NATURAL ANTI-CANCER PLANT USED FOR CANCER TREATMENT

Sonali Kamila
Student
Bengal School of Technology
  (A College Of Pharmacy)

INTRODUCTION

An abnormal growth and spread of cancer (malignant tumour) cells is a horrible disease, as the patient suffers pain, morbidity and many physiological processes. Cancer can be uncontrollable and uncurable and can occur in any part of the body at any time, at any age. This is caused by a complex, poorly understood interplay of genetic and environmental factors. It represents the largest cause of death in the world and claims over millions of millions. Cancer kills around 3500 per million population worldwide. A large number of chemo preventive agents are used to cure various cancers, but they cause side effects that prevent them from being widely used. Although more than 1500 anticancer drugs are in active development with over 500 drugs under clinical trials, there is an urgent need to develop many effective and less toxic drugs [1].

The plant kingdom plays an important role in the life of humans and animals. India is the largest producer of medicinal plants and is rightly called the ―Botanical garden of the World‖. Medicinal plants have been stated to comprise about 8000 species and account for approximately 50% of all the higher flowering plant species of India. In other words, there are about 400 families of the flowering plants; at least 315 are represented by India. Medicinal properties of few such plants have been reported but a good number of plants still used by local folklore are yet to be explored. Ayurveda, Siddha and Unani systems of medicine provide good base for scientific exploration of medicinally important molecules from nature. The rediscovery of Ayurveda is a sense of redefining it is modern medicines. Emerging concept of combining Ayurveda with advanced drug discovery programme) is globally acceptable. Traditional medicine has a long history of serving peoples all over the world. The ethno botany provides a rich resource for natural drug research and development. In recent years, the use of traditional medicine information on plant research has again received considerable interest. The Western use of such information has also come under increasing scrutiny and the national and indigenous rights on these resources have become acknowledged by most academic and industrial researchers [1].

According to the World Health Organization (WHO), about three quarters of the world‘s population currently use herbs and other forms of traditional medicines to treat diseases. Traditional medicines are widely used in India. Even in USA, use of plants and phytomedicines has increased dramatically in the last two decades. It has been also reported that more than 50% of all modern drugs in clinical use are of natural products, many of which have been recognized to have the ability to include apoptosis in various cancer cells of human origin [1].

Cell cycle, the ordered sequence of events that occur in a cell in preparation for cell division. The cell cycle is a four-stage process in which the cell increases in size (gap 1, or G1, stage), copies its DNA (synthesis, or S, stage), prepares to divide (gap 2, or G2, stage), and divides (mitosis, or M, stage). The stages G1, S, and G2 make up interphase, which accounts for the span between cell divisions [1]. On the basis of the stimulatory and inhibitory messages a cell receives, it ―decides‖ whether it should enter the cell cycle and the proteins that play a role in stimulating cell division can be classified into four groups—growth factors, growth factor receptors, signal transducers, and nuclear regulatory proteins (transcription factors). For a stimulatory signal to reach the nucleus and ―turn on‖ cell division, four main steps must occur. First, a growth factor must bind to its receptor on the cell membrane. Second, the receptor must become temporarily activated by this binding event. Third, this activation must stimulate a signal to be transmitted, or transduced, from the receptor at the cell surface to the nucleus within the cell. Finally, transcription factors within the nucleus must initiate the transcription of genes involved in cell proliferation. (Transcription is the process by which DNA is converted into RNA. Proteins are then made according to the RNA blueprint, and therefore transcription is crucial as an initial step in protein production[2].

Cells use special proteins and checkpoint signaling systems to ensure that the cell cycle progresses properly. Checkpoints at the end of G1 and at the beginning of G2 are designed to assess DNA for damage before and after S phase. Likewise, a checkpoint during mitosis ensures that the cell‘s spindle fibers are properly aligned in metaphase before the chromosomes are separated in anaphase. If DNA damage or abnormalities in spindle formation are detected at these checkpoints, the cell is forced to undergo programmed cell death, or apoptosis. However, the cell cycle and its checkpoint systems can be sabotaged by defective proteins or genes that cause malignant transformation of the cell, which can lead to cancer. For example, mutations in a protein called p53, which normally detects abnormalities in DNA at the G1 checkpoint, can enable cancer-causing mutations to bypass this checkpoint and allow the cell to escape apoptosis [2].

The cell-division cycle is a vital process by which a single-celled fertilized egg develops into a mature organism, as well as the process by which hair, skin, blood cells, and some internal organs are renewed. After cell division, each of the daughter cells begin the interphase of a new cycle. Although the various stages of interphase are not usually morphologically distinguishable, each phase of the cell cycle has a distinct set of specialized biochemical processes that prepare the cell for initiation of the cell division [3].

Cancer cells are cells gone wrong in other words, they no longer respond to many of the signals that control cellular growth and death. Cancer cells originate within tissues and, as they grow and divide, they diverge ever further from normalcy. Over time, these cells become increasingly resistant to the controls that maintain normal tissue and as a result, they divide more rapidly than their progenitors and become less dependent on signals from other cells. Cancer cells even evade programmed cell death, despite the fact that their multiple abnormalities would normally make them prime targets for apoptosis. In the late stages of cancer, cells break through normal tissue boundaries and metastasize (spread) to new sites in the body [3].

In normal cells, hundreds of genes intricately control the process of cell division. Normal growth requires a balance between the activity of those genes that promote cell proliferation and those that suppress it. It also relies on the activities of genes that signal when damaged cells should undergo apoptosis [3].

Cells become cancerous after mutations accumulate in the various genes that control cell proliferation. According to research findings from the Cancer Genome Project, most cancer cells possess 60 or more mutations. The challenge for medical researchers is to identify which of these mutations are responsible for particular kinds of cancer. This process is akin to searching for the proverbial needle in a haystack, because many of the mutations present in these cells have little to nothing to do with cancer growth [3].

Different kinds of cancers have different mutational signatures. However, scientific comparison of multiple tumor types has revealed that certain genes are mutated in cancer cells more often than others. For instance, growth-promoting genes, such as the gene for the signaling protein Ras, are among those most commonly mutated in cancer cells, becoming super-active and producing cells that are too strongly stimulated by growth receptors. Some chemotherapy drugs work to counteract these mutations by blocking the action of growth-signaling proteins. The breast cancer drug Herceptin, for example, blocks overactive receptor tyrosine kinases (RTKs), and the drug Gleevec blocks a mutant signaling kinase associated with chronic myelogenous leukemia [3].

