VARIOUS PLANTS USED IN ANTI CANCER THERAPY

Amit Biswas

Student, B.Pharm

Bengal School of Technology

   (A College of Pharmacy)

INTRODUCTION

Cancer disease caused by an uncontrolled division of abnormal cells in a part of the body.. The cancer is very serious if the tumor begins to spread (metastasize) throughout the body. There are many types of cancer. They are named based on where the tumor is located, or where it first started growing in the body. The most common forms of cancer are colon, lung, breast and prostate cancer. Chemotherapy is the use of anti-cancer of drugs. Anti-cancer drugs destroy cancer cells by stopping growth or multiplication at some point in their life cycles. Drugs may be administered intravenously (into a vein), orally (by mouth), by injection into a muscle, topically (applied to the skin) or in other ways, depending on the drug and the type of cancer. Chemotherapy is often given in cycles of alternating treatment and rest periods. Radiation therapy is the treatment of cancer and other diseases with ionizing radiation destroys cells, or the genetic material of cells, in the area being treated, thereby making it impossible for these cells to continue to grow. The search for anti-cancer agents from plant sources started in earnest in the 1950s with the discovery and development of the vinca alkaloids, vinblastine and vincristine, and the isolation of the cytotoxic podophyllotoxins. As a result, the United States National Cancer Institute (NCI) initiated an extensive plant collection program in 1960, focused mainly in temperate regions. This led to the discovery of many novel chemotypes showing a range of cytotoxic activities (Cassady and Douros, 1980), including the taxanes and camptothecins, but their development into clinically active agents spanned a period of some 30 years, from the early 1960s to the1990s. This plant collection program was terminated in 1982, but the development of new screening technologies led to the revival of collections of plants and other organisms in 1986, with a focus on the tropical and sub-tropical regions of the world. It is interesting to note, however that no new plant derived clinical anti-cancer agents have, as yet reached the stage of general use, but a number of agents are in preclinical development.[1]

New therapeutic direction can be created by building novel drug delivery system based on the natural substances and a new window of opportunity can be opened regarding drug discovery. One of the biggest advantages that can be seen in using natural substances is the reduction of cost regarding the chemotherapeutic treatment where the present developmental medicine is out of reach of majority of people because of exorbitant costs. The following project deals with the intricacies of natural drugs in chemotherapy by creating a timeline from the present day natural products in use to the development of emerging therapeutics and tries to asses the direction of future of natural drug discovery[1].

CELL CYCLE & CANCER:-

In a healthy body, the trillions of cells it’s made of grow and divide, as the body needs them to function daily. Healthy cells have a specific life cycle, reproducing and dying off in a way that is determined by the type of cell. New cells take the place of old or damaged cells as they die. Cancer disrupts this process and leads to abnormal growth in cells. It’s caused by changes or mutations in DNA.

The cell cycle, the process by which cells progress and divide, lies at the heart of cancer. In normal cells, the cell cycle is controlled by a complex series of signaling pathways by which a cell grows, replicates its DNA and divides. This process also includes mechanisms to ensure errors are corrected, and if not, the cells commit suicide (apoptosis). In cancer, as a result of genetic mutations, this regulatory process malfunctions, resulting in uncontrolled cell proliferation.

The cell division involves a complex series of molecular and biochemical signaling pathways that cue a cell to divide. The process of cell division, also called mitosis, is accomplished through four phases:

1. The G1, or gap phase(Presynthetic phase), in which the cell grows and prepares to synthesize DNA (synthesis of enzymes and other cellular component needed for DNA synthesis);

2. The S, or synthesis phase, in which the cell synthesizes DNA;

3. The G2, or second gap phase (premitotic phase), in which the cell prepares to divide (synthesis of cellular component for mitosis);

4. The M, or mitosis phase, in which cell division occurs.

5. The G0 or resting phase, in which the cell stop dividing temporarily or permanently.

 As a cell approaches the end of the G1 phase it is controlled at a vital checkpoint, called G1/S, where the cell determines whether or not to replicate its DNA. At this checkpoint the cell is checked for DNA damage to ensure that it has all the necessary cellular machinery to allow for successful cell division. As a result of this check, which involves the interactions of various proteins, a "molecular switch" is toggled on or off. Cells with intact DNA continue to S phase; cells with damaged DNA that cannot be repaired are arrested and "commit suicide" through apoptosis, or programmed cell death.

 A second such checkpoint occurs at the G2 phase following the synthesis of DNA in S phase but before cell division in M phase. Cells use a complex set of enzymes called kinases to control various steps in the cell cycle. Cyclin Dependent Kinases, or CDKs, are a specific enzyme family that use signals to switch on cell cycle mechanisms. CDKs themselves are activated by forming complexes with cyclins, another group of regulatory proteins only present for short periods in the cell cycle. When functioning properly, cell cycle regulatory proteins act as the body's own tumor suppressors by controlling cell growth and inducing the death of damaged cells. Genetic mutations causing the malfunction or absence of one or more of the regulatory proteins at cell cycle checkpoints can result in the "molecular switch" being turned permanently on, permitting uncontrolled multiplication of the cell, leading to carcinogenesis, or tumor development.

