1. INTRODUCTION:

Cancer is a genetic term for s large group of diseases that can affect any part of the body. Other terms used for cancer can be malignant tumorous and neoplasms. The appropriate and significant feature of cancer is the rapid creation of abnormal cell that grow beyond the boundaries. Cancer is one of the leading causes of morbidity andmortality worldwide. The8.8 million deaths in 2015 globally were due to cancer. (WHO, 2017)

1.1 Causes of Cancer:

Cancer is caused by abnormality in DNA called mutations. Normally the cell repairs abnormalities caused due to certain unavoidable factors but when cell is unable to do so the DNA mutations occurs.

This DNA instructs the cell to grow and divide abnormally resulting the transformation of normal cells into tumor cellsin a multistage process that gradually6 progresses from a pre-cancerous lesion into malignant tumor1, 2. These changes are the consequences of the interaction between the genetic factors of the living individual with physical carcinogens such as ultra-violet and ionization radiations, chemical carcinogens such as asbestos, components of tobacco smoke, aflatoxin in food, Arsenic in drinking water, biological carcinogens. Tobacco use weather active or passive is responsible for 20% of cancer patients (WHO survey, 2017)

1.2 Cancer in Ayurveda:

Charaka and sushruta’s3, 4 granth and arbuda5 can be regarded as equivalent to cancer. As per Charaka and Sushruta Samhita imbalance in three Dosha’s “Vata Pitta and Kapha” in body are responsible for diseases. These description “Granthi” arbuda in Samhita is equivalent to modern day carcinoma. In Ayurveda the term “Tridoshi Carbudasare” usually refers to malignancy6 Mamsarbuda (Sarcomas), raktarbuda (leukaemia), mukharbuda (oral cancer), asadhyavrana(incurable or malignant ulcers), mamsaja ostharoga (growth of lips),

asadhya galganda(incurable thyroid tumor), tridosaja gulmas and asadhaya udararoga(abdominal tumor, livercancer or lymphomas), asadhya kamla(incurable Jaundice).

1.3 Staging of Cancer:

Staging of cancer means to describe the extent of spread of cancer. The optimizing therapy is based on the proper staging of carcinoma. The cancer’s stage is based on the size or extent of the primary tumor whether it has spread to nearby lymph nodes or other areas of the body. The various stages of carcinoma are described below:

1.Local stage:

An invasive malignant cancer confined entirely to the organ of origin.

2. Regional:

A malignant cancer that has extended beyond the circuits of the organ of origin directly into the surrounding organs or tissues, involves regional; lymph nodes or has both regional lymph nodes.

3. Distant:

Malignant cancer that has spread to parts of the body remote from the primary tumor either by direct extension or by discontinuous metastasis to distant organs, tissues or via the lymphatic system to distant lymph nodes.

2. DIAGNOSIS AND TREATMENT:

The first important step in treatment of carcinoma is to diagnose and establish the exact location and stage of proliferation. The early diagnosis increases the chances of successful treatment by focusing on the targeted tissues. The delays in this process complicates and decrease the survival rate. The cancer therapy used may work as per the following mechanism7.

a. Inhibiting cancer cell proliferation by stimulating macrophage phagocytosis

b. Promoting apoptosis of cancer cells of increasing production of interferon, interlinking-2, immunoglobulin and complement in blood serum.

c. Stimulating necrosis of tumor and blocking blood source of tumor tissue and inhibiting its translocation.

d. Enhancing the number of leukocytes and platelets by stimulating the hemopoietic function

e. Promoting metabolism, reverse transformation from tumor cells into normal cells.

f. Preventing cell division of cancerous cells.

g. Stimulating appetite, improving quality of sleep and strengthening immune system.

2.1 Radio Therapy:

This treatment is used to cure local stage tumors, cancerous malignant tissues or other outgrowths by irradiating these areas with high energy radiations like gamma-rays, X-rays etc. these rays break down cancer cells and prevent their proliferation but this therapy has drawbacks that radiations may affect the normal cells and cause other allied ailments. The surgery and radiations combined have good impact on breast cancer, lymphoma. The cancer of oral cavity and pharynx is best treated with radiation therapy and surgery, separated or in combination.