Other cancer-related mutations inactivate the genes that suppress cell proliferation or those that signal the need for apoptosis. These genes, known as tumor suppressor genes, normally function like brakes on proliferation, and both copies within a cell must be mutated in order for uncontrolled division to occur. For example, many cancer cells carry two mutant copies of the gene that codes for p53, a multifunctional protein that normally senses DNA damage and acts as a transcription factor for checkpoint control genes [3].

Anti-cancer drug also called antineoplastic drug, any drug that is effective in the treatment of malignant, or cancerous, disease. There are several major classes of anticancer drugs; these include alkylating agents, antimetabolites, natural products, and hormones. In addition, there are a number of drugs that do not fall within those classes but that demonstrate anticancer activity and thus are used in the treatment of malignant disease. The term chemotherapy frequently is equated with the use of anticancer drugs, although it more accurately refers to the use of chemical compounds to treat disease generally [3].

Cancer is the second leading cause of death worldwide. Although great advancements have been made in the treatment and control of cancer progression, significant deficiencies and room for improvement remain. A number of undesired side effects sometimes occur during chemotherapy. Natural therapies, such as the use of plant-derived products in cancer treatment, may reduce adverse side effects. Currently, a few plant products are being used to treat cancer. However, a myriad of many plant products exist that have shown very promising anti-cancer properties in vitro, but have yet to be evaluated in humans. Further study is required to determine the efficacy of these plant products in treating cancers in humans. This review will focus on the various plant-derived chemical compounds that have, in recent years, shown promise as anticancer agents and will outline their potential mechanism of action [4].

The anticancer properties of plants have been recognized for centuries. Isolation of podophyllotoxin and several other compounds (known as lignans) from the common may apple (Podophyllum peltatum) ultimately led to the development of drugs used to treat testicular and small cell lung cancer. The National Cancer Institute (NCI) has screened approximately 35,000 plant species for potential anticancer activities. Among them, about 3,000 plant species have demonstrated reproducible anticancer activity [4].

Curcuma longa Linn (TURMERIC) HALUD

Turmeric is a flowering plant, Curcuma longa of the ginger family,
Zingiberaceae, the roots of which are used in cooking.
 Scientific name: Curcuma longa
 Family: Zingiberaceae
 Kingdom: Plantae
 Order: Zingiberales
 Rank: Species

Curcumin, the phytochemical component in turmeric, is used as a dietary spice and a topical ointment for the treatment of inflammation in India for centuries. Curcumin (diferuloylmethane) is relatively insoluble in water, but dissolves in acetone, dimethylsulphoxide, and ethanol. Commercial grade curcumin contains 10–20% curcuminoids, desmethoxycurcumin, and bisdesmethoxycurcumin and they are as effective as pure curcumin. Based on a number of clinical studies in carcinogenesis, a daily oral dose of 3.6 g curcumin has been efficacious for colorectal cancer and advocates its advancement into Phase II clinical studies. In addition to the anticancer effects, curcumin has been effective against a variety of disease conditions in both in vitro and in vivo preclinical studies. The present review highlights the importance of curcumin as an anti-inflammatory agent and suggests that the beneficial effect of curcumin is mediated by the upr egulation of peroxisome proliferatoractivated receptor-γ (PPAR-γ) activation [5]. 

Curcumin obtained from the turmeric rhizome (Curcuma longa) have shown to possess the ability to protect the skin from harmful UV-induced effects by displaying antimutagen, antioxidant, free radical scavenging, anti-inflammatory and anti-carcinogenic properties [5].

Curcumin, the most active component of turmeric, makes up 2–5% of this spice. The yellow color of the turmeric is due to the curcumin compound. Curcumin (C21H20O6) was first described in 1910 by Lampe and Milobedeska and shown to be a diferuloylmethane, 1,7-bis (4-hydroxy-3- methoxyphenyl)-1,6-heptadiene-3,5-dione ,and is practically insoluble in water. Curcumin is a bis-α- β-unsaturated β-diketone; under acidic and neutral conditions, the bis-keto form of the compound predominates, and at pH above 8, the enolate form is generally found . Hence at pH 3–7, it acts as an extraordinarily potent H-atom donor and above pH 8, it acts mainly as an electron donor, a mechanism more suitable to the scavenging or antioxidant properties of curcumin .Curcumin is quite unstable at basic pH and degrades within 30 minutes. Human blood or antioxidants such as ascorbic acid, or the presence of 10% fetal bovine serum in the culture media prevents this degradation [6]. Curcumin has a molecular weight of 368.7 and the commercial grade curcumin contains curcuminoids, 10–20% desmethoxycurcumin and less than 5% bisdesmethoxycurcumin . The commercial grade curcumin is just as effective as pure curcumin in preclinical models of carcinogenesis[6].

MEDICINAL USES AND ROUTES OF ADMINISTRATION ORAL ROUTE:

Turmeric is used to as a treatment for indigestion (dyspepsia), abdominal pain, hemorrhage, diarrhea, flatulence, abdominal bloating, loss of appetite, jaundice, hepatitis, and liver disease, gallbladder complaints,headaches, bronchitis,colds, respiratory infections,leprosy, fever amenorrhea, and cancer.

TOPICAL ROUTE:

 Effective in treatment of indigestion (dyspepsia). Studies have shown that turmeric may be effective in turmeric is used as an anti-inflammatory treatment for treat skin conditions.

 It is used to treat pain in body, ringworm,bruising, leech bites, eye infections, inflammation of the oral mucosa, infected wounds, joint pain, and arthritis.

 Turmeric is lowering the level of cholesterol in the blood, and may be effective at preventing heart disease.

 Turmeric is also provides an antioxidant benefit, fighting potential damage from free radicals in the body [7].

SIDE EFFECTS:

 Gastrointestinal disturbances are possible with chronic use.

 This is not a complete list of side effects and others may occur[7]

CATHARANTHUS ROSEUS:

It is a flowering plant belonging to the family apocynaceae commonly known as periwinkle, pink periwinkle, bright eyes and old maid [8].

Anticancer substances derived from this plant – vinca alkaloids(vincristine, vinblastine, vinorelbine) [8].

MECHANISM OF ACTION

                                    These vinca alkaloids target the microtubular protein.
                                                                                ⇩
                                Tubulin dimer bound to GTP and are hydrolyzed into GDP.
                                                                                ⇩
                                              Thus they form micro tubulin protein.
                                                                                ⇩
       Vinca alkaloids binds to beta tubulin and prevent tubulin dimer from binding 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) [8].