On the basis of cell cycle we can classify anticancer drugs in two types [2].

ANTICANCER DRUG[3]

HALLMARKS OF CANCER[4]

The hallmarks of cancer constitute an organizing principle that provides a conceptual basis for distilling the complexity of this disease in order to better understand it in its diverse presentations. This conceptualization involves eight biological capabilities—the hallmarks of cancer—acquired by cancer cells during the long process of tumor development and malignant progression. Two characteristic traits of cancer cells facilitate the acquisition of these functional capabilities. The eight distinct hallmarks consist of: 

1. SUSTAINING PROLIFERATIVE SIGNALING:- Cancer cells do not need stimulation from external signals (in the form of growth factors) to multiply. cells of the body require hormones and other molecules that act as signals for them to grow and divide. Cancer cells, however, have the ability to grow without these external signals. There are multiple ways in which cancer cells can do this: by producing these signals themselves, known as autocrine signalling; by permanently activating the signalling pathways that respond to these signals; or by destroying 'off switches' that prevents excessive growth from these signals (negative feedback). 

2. EVADING GROWTH SUPPRESSORS:- To tightly control cell division, cells have processes within them that prevent cell growth and division. These processes are

CELL CYCLE SPECIFIC DRUG

 Act on S phase:-methotrexate, 6-mercaptopurine

 Act on M phase:-vincristine, vinblastine, paclitaxel

 Act on S-G2 phase:-Etoposide , Teniposide

CELL CYCLE NON-SPECIFIC DRUG

 Alkylating agent:-Melphalan, Cyclophosphamide, Busulphan

 Anticancer antibiotic:-Doxorubicin, Actinomycin D

 Metal complexes:-Cisplatin, Carboplatin

orchestrated by proteins known as tumor suppressor genes. These genes take information from the cell to ensure that it is ready to divide, and will halt division if not (when the DNA is damaged, for example). In cancer, these tumour suppressor proteins are altered so that they don't effectively prevent cell division. 

3. RESISTING CELL DEATH:- Cells have the ability to 'self-destruct'; a process known as apoptosis. This is required for organisms to grow and develop properly, for maintaining tissues of the body, and is also initiated when a cell is damaged or infected. Cancer cells, however, lose this ability; even though cells may become grossly abnormal, they do not apoptosis. 

4. ENABLING REPLICATIVE IMMORTALITY:- Cells of the body don't normally have the ability to divide indefinitely. They have a limited number of divisions before the cells become unable to divide (senescence), or die (crisis). The cause of these barriers is primarily due to the DNA at the end of chromosomes, known as telomeres. Telomeric DNA shortens with every cell division, until it becomes so short it activates senescence, so the cell stops dividing. Cancer cells bypass this barrier by manipulating enzymes that increase the length of telomeres. Thus, they can divide indefinitely, without initiating senescence. 

5. INDUCING ANGIOGENESIS:- Angiogenesis is the process by which new blood vessels are formed. Cancer cells appear to be able to kickstart this process, ensuring that such cells receive a continual supply of oxygen and other nutrients. 

6. ACTIVATING INVASION AND METASTASIS:- Cancer cells can break away from their site or organ of origin to invade surrounding tissue and spread (metastasize) to distant body parts.It is the most important properties of cancer cells is their ability to invade neighboring tissues. 

7. DEREGULATING CELLULAR ENERGETICS AND METABOLISM:- Most cancer cells use abnormal metabolic pathways to generate energy. Cancer cells exhibiting the Warburg effect upregulate glycolysis and lactic acid fermentation in the cytosol and prevent mitochondria from completing normal aerobic respiration. Instead of completely oxidizing glucose to produce as much ATP as possible, cancer cells would rather convert pyruvate into the building blocks for more cells. 

8. AVOIDING IMMUNE DESTRUCTION:- Despite cancer cells causing increased inflammation and angiogenesis, they also appear to be able to avoid interaction with the body’s via a loss of interleukin-33 immune system.

TYPES OF CANCER[5]

Cancers are named for the area in which they begin and the type of cell they are made of, even if they spread to other parts of the body. There are also several clinical terms used for certain general types of cancer: 

 CARCINOMA- It is a type of cancer that starts in cells that make up the skin or the tissue lining organs, such as the liver or kidneys. 

 SARCOMA- A type of cancer that begins in bone or in the soft tissues of the body, including cartilage, fat, muscle, blood vessels, fibrous tissue, or other connective or supportive tissue.

 LEUKEMIA- It is cancer of the body's blood-forming tissues, including the bone marrow and the lymphatic system. 

 LYMPHOMA- It is cancer that begins in infection-fighting cells of the immune system, called lymphocytes. These cells are in the lymph nodes, spleen, thymus, bone marrow, and other parts of the body. 

