ISSN: 0973-7510

E-ISSN: 2581-690X

Mini Review | Open Access
Sanjib Kalita1, Anindita Sarma1, Ankur Hazarika2 , Satarupa Hazarika3, Saranga Pani Saikia4 and Dibyajyoti Kalita4
1Department of Botany, Gauhati University, Guwahati – 781 014, Assam, India.
2Department of Zoology, Gauhati University, Guwahati – 781 014, Assam, India.
3Handique Girls’ College, Guwahati – 781 001, Assam, India.
4Department of Zoology, Assam Don Bosco University, Sonapur – 782 402, Assam, India.
Article Number: 7730 | © The Author(s). 2022
J Pure Appl Microbiol. 2022;16(3):1608-1621. https://doi.org/10.22207/JPAM.16.3.57
Received: 31 March 2022 | Accepted: 25 July 2022 | Published online: 24 August 2022
Issue online: September 2022
Abstract

Human beings are affected by different diseases and suffer to different extents. Cancer is one of the major human disease and millions of people suffered from cancer and end their lives every year. Peoples are dependent on herbal medicines since prehistoric time especially from developing countries. It is very common to have different side effects of modern synthetic medicines; hence now-a-days importance of herbal medicines due to no or least side effects increases all parts of the world. But the major problems of using herbal medicines are that plants can produce very limited amount of medicinally important bioactive metabolites and they have very long growth periods. Therefore endophytes are the excellent alternative of plant derived metabolites. Endophytic microbes can synthesize exactly same type of metabolites as the plant produces. North East India is a treasure of plant resources; various types of medicinal plants are present in this region. Different types of indigenous tribes are inhabited in this region who used different plants in traditional system for treating various disease. But with increasing demand it is sometimes not sufficient to manage the demand of medicines, therefore for massive production endophytic study is crucial. In spite of having huge plant resources very limited endophytic studies are observed in this region. In this review, we studied different plants with their endophytes of NE India showing anticancer properties.

Keywords

Medicinal Plants, Anticancer Agent, Secondary Metabolites, Endophytes

Introduction

Cancer is one of the major challenges and is one of the leading causes of death globally. According to International Agency for Research on Cancer, the incidence of mortality and prevalence of major forms of cancer in 184 countries across the globe revealed that there were 8.2 million people lost their lives and 14.1 million new cancer cases across the world annually, and it was estimated that there will be 26 million people newly get infected and 17 million people will die due to cancer per year by 2030.1 Again according to Cancer Research UK 9.6 million people ended up their lives out of 17 million people suffered from cancer in 2018 and they expected that by 2040 about 27.5 million new cancer patients in each year if this increasing trend will continue.2 In cancer the control of growth is lost in one or more cells which lead to either solid mass of cells called tumour or to a liquid cancer like blood or bone marrow related cancers.3 Cancer is not a single disease, it is a group of disease all showing unregulated cell growth and originated due to abnormal functions of genes. Cancer cells can invade nearby tissues or it can spread via lymphatic system or blood to distant part of the body.4,5 A typical cancer cell has the ability to invasion and angiogenesis and they overcome apoptosis.6 In the process of transformation of normal cell to malignant cell sequence of events takes place which results accumulation of genetic instabilities in a cell. Genetic instability leads to mutations, if these mutations take place in oncogenes, tumour suppressor genes, DNA repair genes, apoptotic genes lead to development of cancer.6 Surgery, chemotherapy and radiotherapy are the three main treatment strategy involved in cancer treatment.7 Chemotherapy is the most effective method of cancer treatment, it uses low molecular weight drugs to selectively destroy or reduce their proliferation rate of tumour cells. There are some disadvantages of chemotherapy are also commonly observed, bone marrow suppression, gastrointestinal tract lesions, nausea, hair loss and clinical resistance are some side effects of chemotherapy due to the toxicity to both tumour cells as well as healthy cells of the cytotoxic agents used in chemotherapy.3,8 For reducing these side effects different plants and plant products are alternative ways for cancer treatment. Plants are very rich source of various secondary metabolites, which shows different medicinal properties. It has been reported potential anticancer/antitumor properties in various plant extracts, therefore these plant species can be used as safe and effective drugs for treating cancer.9-11

