Cytotoxic effect on cancerous cells and induces cell death and arrest of cell division | 161 |
75. | Citrullus colocynthis | Vine of Sodom, bitter apple, bitter cucumber, desert gourd | Cucurbitaceae | Root, bark, leaves | HepG2 hepatoma cells, colorectal cancer | Cucurbitacin, flavanoids, alkaloidal, phenoli acids | Increase in caspase-3 activity and inhibiting STAT3 function | 162- 163 |
76. | Syringa vulgaris | Common lilac | Oleaceae | Seeds | MCF-7 cell line,
Hep-2 |
Iridoids, lignans, phenylpropanoids, phenylethanoids | Oxidative stresses induces apoptosis in cancer cells | 164- 165 |
77. | Syzygium cumini | Indian blackberry, jamun | Myrtaceae | Seeds | A2780, MCF7, PC-3, H460 | Anthocyanins, glucoside, ellagic acid, isoquercetin, kaemferol, myrecetin | Antiproliferative and antioxidant activity | 166-168 |
78. | Tabernaemontana divaricata | East Indian rosebay, moon beam, coffee rose | Apocynaceae | Flowers | NIH3T3, HeLA | Α-amyrin acetate, α-amyryloctadecanoate, taraxasterol acetate, calycosin, formononetin, farnisin | Superoxide anion scavenging activity, reduced GSH levels | 169-170 |
79. | Tecoma stans | Yellow trumpetbush, yellow bells | Bignoniaceae | Leaves, flowers | A549 | Alkaloidal, flavanoids, phenylbenzopyrone | inhibit aromatase & disturbs cell division at telophase | 171- 172 |
80. | Terucrium polium | Felty germander | Laminaceae | Stems, Leaves | MCF-7,
CACO-2, Hep-2, |
Agarospirol, caryophyllene, β-caryophyllene, α-humulene, β-bisabolene, β-sesquiphellandrene, dolichodial | Inhibition of DNA oxidation, lipid oxidation | 173-175 |
81. | Tillandsia recurvata | Ball moss | Bromeliaceae | Plant
|
HL60 | Caffeic acid | FMS-like tyrosine kinase 3 get inhibited | 176- 177 |
82. | Verbascums inuatum | Wavy-leaf mullein | Scrophulariaceae | Aerial parts, flowers | MCF-7, Hep-2 | Verbathasin A, luteolin, 3-O-fucopyranosylsaikogenin F, verbascoside | Apoptosis enhanced | 178- 179 |
83. | Vitisv inifera | European wine grape, common grape | Vitaceae | Sap of stem | MCF-7,
HeLa |
Phenolic compounds, flavanoids | Antioxidant, antiproliferative effect because of epicatechin-3-O-gallate present | 180-181 |
84. | Zea mays | Indian corn | Gaminaea | leaves | Hep2 | Quercetin diglucoside, maizenic acid, rutin, chlorogenic acid, hydroxycinnamic acid, flavanoids, saponins, phytosterol, eugenol | Oxidative stress induces apoptosis, upregulation of p53 | 182- 183 |
85. | Allium savitum | Garlic | Amaryllidaceae | Bulb | Skin, colon, lung, prostate, leukemia, breast cancer | S-allylcysteine, allicin, S-allylmercapto-L-cysteine | High radical scavenging activity, antiproliferative growth, inhibits tumor growth | 184-186 |
86. | Acronychiabaueri | Chakkimaram, mootanari, aspen | Rutaceae | Bark | Carcinoma, colon cancer | Alkaloids (normelicopidine, melicopine, acronycine), triterpenelupeol | Antiproliferative and antioxidant effect | 187 |
87. | Alstonia boonei | Cheese wood, pattern wood, stool wood | Apocynaceae | Stem, bark, leaf, root | Pancreas, lung, prostate, colon cancer | Echitamine, eugenol, 1,2 benzene dicarboxylic acid, alstiboonine | Antiproliferative and cytotoxic effect | 188- 189 |
88. | Thymus vulgaris | Thyme | Lamiaceae | Bulb, leaves | MCF-7 cell lines, HeLa | Diallyl disulphide, diallyltrisulphide, allicin, tannins, triterpenes, styerols, flavonoids, glycosides | By controlling interferon signalling, biosynthesis of N-glycxan | 190- 191 |
89. | Tithonia diversifolia | Gaint Mexican sunflower | Composiae | leaves | HL-60, U373, Col2 colon cancer cells | Tagitinin C, 1-β-methoxydiversifolin, 3-O-methyl ether, 1-β- & 2-α-epoxytagitinin C | Inhibit cell proliferation, induces cell death | 192 |
Clinical Trials on Isolated Constituents (https://clinicaltrials.gov/): Herbal drugs are integral to the health care system. Clinical trials are essential to assess the risks associated with herbal drugs.
In clinical trials, herbal medicines must be proven safe and effective before their effectiveness can be determined. Clinical studies about herbal anticancer are interventional, observational, and other types mentioned in the literature. In this article, we consider the clinical studies related to herbal drugs used in cancer.