 MYELOMA- It also known as multiple myeloma, is a blood cancer arising from plasma cells

PLANTS HAVING ANTICANCER ACTIVITY

Sl.No        Botanical Name             Family                 Main active components                  Parts used

1.           Catharanthus roseus      Apocynaceae             vincristine, vinblastine                      Leaves

Catharanthus roseus

PHYTOCHEMISTRY[6]

That plant leaves contains more than 70 types of chemical constituents such as indole type of alkaloids, ajmalicine, serpentine and reserpine. Due to presence of those alkaloids in Catharanthus roseus, it have antihypertensive and antispasmodic properties. One of the important types of alkaloid is the vinblastine produced from Catharanthus roseus due to its antitumour activity and wide pharmaceutical use . Catharanthus roseus to produce modern chemotherapeutic agent for their pain-relieving properties .

Catharanthus roseus contains significant amounts of volatile and phenolic compounds including caffeoylquinic acids and flavonal glycosides which are known to antioxidant activity. It has a important role in the body defence system that is acts as a antioxidants against reactive oxygen species (ROS), which are harmful by forming such products through normal cell aerobic respiration. The flower petals, seeds and other parts of Catharanthus roseus exhibit antioxidant properties. Thus phenolic compounds have redox properties that act as reducing agents, hydrogen donors, singlet oxygen quenchers or metal chelators.

 Anticancer substances derived from this plant – vinca alkaloids(vincristine, vinblastine , vinorelbine)

MECHANISM OF ACTION

 These vinca alkaloids target the microtubular protein. 

Tubulin dimer bound to GTP ( Guanosine tri phosphate ) and are hydrolysed into GDP.

Thus they form microtubulin protein.

Vinca alkaloids binds to beta tubulin and prevent tubulin dimer from bindinding to growing chain.

Thus they prevent tubulin polymerization.

Prevent the formation of mitotic spindle.

Thus they induce terminal mitotic arrest.

Halts of cell division.

Which ultimately leads to cell death.

VINCRISTINE

USE:- Vincristine is used to treat leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, rhabdomyosarcoma (soft tissue tumors), neuroblastoma (cancer that forms in nerve tissue), and Wilms' tumor. It is also used to induce remission in acute lymphoblastic leukemia (ALL) with dexamethasone and L-Asparaginase, and in combination with prednisone to treat childhood leukemia.Vincristine is occasionally used as an immunosuppressant, for example, in treating thrombotic thrombocytopenic purpura (TTP) or chronic idiopathic thrombocytopenic purpura (ITP). SIDE EFFECTS:- 

 bronchospasm (wheezing, chest tightness, trouble breathing); 

 signs of infection such as fever, chills, sore throat, swollen gums, painful mouth sores, cold or flu symptoms; 

 problems with vision, hearing, speech, swallowing, walking, or daily activities; 

 numbness, burning, pain, or tingly feeling; or 

 severe constipation, severe bloating or stomach pain, bloody or tarry stools. 

 temporary hair loss; 

 decreased weight with loss of muscle tissue; 

 diarrhea, nausea, vomiting, loss of appetite; or 

 weight loss. 

VINBLASTINE USES:- 

 Breast cancer that has not gotten better with other treatment. 

 Choriocarcinoma that has not gotten better with other chemotherapy. Choriocarcinoma is a type of gestational trophoblastic disease.
 Hodgkin lymphoma.
 Kaposi sarcoma.
 Mycosis fungoides (a type of cutaneous T-cell lymphoma).
 Non-Hodgkin lymphoma (NHL).
 Testicular cancer. 

SIDE EFFECTS:- 

 severe constipation; 

 easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin; 

 problems with vision, hearing, speech, balance, or daily activities;

 bronchospasm--wheezing, chest tightness, trouble breathing; 

 signs of infection--fever, chills, sore throat, mouth sores; or 

 increased blood pressure--severe headache, blurred vision, buzzing in your ears, anxiety, confusion, chest pain, shortness of breath. 

 temporary hair loss; 

 jaw pain, tumor pain, bone pain; 

 nausea, vomiting.

Sl.No         Botanical Name             Family         Main active components                    Parts used

2                Taxus brevifolia            Txaceae                    Taxol                              Bark Taxus brevif0lia

PHYTOCHEMISTRY[7]

First drug, along the taxanes and paclitaxel, was discovered in extracts from the bark of the Yew tree, Taxus brevifolia, in 1967 by Monrie Wall and Mansukh Wani but its tubulin (tumor) inhibition activity was not known until 1979. Yews are poor source of active agents which limited the development of taxanes for over 20 years until discover of the way of synthesis (Jordan, 2012). In 1977, the trade name of paclitaxel was also known by "Taxol". In December 1992, paclitaxel was approved to be used in chemotherapy (Gordoliza, 2008).