SIDE EFFECT:

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 [8].

VINBLASTINE

USE:-

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 EFFECT:-

 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.

 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.

Andrographis paniculata (Burm. F.) Nees KALMEGH SAG 

Kalmegh (Andrographis paniculate) is a widely cultivated herb in Asia that grows 30 to 110 cm in height. The plant bears yellowish brown seeds with a very bitter taste. The plant part appearing above the ground is harvested in the autumn season. It is a widely used in Ayurveda and used in about 26 Ayurvedic herbal formulations. It serves as an immunostimulant and rids the body of fevers and toxins [9].

Andrographis paniculata, commonly known as creat or green chireta, is an annual herbaceous plant in the family Acanthaceae, native to India and Sri Lanka. It is widely cultivated in Southern and Southeastern Asia, where it has been traditionally used to treat infections and some diseases[9].

 Family: Acanthaceae
 Kingdom: Plantae
 Scientific name: Andrographis paniculata
 Higher classification: Andrographis

Used as Anti-Cancer:

Kalmegh acts as an anti-cancer agent on many types of cancer cells that inhibit the process of anti-cancer duplication and cell division. It is also a potent suppressant of tissue growth in the case of tumors [10]. Traditionally, andrographis has been used for liver complaints and fever, and as an anti-inflammatory and immunostimulant. In clinical trials, andrographis extract has been studied for use as an immunostimulant in upper respiratory tract infections and HIV infection. The potential for use of andrographolide as an anticancer agent as well as for its immune and anti-inflammatory effects is being investigated. However, limited clinical studies have been published to support any of these uses [10].

In animal and in vitro experiments using human cancer cell lines to investigate the potential anticancer effects of A. paniculata, andrographolide was responsible for the observed beneficial effects rather than other diterpenes. Various mechanisms of action have been proposed, including enhancement of chemokine activity, inhibition of tumor-specific angiogenesis affecting cell cycle progression, and induction of apoptosis. Cancer cell lines investigated included prostate, breast, cervical, colon, hepatoma, melanoma, and lymphocytic leukemia. Researchers are now focusing on synthesizing compounds based on andrographolide to improve selectivity and potency. Caution is recommended due to the potential for andrographolide-enhanced SDF-1-chemokine activity, which might induce tumor cell metastasis. A. paniculata extract has also induced cell differentiation in mouse myeloid leukemia cells [10]. Crystalline andrographolide was reported to be highly stable, over a period of three months . Rajani et al. reported a simple and rapid method for isolating andrographolide from the leaf of A. paniculata. They extracted it using a 1 : 1 mixture of dichloromethane and methanol and then isolated

the andrographolide directly from the extract by performing recrystallization. The purity of the compound has been evaluated with thin-layer chromatography (TLC), UV absorption spectrum, high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), and differential scanning calorimetry (DSC), which revealed the melting point of andrographolide to be 235.3°C [11].

MECHANISMS OF ACTION OF ANDROGRAPHOLIDES:

Andrographis pediculate has been extensively studied, particularly with much focus "AP's" pharmacological composition, safety, efficacy, and mechanisms of action during the second half of the 20th century (23, 24, 25). All cells in the body contain receptors on the surface of the cell membrane that surrounds the cell. These receptors function to bind hormones, growth factors, neurotransmitters, and other molecules that regulate (or in the case of cancer, disturb) cell function. Once a molecule binds to the receptor, a chemical message is transmitted to targets in the cell or to other molecules in the cell, which carry the message further. The message eventually reaches the nucleus of the cell where the genetic expression gets modulated and the cell function response is a cell-type specific manner. An example would be a message to make a particular protein, such as insulin, by a cell in the pancreas. The receptor, its cellular target, and any intermediary molecules are referred to as a "signal transduction pathway." Signal transduction technology involves the study of these pathways that affect cell function. Any point in this pathway may be affected by cancer-causing toxins or by viruses. In the case of cancer, changes in the components or in the timing of cellular events can cause abnormal cell division. Uncontrolled cell division results in a tumor or in the spread of cancerous cells. Other diseases can also develop when the signals are disturbed. Many of the steps are involved in signal transduction are well understood, although researches concerning their fine-tuned regulation are still not well understood for understanding pathways holistically. Investigations to understand what and how these pathways can go odd way at a basic level (intracellularly) would allow detection of diseases at a much earlier stage -before there are obvious symptoms and when there is still a good chance to correct the problem. "Scientists at many U.S. companies are using signal transduction technology to determine the effects of natural and synthetic components on the signal transduction pathways in the cell, in particular those involved in cell division. Several applications of signal transduction technology in the development of compounds with therapeutic potential have been reviewed in an excellent editorial published in Genetic Engineering News in January 1996 (26). One of the criticisms made by the conventional medical and scientific community regarding dietary supplements is that their development and use have been based on folklore tradition, not on sequence of scientific evidences in modern set-ups of controls and placebos with statistical tests of hypotheses [11].

Dosing:

The usual daily dose of andrographolide for common cold, sinusitis, and tonsillitis is 60 mg. A clinical trial in children with upper respiratory tract infection reported the use of andrographolide 30 mg daily for 10 days[11].

Side Effects: 

In a clinical trial, headache, fatigue, rash, bitter/metallic taste, diarrhea, pruritus, and decreased sex drive were reported with andrographis 10 mg/kg body weight. One HIV-positive participant experienced an anaphylactic reaction effects. Andrographolide, which exhibits notable pharmacological activities , has attracted the interest of numerous researchers. Because of its rational activity, numerous andrographolide derivatives have been synthesized for the development of biological activities. Thus, this paper summarizes various experimental and clinical pharmacological activities of andrographolide, such as those that are antioxidant, anti-inflammatory, anticancer, antimicrobial and parasitic, hepatoprotective, anti-hyperglycemic, and anti-hypoglycemic. Evidence from clinical studies suggests that andrographolide reduces HIV symptoms, uncomplicated upper respiratory tract infections, including sinusitis and the common cold, and rheumatoid arthritis. Nevertheless, summarizing the effects on cardiovascular disease, NF-kB, and platelet activation of this natural product is worthy of review, and additional studies must be conducted to confirm the toxicological properties of this novel molecule before taking place in clinical studies in patients. This summary offers pharmaceutical chemists and plant scientist‘s additional thoughts for drug discovery. The combined drug discovery of andrographolide analogues will likely transform them into an effective assemblage of inflammation and cancer treatment in the future [11].

