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ISSN (Print): 2320-5148

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PLANT DERIVED ANTICANCER AGENTS FOR THE TREATMENT OF CANCER

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PLANT 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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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

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