North-East India is one of the biodiversity hotspots which is located between 22–30°N latitude and 89–97°E longitude. This region is very rich in plant resources due to diversified topography and climatic conditions. High rainfall, moderate temperature and high humidity and marshes, swamps are characteristics in this region, which favors diversified species and wide range of vegetations from tropical to alpine forests.12 North-East India is topographically mostly hilly and is occupied by different tribes. These ethnic tribal communities mainly depend on herbal medicines for their healthcare needs as they have no adequate knowledge on modern medicines.13,14 The most challenging part of adapting herbal medicine is that in most cases plant can produce these medicinally important bioactive secondary metabolites in very low amount, long growth periods of plants and difficulty in separating the required compound from other compounds.15 Therefore, with the increasing demand to provide required amount of compounds exploitation of natural resources frequently happen. Therefore, for balancing both aspects i.e., production of sufficient amount of pharmacologically active compounds as well as conservation of natural resources without exploitation, scientist thought alternative ways, they exploit the ability of endophytic microbes to synthesize various bioactive secondary metabolites which shows exactly similar properties with the plant derived bioactive compounds.16 Endophytes are quite common in vascular plants, and are present almost every vascular plant of this planet.17 In 1866 De Barry for the first time coined the term endophytes.18 It has great importance to study endophytic microbes present in medicinal plants from both ecological and therapeutic point of view. In this review, we have studied different plant species found in North-East India showing the globe.

Plants from North-East India as a Source of Anticancer Phytochemicals
Plants have been using as source of food, shelter and medicine since the time of starting of human civilization.19 Dioscorides, one of the historically prominent Greek physician and pharmacologist in his 5 volume book “De Materia Medica,” described 600 medicinal plants used in different ailments.20 Herbal medicines are based on various cultural and traditional knowledge, hence, it is very well established way of searching novel phytochemicals for drug development based on traditional knowledge. Plant derived products has very less toxicity and much safer as compared to synthetic chemical drugs. Therefore, they are considered as the ideal candidate for modern drug discovery process. Different types of plant derived compounds and their metabolites are present in the root, stem, bark, leaves, and flower which serve diverse pharmacological activity in human healthcare. Compounds like alkaloids, flavonoids, Phenolics, glycosides, tannins, oils and gums are responsible for different therapeutic purposes. Till now, many phytochemicals such as taxol, topotecan, vinblastine and many more have been used successfully as anticancer drugs in clinical studies.21-23 Since North-East India is a great reservoir of plant resources, various types of bioactive secondary metabolites are produced by these plants which are used in different medicinal purposes including cancer. Table describes some plant species of North-Eastern India showing anticancer properties.

Table:
List of some plants having anticancer properties and associated endophytic microbes.

Sl No
Name of the Plant
Part used
Types of cancer it works
Endophytes
Metabolites
Reference
1
Adenanthera pavonina L.
Bark,