Tinospora cordifolia (Wild) Miers

Biological source: Tinospora cordifolia

Order: Rananculales

Family: Menispermaceae

Genus: Tinospora

Species: T. sinensis (Lour.) Merr

Tinospora cordifolia, also known as guduchi in Sanskrit, giloya in Hindi and heartleaf moonseed plant in English, is a bulky, smooth, climbing deciduous shrub lacking bristles. The most commonly used part of the shrub is the stem, but roots are also known to contain important alkaloids. This shrub is commonly found in India, Myanmar, Sri Lanka and China[12].

According to ancient Ayurvedic lexicons, T. cordifolia is also referred to as ―amrita‖. The term ―amrita‖ is ascribed to this plant due to its ability to impart youthfulness, vitality and longevity. The stem of T. cordifolia is used for general debility, dyspepsia, fever, urinary disease, and jaundice. The extract of its stem is used in treating skin diseases. There are certain curative properties of the root of T. cordifolia which allow for its use as antidote in snake bite, in combination with other drugs. T. cordifolia is well known in modern medicine for its adaptogenic, immunomodulatory and anti-oxidant activities. T. cordifolia is also known to have anti-inflammatory, anti-arthritic, anti-allergic properties. This plant is also useful in treating skin diseases, vomiting, anemia, piles, chronic fever, and emaciation. The methanol extract of Tinospora contains phenylpropanoids, norditerpene furan glycosides, diterpene furan glycosides and phytoecdysones. The roots of T. cordifolia are also reported to contain other alkaloids like choline, tinosporin, columbin, isocolumbin, palmatine, tetrahydropalmatine and magnoflorine[13].

T. cordifolia effectively kills HeLa cells in vitro, suggesting its potential as an anticancer agent. A dose-dependent increase in cell death was observed in HeLa cells treated with T. cordifolia extrac as compared to the controls. The anticancer activity of dichloromethane extract of T. cordifolia in the mice transplanted with Ehrlich ascites carcinoma has been demonstrated. T. cordifolia extract showed a dose-dependent increase in tumor-free survival with highest number of survivors observed at 50 mg/kg dose. Chemical structures of some of the active constituents of T. cordifolia are given below [14].

Podophyllum:

Biological source: Podophyllum peltatum

One of the most important natural products are aryltetralin lactone lignans. Lignans are a family of natural products which are secondary metabolites produced through the shikimic acid pathway. The chemical structure of lignans is composed of two phenylpropane units and has a variety of skeletons and chemical characteristics; lignans can be divided into four groups: Lignans, Neolignans, Trimers and Oxyneolignans, higher analogues and mixed Lignanoids (Luo et al., 2014). It has been reported that natural aryltetralin lactone lignans are present in the plants of the families Cupressaceae, Berberidaceae, Apiaceae, Burseraceae, Verbenaceae, etc. Podophyllotoxin (PTOX) (C22H22O8) is an exclusive lignan because one of its derivatives was recognized as a potent antitumor factor [15].

PTOX: origin and sources Lignans have been found in a large number of species, which are belonged to more than 60 families of vascular plants. Lignans can be isolated from different part of plants: roots and rhizomes, woody parts, stems, leaves, fruits, seeds and, in other cases, from endophytic microorganisms (Kusari et al., 2009; Schulz et al., 2002). Lignans have also been found in the urine of humans and mammals, although some of them are identical to components of the plant primary metabolites. Additionally, several distinct chemical reactions have been suggested, such as internal metabolic transformation (Zhang et al., 2014). It is important to mention that Podophyllum genus is not the only natural source of PTOX. This plant genus and other genera such as Jeffersonia,. However, environmental effects and difficulties in cultivation are the most marked problems in extraction of PTOX from plants [15]

Mechanism of action:

There is growing body of evidence showing the potential anti-cancer activity of PTOX. It has been shown that PTOX has anti-neoplastic properties that prevent the assembly of tubulin into microtubules and persuading apoptosis (Abad et al., 2012). This effect can be achieved by preventing the polymerization of tubulin which thereby could induce cell cycle arrest at mitosis and impede the formation of the mitotic-spindles microtubules. This mechanism of action is comparable with an another alkaloid, colchicine (Passarella et al., 2010). The antitumor activity of PTOX against lung metastatic cancer has been reported (Utsugi et al., 1996). In this study, the inhibitory activity of etoposide and PTOX against topoisomerase II via induction of DNA strand breaks was shown. The results of preclinical studies showed that PTOX prevented the polymerization of microtubule resulting in mitotic detention as shown by accumulation of mitosisrelated proteins, BIRC5 and aurora B (Chen et al., 2013). PTOX reversibly binds to tubulin, and interrupts the dynamic equipoise between the assembly and disassembly of microtubules, and finally causes mitotic arrest (Guerram et al., 2012). Moreover, it has been shown that semi-synthetic products of PTOX, such as etoposide, teniposide and etopophos, have an inhibitory activity on DNA topoisomerase II that prevents the religation of DNA (Choi et al., 2015; Shin et al., 2010; Xu et al., 2009) Pharmacological activity of PTOX Several studies have shown the possible role of natural products in treatment of several disorders (Ardalani et al., 2016; Jandaghi et al., 2016) with different application to be used as antiviral, antifungal, antibacterial and anticancer agents. PTOX is suggested as an antiviral agent in the treatment of condyloma acuminatum caused by human papilloma virus (HPV) and other venereal warts (Wilson, 2002). In another in vitro study, podophyllotoxin derivatives showed promising cytotoxicities against a set of human cancer cell lines HL-60, A-549, HeLa, and HCT-8 (Liu et al., 2013). PTOX also activates pro-apoptotic endoplasmic reticulum stress signaling pathway. Intra-peritoneal injection of PTOX1 2 mg/kg significantly inhibited the growth of P-815, P-1537 and L-1210 tumor cells. The anti-tumor activity of this agent was more or less similar to that of paclitaxel (Wrasidlo et al., 2002). Also, the hematological and biochemical examinations showed that PTOX did not have organ toxicities in animal models (Chen et al., 2013). In a randomized clinical trial, the effects of PTOX on anogenital warts were compared with imiquimod 5% cream. The results showed a potent inhibitory effect on warts growth in PTOX-treated group vs. imiquimod cream-treated group [15].

Mangifera Indica:

Mangifera indica is a nutritional supplement used in several tribes and countries as a folklore remedy.