Taxol, a plant alkaloid, is an anti-cancer chemotherapy drug. Chemical name of Taxol (trade name) is paclitaxel, a natural product with anti tumor activity. Paclitaxel is obtained via semisynthetic process from Taxus contorta, Taxus wallichiana, Taxus baccata, Taxus brevifolia. Paclitaxel is white to off-white crystalline powder with the empirical formula C47H51NO14 and molecular weight 853.9. It is highly lipophilic, insoluble in water and melt at around 216-217 oC. The chemical name for paclitaxel is 5β, 20–Epoxy-1, 2α, 4, 7β,10β,13α–hexahydroxytax-11-en-9-one4,10-diacetate2benzoate13esterwith(2R,3S)-N-benzoyl-3-phenylisoserine. 

 Anticancer substance obtain from this plant – paclitaxol

MECHANISM OF ACTION 

Paclitaxol binds to betatubulin Enhance the polymerization, a mechanism opposite to vincristine.

The microtubules are stabilized

and their depolymerisation is prevente

This stability results in inhibition of normal dynamic reorganization of the microtubules network that is essential for interphage and mitotic function.

Which ultimately leads to cell death

USES:- Treatment of breast, ovarian, lung, bladder, prostate, melanoma, esophageal, as well as other types of solid tumor cancers. It has also been used in Kaposi's sarcoma. 

SIDE EFFECTS:- 

 Low blood counts. Your white and red blood cells and platelets may temporarily decrease. This can put you at increased risk for infection, anemia and/or bleeding. 

 Hair loss 

 Arthralgias and myalgias, pain in the joints and muscles. (see pain) Usually temporary occurring 2 to 3 days after Paclitaxel, and resolve within a few days. 

 Peripheral neuropathy (numbness and tingling of the hands and feet) 

 Nausea and vomiting (usually mild) 

 Diarrhea

 Mouth sores 

 Hypersensitivity reaction.Fever, facial flushing, chills, shortness of breath, or hives after Paclitaxel is given (see allergic reaction). The majority of these reactions occur within the first 10 minutes of an infusion. Notify your healthcare provider immediately (premedication regimen has significantly decreased the incidence of this reaction). 

 Swelling of the feet or ankles (edema). 

 Increases in blood tests measuring liver function. These return to normal once treatment is discontinued. (see liver problems). 

 Low blood pressure (occurring during the first 3 hours of infusion). 

 Darkening of the skin where previous radiation treatment has been given (radiation recall - see skin reactions). 

 Nail changes (discoloration of nail beds - rare) (see skin reactions).

Sl.No        Botanical Name                 Family                  Main active components                Parts used

3        Andrographis paniculata       Acanthaceae            Flavnoid, andrographin                 Whole plant

                                                                                            & andrographolide        

Andrographis paniculata (Acanthaceae)

Chemistry:[8]

Therapeutically active constituent of kalmegh found in aerial parts. The primary active constituent of Andrographis paniculata is the Andrographolide. It is colorless bitter in taste and crystalline and known as diterpene lactone. Investigation of Andrographis paniculata showed that it is a rich source of 14-deoxy-11-oxoandrographolide (C20H28O5), 14 deoxy 11,12didehydroandrographolide/andrgraphlide D (C20H30O4), 14-deoxyandrographolide (C20H30O4) and other non-bitter compounds neoandrographolide (C26H40O8); homoandrographolide (C22H32O9); andrographosterol (C23H38O); andrographone (C32H64O); andrographane (C40H82O); andrographosterin; andrograpanin; stigmesterol; α-sitosterol; andrographin (C18H16O6); and dihydroxy-di-methoxyflavone. Andrographolide [C20H30O5]; (3-[2-{decahydro-6-hydroxy-5(hydroxymethyl)-5,8α-dimethyl-2-methylene-1 napthalenyl}ethylidene] dihydro-4-hydroxy 2(3H)-furanone] is a colorless crystalline bicyclic diterpenoid lactone and present in all parts of the plant, Maximally in the leaves. On the orally consumption of andrographolide, appears to accumulate in organs throughout the viscera. Andrographolide are mainly identified as sulfonic acid adducts and sulfate compounds, as well as glucuronide conjugations. Some metabolites of andrographolide like sulfate ester compounds, sulfonates, and andrographolide analogoues were isolated from rat urine and feces. While those metabolites isolated from the human urine were like as sulfates cysteine S-conjugate, and glucuronide conjugates. One of the metabolites, 14deoxy-12-sulfo-andrographolide was reported to be matching to the anti-inflammatory drug. 14- Deoxyandrographolide Andrographolide Chemical structures of compounds present in Andrographis paniculata.

 Anti-cancer Potential of Andrographolide: Various anti-cancer agents inhibiting the proliferation of cancer cells by inducing apoptosis, necrosis, cell-cycle arrest or cell differentiation; others might involve immunomodulatory activity, by triggering body’s own immune system against these cells. The compounds that inhibit multiple procancer events are of greater interest as they are more likely to inhibit a wider range of cancers under great variety of circumstances. In this review, andrographolide

presents a strong candidature as a therapeutic anticancer Pharmacophore as it exhibits a dual property, acting both directly and indirectly on the cancer cells.