Seed

Leukemia, lymphoma, colon cancer
No data
Quercetin
  

  38

2
Ageratum conyzoides (L.) L.
Root, Leaves
Gastric carcinoma (SGC-7901), human colon adenocarcinoma (HT-29), leukemic, prostate cancer, breast cancer.
Shewanella spp., Pseudomonas spp.
2-amino-3-quinoline, Oleic acid, 1,2-Benzenedicarboxylic acid, Phthalic acid
39-43
3
Allium sativum L.
Bulb
Breast cancer, liver, colon, lung, cervix cancer, bladder carcinoma
Aspergillus terreus, Penicillium spp.
Allylmercaptocysteine, allicin
44-47
4
Aloe vera (L.) Burm.f.
Whole plant
Liver cancer (HepG2), breast cancer (MCF-7), cervical cancer
NAF-1 strain endophytic actinobacteria
Aloesaponarin
48-50
5
Alstonia scholaris (L.) R. Br.
Whole plant
Leukemia, Skin cancer
No data
No data
51,52
6
Annona muricata L.
Fruit
Pancreatic cancer, Nasopharynx cancer
Perconia spp.
Periconiasins
53
7
Azadirachta indica A. Juss.
Leaves, Seed
Lung cancer (U937), leukaemia (HL-60, THP1), skin melanoma (B16), prostate cancer (PC-3)
Fusarium tricinctum Nectria spp.,  Penicillium corylophilum,
Citreoisocoumarinol
54-58
8
Bauhinia variegate L.
Root
Breast, lung, liver, oral cavity, larynx
Bacillus spp.
Saponins, Alkaloids
59, 60
9
Betula pendula Roth.
Leaf
Leukaemia, Lung cancer
Melanconium betulinum
3-Hydroxypropionic acid
61, 62
10
Blumea balsamifera (L.) DC.
Leaves
Breast cancer, epidermal carcinoma of the mouth, myeloid leukaemia, lung cancer
Streptomycetes spp.
Borneol, Camphor
63 – 65

 

11
Cajanus cajan (L.) Millsp.
Leaves
Breast cancer
Hypocrea lixii
Cajanol
66-68
12
Camelia sinensis (L.) Kuntze
Leaves, Buds, Branches
Colorectal cancer
Pestalotiopsis fici
Siccayne [2-(3-Methyl-3- buten-1-ynyl) Hydroquinone]
69-72
13
Camptotheca acuminate Decne.
Whole plant
Colorectal cancer
Fusarium solani
Camptothecin
73
14
Cannabis sativa L.
Leaves
Breast cancer, brain/spine tumour, colorectal cancer, skin cancer
Alternaria spp., Penicillium spp., Rhizopus spp.
Cannabinoid
74-77
15
Capsicum annum L.
Whole plant
Various cancer types
Alternaria alternata
Capsaicin
78
16
Catharanthus roseus (L.) G. Don
Leaves
Nephroblastoma, acute lymphoblastic leukemia
Curvularia verruculosa
Vinblastine
79
17
Citrus medica L.
Root, Fruits, Leaves
Human lung carcinoma
Phyllosticta citricarpa
Taxol, Paclitaxel
80-82
18
Colchicum autumnale L.

 