2.2 Surgery:

In surgical operations the recognized and targeted mass of the malignant tissue and other surroundings probable mass is removed followed by radiation or chemotherapy. Surgery is the most common treatment for cancers of colorectal, kidney, liver, breasts, oral cavities and pharynx, pancreas, urinary bladder and uterine corpus (Endometrium) in early stages but still not a potential and complete treatment in all stages of proliferation of malignant tissue.

2.3 Chemotherapy:

A large number of synthetic and semi synthetic drugs have arrived in forefront for the treatment of early stages of malignant tissues and carcinogens. Some are listed below with their utility functions.

1.Abiraterone (brand names Zytiga, Abiratas, Abretone, and Abirapro) is a steroidal inhibitor which is used in combination with prednisone in prostate cancer.

2. Abitrexate (Methotrexate) used to treat breast cancer, leukemia, lung cancer, lymphoma, and osteosarcoma.

3. Abraxane (Protein-bound paclitaxel)is an injectable formulation of paclitaxel used to treat breast cancer, lung cancer and pancreatic cancer, among others. Paclitaxel destroys cancer cells by preventing the normal breakdown of microtubules during cell division.8, 9, 10.

4. Brentuximab vedotin (trade name Adcetris) used to treat relapsed or refractory Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL). It selectively targets tumor cells expressing the CD30 antigen, a defining marker of Hodgkin lymphoma and ALCL (a type of T cell non-Hodgkin lymphoma).11

5. Doxorubicin (trade name Adriamycin) is used to treat breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used together with other chemotherapy agents.

6. Amifostine(Ethiofos) is a cytoprotective adjuvant used in cancer chemotherapy and radiotherapy involving DNA-binding chemotherapeutic agents. Amifostine is used therapeutically to reduce the incidence of neutropenia-related fever and infection induced by DNA-binding chemotherapeutic agents including alkylating agents. Amifostine is also indicated to reduce the incidence of xerostomia in patients undergoing radiotherapy for head and neck cancer.

7. Anastrozole (trade name Arimidex) is used for the treatment of breast cancer. Specifically it is used for hormone receptor-positive breast cancer. It has also been used to prevent breast cancer in those at high risk.

8. Bevacizumab(trade name Avastin)is medication used to treat a number of types of cancers and a specific eye disease.

9. Azacitidine(trade name Vidaza) is commonly used for promoting cardiomyocyte differentiation of adult stem cells. However, it has been suggested that this drug has a compromised efficacy as a cardiac differentiation factor because it promotes the transdifferentiation of cardiac cells to skeletal myocytes¹².

10. Avelumab (trade name ) is a fully human monoclonal antibody developed by Merck KGaA and Pfizer as a pharmaceutical drug for use in immunotherapy, originally for the treatment of non-small-cell lung carcinoma (NSCLC)¹³

11. Daratumumab (trade name Darzalex) is an anti-cancer drug. It binds to CD38 which multiple myeloma cells overexpress.^{14, 15}

12. Bexarotene (brand name: Targretin) is an antineoplastic (anti-cancer) agent approved by the U.S.Food and Drug Administration (FDA) (in late 1999) and the European Medicines Agency (EMA) (early 2001) for use as a treatment for cutaneous T cell lymphoma (CTCL).^[1] It is a third-generation retinoid.

13. Cabazitaxel (previously XRP-6258, trade name Jevtana) is a semi-synthetic derivative of a natural taxoid. It was developed by Sanofi-Aventis and was approved by the U.S. FDA for the treatment of hormone-refractory prostate cancer on June 17, 2010. It is a microtubule inhibitor, and the fourth taxane to be approved as a cancer therapy¹⁶.

14. Carboplatin, sold under the trade name Paraplatin among others, is a chemotherapy medication used to treat a number of forms of cancer. This includes ovarian cancer, lung cancer, head and neck cancer, brain cancer, and neuroblastoma. It is used by injection into a vein¹⁷.

15. Cisplatin is a chemotherapy medication used to treat a number of cancers. This includes testicular cancer, ovarian cancer, breast cancer, bladder cancer, head and neck cancer, cervical cancer, lung cancer, mesothelioma, esophageal cancer, brain tumors, and neuroblastoma. It is used by injection into a vein¹⁸.

16. Docetaxel, sold under the brand name Taxotere among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer, head and neck cancer, stomach cancer, prostate cancer and non small-cell lung cancer. It may be used by itself or along with other chemotherapy medication. It is given by slow injection into a vein¹⁹.