 Cytotoxicity against Cancer Cells: Methanolic extract of A. paniculata had shown noteworthy toxicity against human epidermoid leukemia and lymphocytic leukemia cell lines. Potent cytotoxicity in a dose dependent manner towards various kinds of cancer cell lines including drug resistant cancer cells has also been reported in another excellent work. The cytotoxic property has been attributed to the ability of andrographolide to inhibit proliferation and induce apoptosis in cancer cells.

 Induction of Cell-cycle Arrest: At G0/G1 stage, various studies have demonstrated that andrographolide effectively induces cell-cycle arrest in cancer cells. A study with human acute myeloid leukemic HL-60 cells, confirmed a 27% increase in G0/G1 phase cells and significant decrease in cells at S and G2/M phase after andrographolide treatment (12 mg/ml) for 36 h. Andrographis inhibits cell cycle progression by modulating the expression of cell cycle related proteins. The induction of cell-cycle arrest is mainly due to the induction of cell cycle inhibitory proteins p16, p21, p27 associated with decreased expression of cyclin A, cyclin D, CDK4 and CDK2, required for G1 to S transition. Here the increased levels of p21 afte andrographolide treatment (3.75-fold) are of particular interest as decreased p21 expression has been associated with aggressive phenotype in many cancers.

Sl.No          Botanical Name          Family                Main active components                   Parts used

4                    Annnoa Glabra        Annonaceae               annonacin                                 leaves ,bark

Annona Glabra (ANNONACEAE )

The leaves and bark of Annona glabra are used in Chinese medicine against cancer and other ailments. If the extracts of leaf, pulp and seed are compared, the seed extracts are more potent than other extracts .the anti-cancer activity of Annona glabra extracts in human leukemia cell line. The results reported by Cochrane et al showed that the total ethanolic extract of Annona glabra seeds induced apoptosis when analyzed by annexin-V. A concentration-dependent increase in the percentage of apoptotic cells was observed with increasing concentrations of extract. The cytotoxicity measurments of Annona glabra leaf, pulp and seed extracts are significantly better than other anti-cancer compounds .[9]

Apium graveolens (Apiaceae)

Apium graveolens significantly inhibited the proliferation of human cancer cell line RD and its activity was in a concentration-dependent manner . The celery seed extracts have growth

Sl.No             Botanical Name           Family             Main active components               Parts used

5                  Apium graveolens       Apiaceae           Apigenin                                             Bark

inhibition action on various cancer cell lines including acute lymphoblastic leukemia cell line CEM-C7H2 and human neuroblastoma SH-SY5Y cells . According to Momin et al and Sultana et al anti-cancer effects of celery may be due to phthalide constituents found in celery seeds . Apigenin, a chemical constituent of Apium graveolens has been reported to possess antioxidant. Apigenin is found to inhibit the growth of many human cancer cell lines like cervical carcinoma cells, breast cancer cells and leukemia by the mechanism of apoptosis of cancer cells . The anticancer effect of apigenin has been suggested by authors to be mediated through induction of p53 expression, which causes cell cycle arrest and apoptosis . Tannins isolated from the seeds of Apium graveolens has been reported to have cancer preventive properties. Many bioactive constituents like luteolin, linolenic acid, psoralen and oleic acid are isolated from the seed of Apium graveolens and has been reported to possess growth inhibition on various cancer cell lines through inhibition of tumor cell proliferation by

inducing cell cycle arrest and by inducing apoptosis . It has been reported that Apium graveolens also contains vitamins A, B and C. These vitamins are antioxidants and helps in reducing the oxidative stress caused by toxic agents . From the above discussion it is revealed that the extracts showed inhibitory effects on cancer cell lines and the plant may be promising anti-cancer drug.[10]

Sl.No      Botanical Name           Family               Main active components                       Parts used

6           Azadirachta indica      Meliaceae        Tetranortriterpenoids, azadirone,       Bark, leaves,
                                                                          epoxyazadiradione, nimbin                 Floowers

Azadirachta indica (Meliaceae)

Azadirachta indica is native of India and naturalized in most of tropical and sub-tropical

countries. In India it occurs naturally in Siwalik Hills, dry forests of Andhra Pradesh, Tamil

BENGAL SCHOOL OF TECHNOLOGY Page 15

Nadu and Karnataka. It is also cultivated in tropical and sub-tropical regions of Sri Lanka,

Pakistan, Thailand, Indonesia, Malaysia, Singapore, Australia, Saudi Arabia and Tropical

Africa.[11] It grows upto the height of 40-50 feet with a straight, rough dark brown trunk and

long spreading branches. The leaves are compound, each comprising 5-15 leaflets. It bears

many flowered panicles in the leaf axils. Fruits are green when unriped and turns yellow

when riped. Fruits are having aromatic garlic like odour. Fruits mature between April and

August.[12]

Polysaccharides and limonoids present in the bark, leaves and seed oil of Azadirachta indica

reduce tumor and cancers. In Japan hot water extracts from neem bark showed significant

effectiveness against several types of tumors. It has been reported that ethanolic extract of