Leaves

Flower

Hepatocellular carcinoma
No data
Colchicine
83, 84
19
Curcuma aromatica Salisb.
Rhizome
Breast cancer, leukaemia
Chaetomium globosum
Chaetoglobosin X
82, 85,  86
20
Daucus carota L.
Root
Leukaemia
Aspergillus ustas
Carotenoids, ascorbic acid, polyacetylenes
80, 87
21
Dillenia indica Linn.
Stem, bark
Breast cancer
Hypocrea spp.
Betulinic acid
88,89
22
Emblica officinalis Gaertn.
Bulb
Various type of cancer
Phomopsis spp., Xylaria spp.
Quercitin, Gallic acid, Ellagic acid
59, 90, 91
23
Enhydra Fluctuans Lour.
Whole plant
Ehrlich’s ascites carcinoma (EAC)
No data
Baicalein 7-O-glucoside, baicalein 7-O-diglucoside
92,93
24
Fagopyrum esculantum (Lehm.) Mansf. ex K.Hammer
Hull seed
Breast cancer, colon cancer
Bionacteria pityroides, Fusarium oxysporum, Alternaria spp.
Phenolic compounds like rutin
94-96
25
Fragaria vesca L.
Fruit
Hepatocellular carcinoma
No data
Borneol, Ellagic acid
59, 97
26
Fritillaria sp.
Whole plant
Inhibits proliferation and colony formation of cancer cells
Fusarium spp.
Peiminine
98
27
Glycyrrhiza glabra L.
Root
Colorectal cancer, breast cancer
Aspergillus spp., Chaetomium spp., Fusarium solani
Glycyrrhizin, rutin, Cinnamic acid, Quercitin, Kaempherol
80, 99
28
Guayana esequiba
Whole plant
Breast cancer, lung cancer, prostate gland cancer
Seimatoantlerium tepuiense
Taxol
100
29
Hevea brasiliensis (Willd. Ex A.Juss.) Mull.Arg.
Whole plant
Breast cancer, lung cancer, skin cancer
Eutypella scoparia
Cytochalasins
101
30
Huperzia serrata (Thunb.) Trevis.
Whole plant
Various types of cancer
Ceriporia lacerate
Ceriponols
102
31
Jatropha curcas L.
Leaves, Seed, Root
Cervical cancer, colon cancer, lung cancer
Collectotrichum truncatum, Nigrospora oryzae
Gallic acid, rutin, Saponin
94, 103,  104
32
Litchi sinensis Sonner
Leaves, Pericarp
Breast cancer, leukaemia, colorectal cancer
No data
Epicatechin, Kaempferol 3-O-β-glucoside, Kaempferol 3-O-α-rhamnoside, procyanidin and rutin
105, 106
33
Maytenus hookeri Loes.
Root nodules
Colon carcinoma
Micromonospora lupine
Lupinacidin
107
34
Mentha pulegium L.
Aerial parts
Gingival cancer, colon cancer, uterus cancer
Stemphylium globuliferum
Altersolanol
108, 109
35
Mimosa pudica L.
Whole plant
Leukaemia, lung cancer
No data
Flavonoids, mimosine
110, 80
36
Mirabilis jalapa L.
Bark, Leaves, Root
Breast cancer, cervical cancer
Aspergillus clavatonanicus
Ribosome-inactivating protein(RIP)
34, 111
37
Monarda citriodora Cerv. Ex Lag.
Whole plant
Prostate cancer
Fusarium oxysporum
Paclitaxel
112, 113
38
Nicotiana tabacum L.
Leaves
Breast cancer
Fusarium sambucinum
Flavonoids like nicotelline, nicotianine, nicotine, Anatabine, Cotinine
114, 80, 115
39
Ocimum sanctum L.
Leaves
Cervical cancer, Fibrosarcoma, Laryngeal epithelial sarcoma
Macrophomina phaseolina
Eugenol, carvacrol, methyl eugenol, carphyllene, flavonoids
71, 116
40
Panax ginseng C.A.Mey
Whole plant
Breast cancer
Paecilomyces spp.
Ginsenosides-Rg3, Rh2
117
41
Piper nigrum L.
Leaves, Fruit
Colorectal cancer, lung cancer
Colletotrichum gloeosporioides
Piperine
118
42
Pleurothallis immerse Linden & Rchb.f.
Whole plant
Acute lymphoblastic leukemia
Fusarium spp., Plactosphaerella spp., Stemphylium spp., Septoria spp., Cladosporium spp.
Sitostenone, Tyrosol, L- asparginase
119, 120
43
Podophyllum hexandrum Royle
Rhizome
Testicular gland cancer, Leukemia and solid tumors
Fusarium spp.
Podophyllotoxin
121-124
44
Potentilla fulgens var. macrophylla Cardot
Root
Leukaemia, lung cancer, liver cancer
Curvularia clavata, Curvularia lunata, Fusarium oxysporum
Kaempferol (KMP), Ellagic acid (ELA)
39, 125, 126
45
Salacia oblonga Wall.
Whole plant
Disruption of microtubulin equilibrium
Alternaria spp., Fusarium solani
Taxol
127
46
Silybum marianum (L.) Gaertn.
Whole plant
Lymphoblastic leukaemia, Breast cancer
Aspergillus izukae
Flavonolignans, Silybin A, Silybin B
128
47
Sinopodophyllum hexandrum (Royle) T.S.Ying
Whole plant
Hepatoma , lung cancer, neuroblastoma, testicular cancer,
Pestalotiopsis adusta
Pestalustaine B
129
48
Smilax china L.
Rhizome
Colon cancer, Leukaemia, prostate cancer
Mycosphaerella nawae
Isoflavone genistein, Quercitin, Baicalin, Kaempferol
130, 131
49
Solanum nigrum L.
Tuber
Breast cancer
SNFSt, SNFL and SNF
Solamargine
132, 133
50
Taxus baccata L.
Whole plant
Prostate gland cancer
Acremonium spp.
Leucinostatin A
134-136
51
Taxus wallichiana Zucc.
Inner bark
Breast cancer, lung cancer, prostate gland cancer
Seimatoantlerium nepalense
Taxol
137
52
Terminalia arjuna (Roxb. Ex. DC.) Wight & Arn.
Stem, Bark
Colon cancer, liver cancer oral cancer,  ovarian cancer,
Chaetomella raphigera
Arjunic acid, Arjungenin, Arjunetin, arjunoglucoside
138-140
53
Tinospora cordifolia (Willd.) Miers
Leaves
Colon cancer, cervical cancer, oral squamous cancer, ocary cancer
Cladosporium uredinicola
N-formylannonain magniflorin, jatrorrhizine, palmitin, 11-hydroxymustakone, cordifolioside A, Tinocordiside, Yangambin
39, 141, 142
54
Vitex trifolia L.
Leaf, Fruit
Leukaemia, Cervical cancer, breast cancer
Pestalotiopsis fici
Casticin, Trimethylquercetagetin
39, 143
55
Withania somnifera (L.) Dunal
Root
Human cervical cancer
Alternaria spp., Cladosporium spp., Colletotrichum spp., Fusarium spp., Xylaria spp.
5-Fluorouracil
144, 145
56
Xanthium strumarium L.
Root, Leaf, Fruit
Colon cancer, breast cancer, Lung cancer
Paecilomyces sp.
Xanthin, Xanthinocin, Xanthatin
34, 146
57
Zingiber officinale Roscoe
Rhizome
Breast cancer, colon cancer, Melanoma
Aplosporella javeedi
6-shogaol, Gigerol, Zingerone
147-149