This aqueous extract is considered in Cuba beneficial and used in healthy people to reduce environmental, nutritional risk factors, and also prolong the quality of life through increasing free radical scavenging mechanism. Ethno-botanical studies resulted in a great improvement of life quality in cancer patients. Research studies have exhibited immune-modulator effects of mango in different cell lines. The principle active constituents of mango consists of a mixture of terpenoids, polyphenols, steroids, fatty acids and microelements that imparts properties and provide antioxidant supplements [11].

Other Anti-cancer Plants

Botanical name of               Part used               Parts used and their                  Origin / native place
plant with family                                             main active components
name 

Agave americana                  Leaf                Steroidal saponin, alkaloid,               Central America
(Agavaceae)                                            coumarin, isoflavonoid, hecogenin                         
                                                                            and vitamins (A, B, C)

Agropyron repens             Rhizomes          Rhizome contains essential oil,                 Europe
 (Poaceae)                                                     polysaccharide and mucilage



Agrimonia pilosa                Herb             Agrimonolide, flavonoid, triterpene,     China, Japan, Korea,
 (Rosaceae)                                                        tannin and coumarin                                India


Ailanthus altissima           Bark                   Triterpene, tannin, saponin and            China, Korea
(Simaroubaceae)                                                quercetin-3-glucoside



Akebia quinata                 Fruit                        Flavonoid and saponin               China, Japan, Korea
(Lardizabalaceae)


Alpinia galanga           Rhizomes                   Kaempferide and flavone                      Europe
 (Zingiberaceae)



Aristolochia contorta     Root and fruit       Lysicamine and oxaaporphine              China, Korea
(Aristolochiaceae)


Aster tataricus               Whole plant                Triterpene, monoterpene                  Japan, Korea
(Asteraceae)                                                           and epifriedelanol
 

Bryonia dioica                   Root                     Cucurbitacin and glycoside                     Europe


Cannabis sativa                 Leaf                    Stereo isomers of cannabitriol              South Africa
(Cannabinaceae)



Chelidonium jajus var.        Herb          Alkaloids (sanguinarine, chelerythrine,         Asia, Europe
asiaticum (Papaveraceae)                                                  berberine)


Chimaphila umbellate     Whole plant       Ericolin, arbutin, urson and tannin           Asia, Europe
(Ericaceae)



Coix lachryma jobi          Seed                        Trans-ferulyl stigmasterol                      China
(Poaceae)


Dryopteris                     Rhizomes             Filicinic and filicic acids, aspidinol       China, Japan, Korea
crassirhizoma

ANTI CANCER DRUG ON CLINICAL TRIALS:

Targeting the Micro tubular Network of Cancer Cells: Microtubules, being one of the most important structural components facilitating cell division, qualify as a natural target of various anticancer drugs. Scientists have been able to identify many natural compounds that have an intrinsic affinity for microtubules and have proved their ability by successfully binding/disrupting the mitotic spindle apparatus in cancer cells. These agents have emerged as one of the best classes of cancer chemotherapeutic drugs. In view of the success of these drugs, it has been argued that microtubules represent the single best cancer target identified till date, and it seems likely that drugs in this class will continue to remain an important chemotherapeutic class even as more selective chemotherapeutic approaches are developed. To understand the specificity, design and assertive combination of the various drugs of this class, we need to have a better knowledge of the mechanistic differences that lies between them. There is expanding evidence demonstrating that even minor modification of microtubule dynamics can rapidly hamper the spindle checkpoint, arresting cell cycle at mitosis and in this manner promoting an event of programmed cell death. With time, the more we have been able to deduce about the exciting biology of tumor cells and the mechanistic valor of the agents targeting microtubules, it has helped intensely in framing new treatment regimens for cancer therapeutics. In this chapter we have tried to briefly discuss the molecular events related to the microtubule dynamics, the dedicated role of microtubules during the events of mitosis, and also presented a concise summary of the different microtubule-targeting drugs currently undergoing clinical trials and are available for treatments [11].

DRUG RESISTANCE OF ANTI CANCER DRUGS: 

Chemotherapy fails to cure most cancer patients with advanced disease, particularly patients with the most common forms of solid tumors. The presence or development of resistance to anticancer agents is the major cause of this failure. Several of the mechanisms underlying drug resistance to cytotoxic drugs have been elucidated in the last two decades, largely by employing in vitro drug-selected cancer cell lines. In unselected cell lines and probably also in human cancer, multiple mechanisms are redundantly present to defend the organism from the insults of drugs. Mechanisms have been unraveled by which cross-resistance ensues to multiple drugs (multidrug resistance), similar to what is commonly seen in patients. More recently, the identification of downstream genes, intimately involved in cell-cycle checkpoints, appears also to directly contribute to determining the sensitivity to cytotoxic drugs by regulating the response of the cell to the drug damage. The identification of mechanisms of drug resistance has provided ways of attempting to revert the drug resistance. Although, so far, attempts to revert P-glycoprotein-mediated multidrug resistance have only sorted out limited efficacy, new drugs and new strategies are being devised and implemented, such as high-dose chemotherapy and gene transfer [11].

The presence or development of resistance to anticancer drugs is the main cause of failure of chemotherapy in the majority of the most common forms of cancer (e.g., lung, colon, breast). Resistance to chemotherapeutic drugs can be already present at diagnosis or it can develop after treatment with chemotherapy. These two forms of drug resistance are respectively called intrinsic and acquired. It is unknown whether the underlying mechanisms of drug resistance are the same in these two forms of drug resistance [17].

Many causes of drug resistance are well recognized, such as those due to administration of inadequate doses or scheduling of the drug, or to altered pharmacokinetics, or to limited penetration of the drug into the tumor. Limited penetration may be caused by poor vascularization, or extensive necrosis of parts of the tumor. It can also be due to localization of the tumor in areas of the body which are difficult to reach (sanctuary sites) because of the presence of a tissue-blood barrier (e.g., blood-brain, blood-testis, placenta) [16].

A well-known reason for poor sensitivity to chemotherapy is the slow growth kinetics of the tumor; in fact, most known anticancer agents exquisitively act on proliferating cells.

Research on drug resistance in the last two decades has focused primarily on the study of cellular mechanisms of drug resistance. Whether these are more important than physical mechanisms or drug-related mechanisms is still rather unclear, and numerous examples of both cases are present in the literature [16].