Azadirachta indica leaves, when administered at doses of 250-500mg/kg, suppressed the

average number of papilomas as well as overall tumor burden induced by BαP and DMBA in

the 7-week old swiss albino mice model . Subapriya et al investigated molecular pathways of

anticancer effects of the ethanolic extract of Azadirachta indica leaves on DMBA-induced

carcinogenesis in bucal pouch of hamster. Their observations suggest the involvement of the

PCNA (Proliferating cell nuclear antigen), mutant p53 and bcl2 genes . Azadirachta indica

has been reported to induce apoptosis in cancer cells. The extracts and its purified products of

Azadirachta indica have been examined for induction of apoptosis among cancer cells. The

ethanolic extract of Azadirachta indica has been shown to induce apoptosis in prostate cancer

cells (PC-3) in a dose-dependent manner . According to the observations of Kumar et al

nimbolide, which is active anti-cancer principle of leaves and flowers induces apoptosis

through engagement of the mitochondrial pathway.[13]

7. Bacopa monnieri (Scrophulariaceae)

The anti-cancer activity of Bacopa monnieri has been also revealed by various workers. E.P

Kumar et al revealed the potential cytotoxic and anti-tumor activity of Bacopa monnieri.

According to them, the ethanolic extract of Bacopa monnieri has shown significant

cytotoxicity towards transformed cell lines. In solid tumor reduction studies, ethanolic extract

of Bacopa monnieri exhibited significant tumor reducing property. E.P Kumar et al proposed

the possible mechanism of anti-tumor activity of ethanolic extract of Bacopa monnieri

against DLA cells may be due to radiomimetic, nucleotoxic and cytotoxic effect and inhibits

cell mitosis .[14]

8. Euphorbia neriifolia (Euphorbiaceae) 

Euphorbia neriifolia is found in throughout the Deccan peninsula of India. The plant is a large

succulent shrub, with stipular thorns. Leaves of the plant are succulent, deciduous, 6-12 inch

long, terminal on the branches, waved narrowed into a very short petiole. The arrangement of

flowers in a bunch on the plant is 'cyathium' type, means one female and several male flowers

are found on a same bunch. Female flowers consist of a trichambered ovary. Fruits are three

chambered and tricoccaus . The plant has been reported to contain triterpenes such as

nerifolione and cycloartenol .

Free radical damage is one of the major processes that contribute to degenerative diseases

such as cancer. Free radical scavengers protect cellular DNA against indirect effect of

ionizing radiation where hydroxyl radicals are believed to be the primary act ive species responsible for the damage . Yen GC et al demonstrate the antioxidant activity of the sapogenin isolated from the leaf extract of Euphorbia neriifolia. Peripheral blood lymphocytes are extensively used biomonitoring of populations exposed to various mutagenic or carcinogenic compounds. γ-radiatisons produces morphological changes in lymphocytes by decaying their proliferation γ-rays generate hydroxyl radicals .in cells and induce DNA damage that leads to mutations and chromosomal aberrations. Total sapogenin at a concentration of 75μg/ml significantly decreased total chromosomal aberration. This revealed that sapogenins reduce gamma radiation-induced genomic instability. Total sapogenin exhibits cytotoxic activity on murine F1 B16 melanoma cell line .[15].