17. Elotuzumab (brand name Empliciti, previously known as HuLuc63) is a humanized monoclonal antibody used in relapsed multiple myeloma.²⁰ The package insert denotes its mechanism as a SLAMF7-directed (also known as CD 319) immunostimulatory antibody.²¹

18. Letrozole (INN, trade name Femara) is an oral non-steroidal aromatase inhibitor for the treatment of hormonally-responsive breast cancer after surgery.

19. Flutamide, sold under the brand name Eulexin among others, is a synthetic, non-steroidal antiandrogen (NSAA) used primarily to treat prostate cancer.It acts as a selective antagonist of the androgen receptor (AR), competing with androgens such as testosterone and its powerful active metabolitedihydrotestosterone (DHT) for binding to ARs in the prostate gland. By doing so, it prevents them from stimulating the prostate cancer cells to grow.

20. Gefitinib (ZD1839) (trade name Iressa) is a drug used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells. Therefore, it is only effective in cancers with mutated and overactive EGFR. It is marketed by AstraZeneca and Teva.

21. Glucarpidase (Voraxaze) is an FDA-approved intravenous drug for the treatment of elevated levels of methotrexate (defined as 1 micromol/L) during treatment of cancer patients who have impaired kidney function (and thus cannot reduce the drug to safe levels sufficiently after the drug has been given). Glucarpidase is an enzyme that inactivates methotrexate rapidly after injection. Because this agent reduces systemic levels of methotrexate and could therefore interfere with efficacy, it is not recommended for use in patients with normal or only slightly impaired kidney function or in whom serum levels are normal

22. Trastuzumab, sold under the brand name Herceptin among others, is a monoclonal antibody used to treat breast cancer. Specifically it is used for breast cancer that is HER2 receptor positive. It may be used by itself or together with other chemotherapy medication²².

23. Ifosfamide (IFO), sold under the brand name Ifex among others, is a chemotherapy medication used to treat a number of types of cancer. This includes testicular cancer, soft tissue sarcoma, osteosarcoma, bladder cancer, small cell lung cancer, cervical cancer, and ovarian cancer. It given by injection into a vein.²³

24. Lanreotide (INN) is a medication used in the management of acromegaly and symptoms caused by neuroendocrine tumors, most notably carcinoid syndrome.

25. Oxaliplatin, sold under the brand name Eloxatin, is a cancer medication used to treat colorectal cancer. Often it is used together with fluorouracil and folinic acid (leucovorin) in advanced cancer.

2.4 Plant derived anticancer agents:

Plants have a long history of use in treatment of cancer. The various products from different plant are in clinical use in various stages of cancer. The plant products are more effective and show least toxicity and side effects. Some of the plant derived are compounds are listed below.

2.4.1. Vinca alkaloids:

Vinblastine(VLB) and vincristine(VCR) was the first plant products used as anti cancer agents. These are antimitotic and anti-microtubule alkaloid agents obtained from plant catharanthus roseus (Basionym vinca rosea) and other vinca plants. They are a class of cell-cycle-specific cytotoxic drugs that work in inhibiting the ability of cancer cells to divide. These act on tubulin and prevented from forming of microtubules, necessary component for cellular division²⁴. The recently synthesized semi synthetic analogues of vinca alkaloids are vinoerlbine(VRLB) and Vindesine(VDS). Vinpocetin is a semisynthetic derivative of vincamine(or simply called as ethylester of apovincamine,methoxyminovincine, vinovincinine, desoxyvincaminol, etc.)

Figure. Vinblastine

2.4.2 Podophyllotoxin Derivatives:

Podophyllotoxins is a non-alkaloid toxin lignin extraxted from roots and rhizomes of podophyllum species25. The extracts of roots of such plants were used in treatment of skin cancers and wards in America. Other closely related Podophylloxins like lignans were isolated which were very toxic and could not be used as anticancer agents. Researchersstudied at Sandoz Laboratories in Switzerland in 1960s and 1970s led to development of etoposide and tenniposide as clinical agents whish were used in treatment of lymphomas, bronchial and festicular cancers²⁶.