Importance of Endophytes as a Source of Cancer Drugs
Endophytes are a good source of anticancer activities that could have vital impact as an anticancer drug.24 Till date, many endophytes had been already reported that can produce bioactive compounds which are effective in anticancer assays.25 The first and famous anticancer drug, Taxol, was produced from the endophytic fungus Taxomyces andreanae isolated from Taxus brevifolia Nutt that produce good anticancer activity against the cancer cell lines26. Figure 1 shows the recovering of fungal endophytes from plants and microscopic view of potent fungal endophyte. Several studies in recent times have been conducted where the taxol production by endophytes was boosted to maximum level via conjugation with gold nanoparticles which is then mediated by ɤ-irradiation27. Similar studies on enhancement of anticancer activity by gamma irradiation using extracts of Aspergillus sydowii isolated from the bark of Ricinus communis are also observed.28 The endophytic fungi Leptosphaerulina australis, Xylariaceae sp., and Stemphylium solanithat were isolated from Morinda citrifolia Linn. (Noni)inhibits the growth of human carcinoma cell linesMCF-7 (breast), LU-1 (lung), and PC-3 (prostate).29 Colletotrichum gloeosporioides isolated from Barringtonia acutangulawas reported by Lakshmi et.al. to shows anticancer activity against the Human Colon Cancer HT29 cell lines.30 The bioactive compound Eremofortin F isolated from the endophyte Diaporthe pseudomangiferae showed cytotoxic activity on MRC5 cells and KB cells.31 The endophytic fungus Pestalotiopsis clavispora that was isolated from Rhizophora harrisonii produce the compound pestalpolyol that showed strong cytotoxic activity against the mouse lymphoma cell line L5178Y.32 The endophytic fungi Alternaria sp. isolated from Eremophila longifolia showed cytotoxic activityagainst a lung cancer cell line and human broblast cell line.33 Cytotoxic activity was also shown by the endophytic fungi Penicillium sp. isolated from Centella asiatica against HeLa, A431, and human breast cancer (MCF7).34 All these studies reported by various researchers proved that endophytes are a very good source of anticancer drugs which can be used in various pharmaceutical industries. Penicillium oxalicum, the endophytic fungi isolated from Amoora rohituka was found to have anticancer activity. The breast cancer and T lymphoma cells was found to be inhibited by the ethyl acetate extract of P.oxalicum.35 Several reports are also there where the cytotoxic and anticancer activities are observed by the endophytic bacteria. Species of Bacillus as well as Micromonospora isolated from Ibervillea sonorae was found to have antitumor activities against L5178Y-R lymphoma cells.36 In addition to the plants, endophytes from liverworts also are reported to have anticancer properties. The endophytic extract from Marchantia polymorpha was tested for anticancer activity and was found to be effective against a panel of cancer cell lines (FaDu, HeLa etc.).37