9.Curcuma longa

Zingiberaceae

Curcumin

Root ,Rhizome

TURMERIC ( Curcuma longa ) Curcuma longa, commonly known as turmeric, is native to South Asia, India and Indonesia and is predominantly grown in South India. The root and rhizome (underground stem) of Curcuma longa is crushed and powdered into ground turmeric. Ground turmeric is used worldwide as a seasoning and as a key ingredient in curry. Curry contains ~2% curcumin, which was first identified in 1910 by Miłobȩdzka et al . Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant. Curcumin has been used extensively in Ayurvedic medicine, as it is nontoxic and exhibits a variety of therapeutic properties, including antioxidant, analgesic, anti-inflammatory and antiseptic activities. Recently, certain studies have indicated that curcumin may exert anticancer effects in a variety of biological pathways involved in mutagenesis, apoptosis, tumorigenesis, cell cycle regulation and metastasis. The present study reviewed previous studies in the literature, which support the therapeutic activity of curcumin in cancer. In addition, the present study elucidated a number of the challenges concerning the use of curcumin as an adjuvant chemotherapeutic agent. Phytochemistry Curcumoids consist of two methoxylated phenols connected through two α,β-unsaturated carbonyl groups. Curcumin is rich in terpene derivates and contains predominantly monocyclic sesquiterpenes and oxygenated derivatives, such as turmerone and zingibrene . The rhizome contains 3–5% curcuminoids and 2–7% essential oil. Three polyphenols were isolated from Curcuma longa, of which curcumin (bis-α,β-unsaturated β-diketone) is the most abundant, potent and extensively investigated . Anti Cancer Activity A number of activities of curcumin, which are exerted in a chemopreventive and a directly therapeutic manner, indicate that it may be a potential anticancer remedy.The first clinical report of the anticancer properties of curcumin was from Kuttan and coworkers, who used 1% curcumin ointment on skin cancerous lesions with a reduction in smell in 90% of patients 10% patients experienced a reduction in pain and lesion size. In an experimental model of mammary cancer induced by 7,12-dimethylbenz-[a]-anthracene (DMBA) in female rats, the initiation of DMBA-induced mammary adenocarcinoma was significantly decreased by intraperitoneal infusion of curcumin 4 days before DMBA administration . Molecular Pathway Turmeric and curcuminoids influence tumor angiogenesis through multiple, interdependent processes , that are described below : i) Action at the level of transcription factors NF-κB, AP-1 (associated with inflammatory processes) and early growth response protein 1, which attenuates the expression of IL-8 in pancreatic and head and neck cancer cell lines and prevents the induction of VEGF synthesis. ii) Inhibition of angiogenesis mediated by NO and iNOS. iii) Inhibition of COX-2 and 5-LOX. iv) Action at the level of angiogenic factors: VEGF, the primary factor for migration, sprouting, survival and proliferation during angiogenesis, and basic fibroblast growth factor. v) Action at the level of stability and coherence of the ECM, including the downregulation of MMP-2 and MMP-9, and upregulation of tissue inhibitor of metalloproteinase-1. Turmeric also interferes with the release of angiogenic factors stored in the ECM. Curcumin induces cell death in numerous animal and human cell lines, including leukemia, melanoma, and carcinomas of the breast, lung, colon, kidney, ovaries and liver. It appears to function by caspase-dependent and independent (mitochondrial) mechanisms, which are associated with the presence and absence of p53. Certain data have demonstrated that curcumin exhibits a biphasic action, which acts on the proteasome, with an activation at lower doses and with inhibition at higher doses. As the inhibition of the proteasome leads to apoptosis, and its stimulation leads to cell survival, it is possible that curcumin results in apoptosis or survival depending on the dosage used. In addition, turmeric at different doses may also affect the type of cell death: Low doses lead to oxidative stress and apoptosis, while higher doses lead to reduced production of reactive oxygen species, reduction of ATP and necrotic cell death.[16]

10. Annona muricata (Annonaceae Annomuricin) 

Annona muricata is a lowland tropical, fruit-bearing tree of the family Annonaceae found in the rainforests of Africa, South America, and Southeast Asia. A. muricata, commonly known as soursop, graviola, guanabana, or Brazilian pawpaw, has large, glossy, dark green leaves , with edible, green heart-shaped fruits . Soft, curved spines cover the leathery skin of the fruits, each of which may contain 55–170 black seeds distributed in a creamy white flesh with a characteristic aroma and flavor. All portions (leaves , pericarp , fruits , seeds , and roots ) of A. muricatahave been used in traditional medicine, but the most widely used in the preparations of traditional medical decoctions are stem barks, roots, seeds, and leaves . Coria-Téllez et al. have reported 212 bioactive compounds in A. muricataextracts . Reports in the literature indicate that seventy-four of these bioactive compounds exhibit a variety of anticancer effects in preclinical cell culture and animal model systems.

Phytochemistry:

Purified AGEs, such as annocatacin (A or B) orannocatalin , have been found to induce significant cytotoxicity in Hep G2 and Hep 2,2,15 hepatic cancer cells in vitro . In breast cancer, cytotoxicity can be induced in MCF-7 cells using any of the following purified AGEs: annomuricin A, B , C , or E ; muricatocin A, B, or C ; muricapentocin ; annomutacin ; annohexocin ; annopentocin A, B, or C ; murihexocin A, B , or C ; muricoreacin. In addition, synergistic therapeutic effects have been shown with the combination of AGEs. For example, cytotoxicity in breast cancer has been observed using a combination of (2,4-cis)-10R-annonacin-A-one and (2,4- trans)-10R-Annonacin-A-one , or a mixture of cisannomuricin- D-one and trans-annomuricin-D-one . Organic solvent extracts derived from the different parts of A. muricata (presumably containing multiple bioactive compounds) have also been shown to induce cytotoxicity in a variety of cancer cell lines. For example, leaf extracts induced cytotoxicity in human A375 melanoma , immortalized HaCaTkeratinocytes, and MDA-MB-435S, previously cross-contaminated and mislabeled as breast carcinoma cells , but currently identified and authenticated as a melanoma cell line (M14) , or head and neck squamous cell SCC-25 carcinoma , pancreatic (CD18/HPAF and FG/COLO357) , colorectal (HT-29 and HCT-116) , Liver HepG2 , and lung A549 cancer cell lines.[17]