An early phase 1 (NCT01568996) study on Sulforaphane was done to determine the chemopreventive action and modulate the melanoma.
Another phase 1 (NCT03980509) study is performed on curcumin to study its effect on breast cancer. Effect of qucertein (NCT03980509) has been tested on polyphenols uptake subject’s suffering from prostate cancer. Similarly, clinical trials on the herbal drug used as an anticancer drug are listed in Table 4.
TABLE 4: CLINICAL TRIAL ON HERBAL DRUGS
Description | Type of study | Phase of study | Design of study | Age
(years) |
Subject participated | Status of study | Reference |
Traditional Chinese Medicine in breast and other cancers
|
Interventional | Phase 2 | Randomized | ≥21 | 80 | Recruiting | NCT04104113 |
Teng-Long-Bu-Zhong-Tang herbal along With Chemotherapy in Colorectal cancer patients | Interventional | Phase 1 | Randomized | 18-70 | 72 | Completed | NCT01975454 |
Herbal drug products in patients of breast cancers for reduction of dermatitis induced by radiation | Interventional | Phase 2 | Randomized | ≥20 | 150 | Completed | NCT02922244 |
TPE-1 herbal formula effect in breast cancer patients | Interventional | Not Applicable | Randomized | 18-70 | 60 | Completed | NCT01142479 |
KD018 and Sorafenib in patients with hepatic carcinoma | Interventional | Phase 2 | Not applicable | ≥18 | 18 | Completed | NCT01666756 |
Dendrobium Huoshanense Granules effects in rectal cancer patients | Interventional | Phase 3 | Randomized | 18-70 | 210 | Recruiting | NCT04394598 |
Traditional Chinese Medicine regulation in cancer patients | Interventional | Phase 1 | Not applicable | ≥20 | 300 | Recruiting | NCT04438564 |
Da Huang Gang Tsao Tang effect for improving appetite in patients of cancer at late-stage | Interventional | Phase 2 | Not applicable | ≥20 | 4 | Completed | NCT01503346 |
Effect of Chinese herbal therapy in women of breast cancer undergoing chemotherapy | Interventional | Not Applicable | Randomized | ≥18 | Unknown | Completed | NCT00028964 |
Herbal drug therapy in patients of prostate cancer | Interventional | Phase 2 | Not applicable | ≥18 | 43 | Completed | NCT00669656 |
Effect of ACAPH in patients of Intraepithelial neoplasia having smoking history | Interventional | Phase 1 | Randomized | 45-75 | 90 | Completed | NCT00522197 |
Effect of combination of chinese and western medicine in cancer patients having constipation | Interventional | Phase 2 | Randomized | ≥18 | 60 | Completed | NCT02795390 |
TCM-TSKSR effects in patients having cancer at different stages | Interventional | Phase 2 | Randomized | 18-75 | 400 | Recruiting | NCT03716518 |
Herbal Mouth rinse in patients of cancer having mucositis | Interventional | Phase 2 | Randomized | 18-89 | 50 | Completed | NCT01898091 |
Angelica Sinensis effect in prostate cancer for treatment of hot fleshes | Interventional | Phase 2 | Randomized | ≥18 | 44 | Completed | NCT00199485 |
Traditional and complementary medicine effect in Ovarian Cancer | Interventional | Phase 3 | Not applicable | ≥18 | 28 | Completed | NCT01419210 |
Food supplements in cancer threapies | Interventional | Phase 2 | Non-Randomized | ≥18 | 60 | Recruiting | NCT04474951 |
Effect of KD018 in colorectal cancer | Interventional | Phase 4 | Randomized | ≥18 | 33 | Completed | NCT00730158 |
Sho-Saiko in hepatic cancer | Interventional | Not Applicable | Not applicable | ≥18 | Completed | NCT00040898 | |
Traditional chinese medicine effect in triple-negative breast cancer | Interventional | Not Applicable | Randomized | 18-70 | 200 | Recruiting | NCT04403529 |
Effect of SH003 in Solid Cancer | Interventional | Phase 2 | Sequential Assignment | ≥19 | 11 | Completed | NCT03081819 |
Blue Citrus in breast cancer | Interventional | Phase 2 | Randomized | ≥18 | 30 | Completed | NCT00702858 |
Dietary supplement effect in breast cancer | Observational | Phase 3 | Cohort | ≥18 | 200 | Completed | NCT03959618 |
FuzhengYiliu effect in chemotherapy patients | Interventional | Phase 1 | Non-Randomized | 18-75 | 189 | Recruiting | NCT04459754 |
Chemotherapy and Traditional chinese medicine effect on Lung Cancer | Observational | Not Applicable | Not Applicable | 65-80 | 82 | Completed | NCT01780181 |
Sipjeondaebo-tang in patients of cancer having anorexia | Interventional | Not Applicable | Randomized | 20-80 | 32 | Completed | NCT02468141 |
Siliphos in hepatic cancer patients | Interventional | Phase 2 | Non-Randomized | ≥18 | 3 | Completed | NCT01129570 |
Artemi Coffee in Patients of ovarian cancer at advanced stage | Interventional | Not Applicable | Non-Randomized | ≥18 | 18 | Recruiting | NCT04805333 |