CELLULAR DRUG RESISTANCE:

The establishment of cancer cell lines which are in vitro-selected resistant by exposure to increasing concentrations of anticancer agents has made possible the identification of a number of mechanisms of cellular drug resistance. The cell clones that survive in culture in the presence of escalating concentrations of drug can be analyzed, and alterations at biochemical and/or genetic levels identified.

Several biochemical causes of drug resistance have been described for exposure to several drug types and are summarized in Table 1⇓. Some drugs, such as methotrexate, are transported into the cell through a high-affinity transport system; a loss of, or reduced activity of, this system may induce resistance.

There are now at least two well-known cell membrane proteins which can extrude a number of drugs from the cell and cause multidrug resistance (MDR); this mechanism is extensively described later in the text. Obviously, a reduced uptake or an increased efflux will lower the intracellular concentration of the drug, thereby diminishing its activity.

Some anticancer agents require metabolic activation in the body, such as the alkylating agent cyclophosphamide; an alteration of the metabolic conversion (e.g., loss of deoxycytidine kinase activity for Ara-C activation) can lead to reduced activity of the drug. A mechanism of this sort has also been recently described for the new camptothecin analog Irinotecan (CPT-11), a DNA topoisomerase I inhibitor, which requires conversion to the active metabolite SN-38 in order to exert antitumor efficacy. This conversion is catalyzed by carboxyestherase, an enzyme present in several cell types. Reduced levels of this enzyme have been observed in cell lines resistant to CPT-11 as a possible cause of drug resistance. Of course, this mechanism is difficult to extrapolate to the in vivo situation, where, in fact, the conversion will occur very rapidly after intravenous administration and the tumor will be exposed directly to SN-38, bypassing the need for activation of CPT-11 in the tumor cells.

Drug inactivation is also a well-described mechanism of drug resistance, such as the one due to increased glutathione-S-transferase activity in resistance to alkylating agents [11].

Decreased formation of drug-target complexes can occur in one of several different ways:

1) An amino acid substitution in the target enzyme determines a decreased affinity of the enzyme for the drug.

2) Overproduction of the target enzyme, making impossible a complete inhibition.

3) An increased level of normal substrate competes with the drug for the target enzyme

4) A decrease of essential substrates reduces the formation of the complex.

More than one of these mechanisms are implicated in resistance to the antimetabolites methotrexate and 5-fluorouracil. Finally, an increased repair of damage produced by the drug can also lead to resistance (e.g., increased repair of DNA damage induced by alkylating agents or topoisomerase inhibitors)[11].

Genetic analysis of cell lines selected for resistance to anticancer drugs has shown that various genetic alterations can ensue in these cells . The mutation rate is usually low in a normal cell population, but it can increase by exposure to mutagenic agents. Drug resistant mutants have been hypothesized to appear with a frequency of 10−6 cell divisions. Large tumors have a greater chance of developing mutants which are drug resistant because more duplications will have occurred. This may be an additional reason why, in general, large tumor masses are less sensitive to eradication by chemotherapy. Several different types of biochemical changes leading to drug resistance are associated with gene alterations, such as mutations or amplifications of genes involved in resistance to specific drugs. Mutations in a gene can lead to decreased production of a protein, synthesis of an unstable or nonfunctional protein, production of a protein with altered drug affinity (often caused by point mutations), or increased production of a normal protein. This last alteration is, however, caused mainly by transcriptional activation or gene amplification in the absence of mutations[16].

Multiple pathways and different mechanisms of action have been described for a number of drugs, but in particular for antimetabolites. It is therefore not surprising that tumor cells can present many mechanisms of drug resistance to a single drug. As an example, resistance to the antimetabolite methotrexate can occur through decreased activity of the membrane transport system, decreased polyglutamation of methotrexate, alteration or increased production of dihydrofolate reductase, decreased levels of thymidilate synthase, or increased nucleoside salvage. Although one specific mechanism is usually overwhelming, multiple mechanisms can coexist in the same cell line[17].

All of the above-mentioned mechanisms have been primarily described in in vitro-selected cell lines, whereas much less is known about the mechanisms of resistance and differential sensitivity to drugs of unselected cell lines. In general, it would appear that the process of selection drives the cells, in a rather extreme fashion, to develop mechanisms to escape death; it is dubious whether these same mechanisms are in place or expressed at comparable levels in unselected cell lines as in in vitro-selected resistant cell lines. This is, of course, a matter of great concern, as drug exposure in patients is rather different from that obtained in vitro. Whether in vitro findings at all reflect the basis of drug resistance at the cellular level in the patient remains to be elucidated [11].

MULTI DRUG RESISTANCE ON ANTI CANCER CELL:

By exposing cells in vitro to one drug, clones may be selected which display resistance mechanisms to the single drug or class of drugs, but cells can also simultaneously become resistant to several anticancer drugs not belonging to the same type. This phenomenon is called cross-resistance and mirrors the clinical setting where patients who have become resistant to the first chemotherapy are very frequently also resistant to the second chemotherapy, regardless of whether the drugs employed are different by mechanism of action or chemical class [11].

The best characterized of this type of drug resistance has been called multidrug resistance. MDR is the in vitro resistance induced by exposure to a drug, which leads to cross-resistance to a number of other drugs which are not related by chemical structure or mechanism of action. MDR is due to overexpression of P-glycoprotein, a cell membrane protein of 170 kDa molecular weight (P-170) The anticancer drugs involved in this phenotype are natural products such as anthracyclines, Vinca alkaloids, epipodophyllotoxins, actinomycin D and taxanes [17].

P-170 is a transmembrane protein present in tumor and normal cells and is responsible for the active transport of anticancer agents and possibly several other physiological substances from the cytosol of the cell to the extracellular space. By active drug extrusion, the drug concentration at the intracellular target site is insufficient, thereby resistance occurs. P-170 is encoded by the MDR-1 gene. From the amino acid sequence of the protein it is hypothesized that P-170 consists of two similar halves, each containing six transmembrane domains and an ATP binding site; the transmembrane segments probably form a channel through which the drug can be extruded.

P-170 expression occurs in cells of several normal tissues, such as adrenal cortical cells, apical surface of intestinal epithelium, a small percentage of biliary canaliculi, some CD34+ cells, brush border of proximal tubules of the kidney, pancreas excretory ducts, and endothelial cells of brain, testicles and placenta. The latter localizations provide evidence for the presence of the blood-tissue barrier in these organs, which is also likely responsible for the difficult penetration of most of the cytotoxic drugs into those organs. The other localizations in normal tissue are consistent with a functional extrusion of toxins from the organism, steroid transport in the case of adrenals, and defense mechanism in CD34+ bone marrow cells [17].