CONCLUSION: Any practical solution to controlling the initiation and progression of cancer is of paramount importance. The use of medicinal plant products to manage or arrest the carcinogenic process provides an alternative to the use of conventional allopathic medicine for treatment of the disease. Many herbs have been evaluated in clinical studies and are currently being investigated to understand their tumouricidal properties against various cancers. There seem to be emerging approaches, that include, not only cytotoxic approaches but also molecular management of cancer physiopathology. The goal in these integrative approaches, which extend beyond eradicating the affected cells, is to control the cancer phenotype. A number of plant-derived products have shown promise in anticancer therapies. Attempts have been made to characterize the effectiveness of single constituents isolated from natural products as chemo-preventive agents. Keeping that perspective in mind, auyurveda which uses a holistic approach in the treatment of disease may provide effective alternative to individual plant isolates in the treatment of cancer. The ayurvedic system of medicine incorporates herbs into its treatment regimens for a number of diseases and disorders. The well known texts of Charaka Samhita and Sushruta Samhita date back to approximately 1000 B.C. and document the use of plant products in treatment of disease Charaka and Sushruta samhitas, two well-known Ayurvedic classics, describe cancer as inflammatory or non-inflammatory swelling and mention them as either Granthi (minor neoplasm) or Arbuda (major neoplasm). T. cordifolia for example is known for its various medicinal properties including anti-inflammatory, anti-arthritic and anti-allergic properties In vitro experiments have shown anticancer potential for T. cordifolia . A. Paniculuta extracts have been shown to have anti-oncogenic properties. Oral administration of C. asiatica extracts slowed the development of solid and ascites tumors and increased the total life span of tumor-bearing mice. Turmeric has also been shown to inhibit tumor cell invasion and metastasis in vitro. Oral administration of P. amarus extract significantly increased the life span and reduced tumor size in mice bearing Dalton’s Lymphoma Ascites (DLA) and Erlich Ascites carcinoma (EAC). Thus, there is evidence that plant products can have antitumor properties with relatively few side effects. More research on plants and plant-derived chemicals may result in the discovery of potent anticancer agents.[18]

REFERENCES: [1] Lichota, A. and Gwozdzinski, K. (2018) ‘Anticancer Activity of Natural Compounds from Plant and Marine Environment’, International journal of molecular sciences, 19(11). doi: 10.3390/ijms19113533. [2] Vermeulen, K., Van Bockstaele, D. R. and Berneman, Z. N. (2003) ‘The cell cycle: A review of regulation, deregulation and therapeutic targets in cancer’, Cell Proliferation, 36(3), pp. 131–149. doi: 10.1046/j.1365-2184.2003.00266.x. [3] V Tara Shanbhag, Shenoy Smita , “ Pharmacology for Medical Graduates “ Third Edition, pp-504 to 05. [4] Hanahan, D. and Weinberg, R. A. (2011) ‘Hallmarks of cancer: The next generation’, Cell. Elsevier Inc., 144(5), pp. 646–674. doi: 10.1016/j.cell.2011.02.013. [5] Sriram D and Yogeeswari P, “ Medicinal Chemistry “ Second Edition, pp-557 to 08. [6] Kabesh, K. et al. (2015) ‘Phytochemical Analysis of Catharanthus roseus Plant Extract and its Antimicrobial Activity’, International Journal of Pure & Applied B. [7] Subedi, T. (2018) ‘Phytochemical Studies of Taxus Species and Their Uses in Cancer Treatment’, Janapriya Journal of Interdisciplinary Studies, 6, pp. 160–171. doi: 10.3126/jjis.v6i0.19317. [8] Bharati, B. D. et al. (2011) ‘Pharmacological activity of Andrographis paniculata: a brief review.’, Pharmacologyonline, (2, Newsletters), pp. 1–10. Available at: http://www3.unisa.it/uplsoads/4979/001.deepak.pdf. [9] Cochrane CB, Nair Raveendran PK, Steven J, Resek Anna P, Ramachandran C. Anticancer Research 2008; 28:965-972. [10] Fazal SS, Singla RK. Indo Global Journal of Pharmaceutical Sciences 2012;2:36-42. [11] Parotta JA. Healing plants of peninsular India. New York CABI Publishing 2001: 495-496. [12] Ross IA. Totowa, New Jersy 2001; 2: 81-85. [13] Dasgupta T, Banerjee S, Yadava PK and Rao AR. J Ethnopharmacol 2004; 92: 23-36. [14] Kumar EP, Elshurafa AA, Elango K, Subburaju T and Suresh B. Ancient Science of Life 1998; 17: 1-7 [15] Sultana S, Ahmed S, Jahangir T & Sharma S. Cancer Lalt 2005; 221:11-20. [16] Sa, G. and Das, T. (2014) ‘Anti cancer effects of curcumin: Cycle of life and death’, Recent Advances in Plant-Based, Traditional, and Natural Medicines, 14, pp. 151–180. doi: 10.1186/1747-1028-3-14.

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[17] Rady, I. et al. (2018) ‘Anticancer Properties of Graviola (Annona muricata): A Comprehensive Mechanistic Review’, Oxidative Medicine and Cellular Longevity. Hindawi, 2018. doi: 10.1155/2018/1826170. [18] . Sharma H, Parihar L, Parihar P. Review on cancer and anticancerous properties of some medicinal plants. J Med Plant Res. 2011;5:1818–1835.