Oligo-Fucoidan effect in hepatic cancer | Interventional | Not Applicable | Randomized | ≥18 | 100 | Recruiting | NCT04066660 |
Chamomile gel in prevention of oral mucositis induced by chemotherapy | Interventional | Phase 1 | Randomized | 20-70 | 45 | Recruiting | NCT04317183 |
Effect of curcumin on radiation induced dermatitis among the person suffering from breast cancer | Interventional | Phase 1 | Randomized | 21 | 35 | Completed | NCT01042938 |
Effect of curcumin on pancreatic cancer was studied. | Interventional | Phase 2 | Not applicable | 18 | 50 | Completed | NCT00094445 |
Resveratrol effect on patients with colon cancer. | Interventional | Phase 2 | Not applicable | 18 | 11 | Completed | NCT00256334 |
Artesunate effect in Colorectal Cancer at different stages. | Interventional | Phase 2 | Randomized | 18-70 | 200 | Recruiting | NCT03093129 |
The effect of Chinese herbs on syndrome differentiation with reduced side effects and increased antitumour effect was studied. | Interventional | Phase 2 | Randomized | 18 | 200 | Unknown | NCT02737735 |
This study aims to know the effect of berberine to prevent colorectal adenomas in patients with previous colorectal cancer. | Interventional | Phase 1 | Randomized | 18-80 | 1000 | Unknown | NCT03281096 |
To study the effect of lycopene in colorectal carcinoma patients. | Interventional | Phase 2 | Randomized | 18 | 28 | Completed | NCT03167268 |
This study aims to know the chemoprevention effect of Sulforaphane in lung cancer in former smokers. | Interventional | Phase 1 | Randomized | 55-75 | 72 | Recruiting | NCT03232138 |
The effect of Chinese herbs on syndrome differentiation with reduced side effects and increased antitumour effect was studied | Interventional | Phase 2 Phase 3 | Randomized | 18 | 200 | Unknown | NCT02737735 |
This study aims to know the effect of berberine to prevent colorectal adenomas in patients with previous colorectal cancer. | Interventional | Phase 2 | Randomized | 18-80 | 1000 | Unknown | NCT03281096 |
This study aims to know the chemoprevention effect of Sulforaphane in lung cancer in former smokers. | Interventional | Phase 2 | Randomized | 55-75 | 72 | Recruiting | NCT03232138 |
To study the effect of epigallocatechin gallate colorectal cancer patients. | Interventional | Early Phase 1 | Randomized | ≥18 | 50 | Recruiting | NCT02891538 |
A Phase 1 Dose Escalation of Artemi Coffee in Patients With Advanced Ovarian Cancer | Interventional | Phase 1 | Non-Randomized | ≥18 | 18 | Recruiting | NCT04805333 |
Kanglaite ( Coix Seed Oil ) in head and neck Cancer | Interventional | Phase 2 | Not applicable | 18-80 | 53 | Completed | NCT03101514 |
Effect of Kanglaite Injection with gemcitabine in pancreatic cancer | Interventional | Phase 2 | Randomized | 18-75 | 85 | Completed | NCT00733850 |
CONCLUSION: Throughout the world, cancer threatens millions of lives each year. Aside from affecting a patient's physical health and quality of life, treatments such as surgery and chemotherapy do not dramatically improve the chances of survival. Even though modern medicine has greatly influenced people's lives and synthetic drugs have become more readily available; still, most of the people depend on plant remedies. WHO data shows that greater than 75% of the population rely on plant remedies or extracts for health care needs. Research results have directed to expanding plant-derived products after achieving excellent results and are now conducting clinical trials. An effective way to inhibit cancer cells is with plant-derived anticancer agents, making them highly valuable. To meet demand and remain sustainable, herbal drugs must be exploited efficiently. The current review may provide researchers with a great deal of information about herbs, their effects on disease, and the safety of using them.
ACKNOWLEDGEMENT: None
CONFLICTS OF INTEREST: The authors declare no conflict of interest.
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How to cite this article:
Kumar V, Garg V and Dureja H: Plant derived anticancer agents for treatment of cancer. Int J Pharm Sci & Res 2022; 13(9): 3375-96. doi: 10.13040/IJPSR.0975-8232.13(9).3375-96.
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Article Information
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3375-3396
1774 KB
489
English
IJPSR
Virender Kumar, Vandana Garg * and Harish Dureja
Faculty of Pharmaceutical Sciences, M. D. University, Rohtak, Haryana, India.
Vandugarg@rediffmail.com
18 January 2022
25 April 2022
27 April 2022
10.13040/IJPSR.0975-8232.13(9).3375-96
01 September 2022