A number of tumors overexpress the MDR-1 gene; among these are: neuroblastoma, rhabdomyosarcoma, myeloma, non-Hodgkin‘s lymphomas, colon carcinoma, breast carcinoma and renal cell cancer. Several tumor types with high MDR-1 expression actually derive from tissues which have a high expression of the gene (e.g., colonic epithelium). Expression of the MDR-1 gene has been shown to increase after exposure to chemotherapy on several occasions but whether this increase is responsible for enhanced resistance to anticancer agents or is simply a feature of a more malignant phenotype is still a matter of discussion [17]

A number of cell lines have been described with cross-resistance patterns which are very similar to those of P-170-mediated MDR, but in which MDR-1 is not overexpressed. These other MDR phenotypes have been generically identified as non-P-glycoprotein-mediated MDR. Recently, another drug transport protein has been identified, called MRP, or multidrug resistance-associated protein, which, like P-glycoprotein, is localized mainly on cell membranes The MRP gene is overexpressed and amplified in a number of cell lines which were selected in vitro for resistance to doxorubicin. These cell lines lack expression of the MDR-1 gene. The patterns of cross resistance are very similar, although paclitaxel does not seem to be a substrate of MRP, whereas it is for P-170

Both MRP and MDR-1 genes belong to the ATP-binding cassette superfamily of transporter proteins which can transport a number of different substrates from drugs to peptides to ions .Actually, the MRP gene sequence is much closer to the cystic fibrosis and other genes encoding for transport proteins, than to the MDR-1 and MDR-3 genes. As with the MDR-1 gene, transfection experiments can induce MDR in cells transfected with the MRP gene. Recently, the MRP gene product has been shown to be a primary-active ATP-dependent export pump for conjugates of lipophilic compounds with glutathione and several other anionic residues . suggesting that MRP overexpression can cause MDR by promoting the export of drug modification products from cells . Whether overexpression of the MRP gene is of clinical importance is a matter of current investigation.

More recently, another gene has been cloned and identified which might be responsible for yet other forms of non-P-glycoprotein-mediated MDR. The gene product is targeted by a monoclonal antibody called LRP56 (Lung Resistant Protein), because it was identified in a lung cancer cell line. Overexpression of LRP56 has been observed in in vitro-selected resistant lung cancer cell lines, mainly after exposure to anthracyclines .Interestingly, there is no analogy between the LRP gene and the ATP-binding cassette superfamily of transporter proteins, and the gene appears to be the human major vault protein .This 110 kDa protein is one of a complex of four proteins and RNA which is found in the nucleopore complex and in cytoplasmic organelles [11].

The overexpression of this protein is more frequently present in tumors which are intrinsically resistant to chemotherapy than in tumors that can be cured by chemotherapy . Furthermore, ovarian cancer patients whose tumors had higher LRP expression had poorer response to cisplatin-containing chemotherapy and shorter progression-free survival and overall survival . Additional clinical studies investigating the expression of the LRP gene are in progress and results are awaited [16].

Finally, another type of non-P-glycoprotein-mediated MDR, also called atypical MDR, is due to alterations of the function of the enzyme DNA topoisomerase II and concerns cross-resistance between drugs which are targeted to the enzyme. DNA topoisomerase II is an essential nuclear enzyme which catalyzes conformational changes of DNA, important for several steps of DNA metabolism such as transcription, DNA synthesis, chromosome segregation, and recombination. The conformational modifications are rendered possible by formation of a transient double DNA break, followed by a DNA strand passage and eventually by relegation. Inhibitors of topoisomerase II prevent the relegation process from occuring by freezing the so-called ―cleavable complex‖ formed between the enzyme and DNA. DNA topoisomerase II-targeted drugs are anthracyclines, anthracenediones, epipodophyllotoxins, actinomycin D and amsacrines. The drugs involved in MDR due to alteration of topoisomerase II are essentially the same drugs involved in the P-170-mediated MDR, with the exception of Vinca alkaloids and taxanes The reduced activity of the enzyme and/or reduced expression of the gene have been identified as responsible for the decreased chemosensitivity to topoisomerase II inhibitors in cell lines which had been selected by exposure to several topoisomerase II-targeted drugs. Nevertheless, a good correlation between activity/expression and antitumor efficacy could also be found in unselected cell lines of various types, indicating that topoisomerase II-mediated MDR might be responsible for a more generalized form of drug resistance than the transport-mediated MDR types

In recent years, some genes involved in response to cell damage (particularly DNA damage) have also been investigated as possibly responsible for drug resistance. p53 and bcl-2 are important genes that control programmed cell death (apoptosis). Tumor cells which have mutant p53 are less sensitive to a large spectrum of drugs including doxorubicin, cisplatin and 5-fluorouracil .Given the fact that p53 appears to be the gene that most frequently is altered in human malignancy, these considerations may be of extreme importance. This is a field in very rapid development, and it now appears clear that downstream genes may play an important role. This new understanding of the tumor biology opens up new therapeutic possibilities, including gene therapy.

With the advances in understanding the mechanisms of drug resistance, it appears more and more clear that within a given tumor there may well be multiple mechanisms in action [16].

OVERCOMING DRUG RESISTANCE ON ANTI CANCER CELL :

A large number of trials attempting to revert P-glycoprotein-mediated MDR have been performed. Many substances with drug-resistance-modifying capabilities are known. They belong to different chemical classes, ranging from beta-blockers to anti-arrhythmics, to hormones, to immunosuppressives (Table 2⇓). Although the mechanism of MDR reversal can be complex, nearly all reversal compounds are substrates of P-glycoprotein and compete with the cytotoxic drug for extrusion from the cell. The first of these substances to be tested was verapamil, which unfortunately was found to be extremely cardiotoxic at doses which give patients plasma concentrations necessary to revert drug resistance in vitro. More recently, cyclosporin-A and analogs like PSC-833, which is devoid of cardiac, renal and immunosuppressive properties, have been developed and are under clinical investigation [11].

A large number of phase I and dose-finding studies have been performed with drug resistance reversal agents and cytotoxic drugs; however, randomized trials are few. Despite occasional responses in patients with hematological malignancies, and a small positive randomized study of verapamil added to chemotherapy in untreated non-small cell lung cancer three large randomized trials failed to show any benefit of reverters in influencing response to chemotherapy or survival in refractory patients with multiple myeloma ,untreated small cell lung cancer and breast cancer [11].