Figure 1. A) Isolation of endophytic fungi from Cannabis sativus and microscopic view of potent fungal endophyte Alternaria alternata. B) Isolation of endophytic fungi from Capsicum annuum and microscopic view of potent fungal endophyte Colletotrichum gleosporioides

Figure 2. Chemical structure of some major anticancerous compounds (SOURCE: Pubchem)

CONCLUSION

Since time immemorial human beings are dependent on plant resources for fulfilling their various needs, medicines are one of the most essential parts of daily needs. Medicinal plants are a very rich source of various types of bioactive compounds, due to which they can show medicinal properties and can be used for remediation of different ailments. In developing countries, about 80% of the population especially from rural areas depends on herbal medicines for their health care needs (WHO report 2001). Different types of diseases cause suffering to different extent in human health. Cancer is one of the most serious health issues across the world, which takes millions of lives every year. The first time written record of human cancer was seen in ancient Egyptian manuscript. Though, cancer has afflicted human population since prehistoric time, but in recent few decades due to presence of increased amount of carcinogens in environment and in consumable products, prevalence of cancer is increasing day by day.150 In North-Eastern part of India also cancer has become a very common disease. Therefore, there is a very urgent need to search for potent plant bioactive metabolites for the effective treatment of cancer.

North East India is a biodiversity hotspot and inhabited by many tribal communities. These indigenous tribes use different medicinal plants for treating various diseases including cancer. Figure 2 shows structures of some of the major anticancer compounds. But with the increasing population rapid commercialization demand for these plant derived products increases tremendously, which leads to biodiversity loss. Many plants have undergone destruction and are on the threat status. Therefore an alternative way of obtaining necessary bioactive compounds to combat with disease is very crucial. It is very fortunate that endophytic microbes have the capability to produce these metabolites. Therefore, they can be used as alternative source for bioactive metabolites. In North-Eastern India till now very few endophytic studies are carried out, it is a very bright research approach for exploring the potentiality of endophytic microbes in synthesizing various metabolites. Therefore, we conclude that by extensive endophytic study we can save millions of people from deadly cancer without destroying biodiversity. In North-East India extensive endophytic study can open new doors for pharmaceutical companies which can make better human health.

Declarations

ACKNOWLEDGMENTS
The authors would like to thank Gauhati University and Assam Don Bosco University for providing the necessary library facilities to study the relevant literature in doing all review process.

CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.

AUTHORS’ CONTRIBUTION
SK and AS conceptualised the idea, reviewed and prepared the draft manuscript. AH, SH, SPS and DK helped in reviewing, formatting and editing the manuscript. All authors read and approved the final manuscript for publication.

FUNDING
None.

DATA AVAILABILITY
All datasets generated or analyzed during this study are included in the manuscript.

ETHICS STATEMENT
Not applicable.

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