Some reverters, such as verapamil and cyclosporin A, including the analog PSC-833, substantially influence the pharmacokinetics of the anticancer drug possibly by decreasing their elimination and increasing their plasma concentration over time by 40%-60%, thereby increasing their toxicity. Reverters which are active in vitro in reverting P-glycoprotein-mediated MDR appear to have significantly less activity in reverting MDR which is due to MRP overexpression. Other substances that appear to more efficiently block the drug efflux due to overexpression of MRP rather than of MDR-1 are being investigated [16].

Another approach for reversing or preventing the development of drug resistance to anticancer agents is the use of very high doses of chemotherapy. Many anticancer agents, in fact, possess a steep dose-response relationship, and higher doses of a drug have a much higher therapeutic activity in several tumor types. The recent introduction of colony-stimulating factors and peripheral stem cell infusions into routine use has replaced, at least in solid tumors, the use of bone marrow transplantation, which is complicated by much higher morbidity and mortality rates. These improvements have made the administration of high-dose chemotherapy more feasible by substantially reducing the intensity and length of myelosuppression. Randomized studies comparing traditional chemotherapy doses with high-dose chemotherapy are ongoing in several tumor types [11].

CURRENT RESEARCH ON ANTI CANCER DRUGS:

Cancer Immunotherapy Drug Simultaneously Targets Two Proteins that Block Immune Response

Two independent groups of researchers have fused a TGF-beta receptor to a monoclonal antibody that targets a checkpoint protein. The result is a single hybrid molecule called a Y-trap that blocks two pathways used by tumors to evade the immune system [16].

Targeted Therapy Larotrectinib Shows Promise in Early Trials, Regardless of Cancer Type

Initial results from a series of three small clinical trials of a targeted cancer therapy called larotrectinib suggest that it may be effective in patients—children and adults—with a wide variety of cancer types [16].

Oncolytic Virus Therapy: Using Tumor-Targeting Viruses to Treat Cancer

A small but growing number of patients with cancer are being treated with oncolytic viruses, which infect and kill tumor cells. But research now suggests that these treatments also work against cancer by spurring an immune response [16].

Ibrutinib Becomes First FDA-Approved Drug for Chronic Graft-Versus-Host Disease

A drug used to treat several blood cancers, ibrutinib, has been approved by FDA to treat chronic graft-versus-host disease, making it the first approved therapy for this potentially f Immunotherapy Drug with Two Targets Shows Promise against HPV-Related Cancers

The investigational immunotherapy drug bintrafusp alfa (also called M7824), a bifunctional fusion protein, shrank the tumors of some patients with advanced HPV-related cancers, according to results from a phase 1 clinical trialatal side effect of cancer-related stem cell transplants [16].

CONCLUSION:

From this project we can observed that various natural products are coming with anticancer properties and research is going on this natural compounds for creating new molecules and drugs for the life threatening disease CANCER.

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 propertiesOral administration of C. asiatica extracts slowed the development of solid and ascites tumors and increased the total life span of tumor-bearing mice Tumeric 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.

Reference

[1] W.H.O., Preventing chronic diseases: a vital investment, in WHO press : WHO Global
report,Geneva, 2005.
[2] Mathers, C.D. and Loncar, D. (2006) PLoS Med., 3(11), 442.
[3] Lopez, A.D.; Mathers, C.D.; Ezzati, M.; Jamison, D.T. and Murray, C.J. (2006) Lancet,
367(9524), 1747-1757. [4] Demain, A. L. and Vaishnav, P. (2011) ‗Natural products for cancer chemotherapy‘, Microbial Biotechnology, 4(6), pp. 687–699. doi:10.1111/j.17517915.2010.00221.x.
[5] McMichael AJ, McCall MG, Hartchorne JM, Woodings TL: Patterns of gastrointestinal
cancer in European migrants to Australia: the role of dietary change. Int J Cancer 1980,
5:431-437.
[6] Lowe SW, Cepero E, Evan G: Intrinsic tumor suppression. Nature 2004, 432:307-315.
[7] 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.
[8] Sandeep, P. et al. (2014) ‗Catharanthus roseus: A medicinal plant with potent anti-tumor
properties‘, International Journal of Research in Ayurveda and Pharmacy, 5(6), pp. 652
656. doi: 10.7897/2277-4343.056133.
[9] Siripong P.; Preechanukool, K.; Picha, P.; Tunsuwan, K. and Taylor, W.C. (1992) J. Sci. Soc.
(Thailand), 18, 187-194.
[10] Kumar, R.A.; Sridevi, K.; Kumar, N.V.; Nanduri, S. and Rajagopal, S. (2004) J.
Ethnopharmacol., 92(2-3), 291-295
[11] Desai, A. et al. (2008) ‗Medicinal Plants and Cancer Chemoprevention‘, Current Drug
Metabolism, 9(7), pp. 581–591. doi: 10.2174/138920008785821657.
[12] Diwanay, S.; Chitre, D. and Patwardhan, B. (2004) J. Ethnopharmacol., 90(1), 49-55
[13] Singh, S.S.; Srivastava, S.; Gupta, V.S.; Patro, B. and Ghosh, A.C. (2003) Ind. J.
Pharmacol., 35, 83-91.
[14] Jagetia, G.C. and Rao, S.K. (2006) Biol. Pharm. Bull., 29(3), 460466.
[15] Lee K.H., Xiao Z., Podophyllotoxins and analogs. In Anticancer Agents from Natural
Products, edited by Cragg GM, Kingston DGI, Newman DJ. Brunner-Routledge
Psychology Press, Taylor & Francis Group, Boca Raton, Chapter 5. 71. 2005.
[16] Chan, L.; Chou, T.; Ding, H.; Chen, P.; Chiang, F.; Kuo, P.; Liang, C. Apigenin induces
apoptosis via tumor necrosis factor receptor- and Bcl-2-mediated pathway and enhances
susceptibility of head and neck squamous cell carcinoma to 5-fluorouracil and cisplatin.
Biochim. Biophys. Acta Gen. S. 2012, 1820, 1081–1091 [17] Hossain MS, Urbi Z, Sule A, Hafizur Rahman KM. Andrographis paniculata (Burm. f.) Wall. Ex Nees: a review of ethnobotany, phytochemistry, and pharmacology. ScientificWorldJournal. 2014;2014:274905.25950015