2.4.3. Taxanes:

Taxanes are a class of diterpenes. They were originally identified from plants of the genus Taxus (yews), and feature a taxadiene core. Paclitaxel (Taxol) and docetaxel (Taxotere) are widely used as chemotherapy agents.Paclitaxel also named as taxol was first isolated from the bark of taxus brevifolia Nutt (Taxaceae). Its is used in the treatment of wide vriety of cancer including breast, ovarian and non small cell lung cancer and used against Kaposi sarcoma.

Docetaxel is a chemotherapy medication used to treat a number of types of cancer²⁷. This includes breast cancer, head and neck cancer, stomach cancer, prostate cancer and non small-cell lung cancer.²⁸ It may be used by itself or along with other chemotherapy medication. It is given by slow injection into a vein.

Common side effects include hair loss, low blood cell counts, numbness, shortness of breath, vomiting, and muscle pains. Other severe side effects include allergic reactions and future cancers. Side effects are more common in people with liver problems. Use during pregnancy may harm the baby. Docetaxel is in the taxane family of medications.²⁹ It works by disrupting the normal function of microtubules and thereby stopping cell division.

2.3.4 Campothecin Derivatives:

Camptothecin(CPT) is cytotoxic quinoline . It was discovered in 1966 by M. E. Wall and M. C. Wani in systematic screening of natural products for anticancer drugs. It was isolated from the bark and stem of Camptotheca acuminata (Camptotheca, Happy tree), a tree native to China used as a cancer treatment in Traditional Chinese Medicine.³⁰ CPT showed remarkable anticancer activity in preliminary clinical trials but also low solubility and (high) adverse drug reaction. Because of these disadvantages, synthetic and medicinal chemists have developed numerous syntheses of Camptothecin and various derivatives to increase the benefits of the chemical, with good results. Two CPT analogues have been approved and are used in cancer chemotherapy³¹ today, topotecan and irinotecan.^{32, 33}

2.3.5 Homoharringtonine:

Homoharringtonine or HHT is a natural product first discovered in Cephalotaxus harringtonii, now manufactured by hemi-synthesis. It was approved by the US FDA in October 2012 for the treatment of adult patients with CML with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs).³⁴

Homoharringtonine is used for the treatment of patients with chronic myeloid leukaemia who are resistant or intolerant of tyrosine kinase inhibitors.^{35, 36, 37}

In June 2009, results of a long-term open label Phase II study were published, which investigated the use of homoharringtonine (omacetaxine) infusions in CML patients. After twelve months of treatment, about one third of patients showed a cytogeneticresponse.³⁸ A study in patients who had failed imatinib and who had the drug resistant T315I mutation achieved cytogenetic response in 28% of patients and hematologic response in 80% of patients, according to preliminary data.³⁹

Phase I studies including a small number of patients have shown benefit in treating myelodysplastic syndrome (MDS, 25 patients)⁴⁰ and acute myelogenous leukaemia (AML, 76 patients).⁴¹ Patients with solid tumors did not benefit from Homoharringtonine.⁴¹

2.3.6 Favopiridol:

It is a flavone derived from the plant alkaloid rohitukine and isolated from plant Dysoxylum binectariferums is under phase I and phase II clinical trials. This flavone has shown god activity against tumors leukemia, lymphomas and solid tumors.⁴²

2.3.7 Betulinic acid:

Betulinic acid is a common pentacyclic triterpenoid found in the species of genus Betula, also isolated from zizyphus species, recently discovered potential as an anticancer agent, by inhibition of topoisomerase.⁴³Regarding the mode of action of betulinic acid, little is known about its antiproliferative and apoptosis-inducing mechanisms. In neuroectodermal tumor cells, betulinic acid–induced apoptosis is accompanied by caspase activation, mitochondrial membrane alterations and DNA fragmentation.^{44, 45}

2.3.8 Silvesterol:

Silvestrol and various derivatives can be prepared from fruit and twigs of the tropical plant Aglaia foveolata and related species extracts. ⁴⁶ The genusAglaia belongs to the family of the mahogany ("Meliaceae"), which are mainly endemic in Indonesia and Malaysia. In preclinical cancer research, Silvestrol has been used for several years to inhibit tumor cell growth in human cell cultures and in tumor models. ^47,
48Silvestrol shows a low cytotoxicity against healthy cells.

In a recent study of Ebola- infected human cells, Silvestrol has been shown to be effective in reducing the viral load in primary human macrophages and in the Huh-7 cell line (isolated from human liver carcinoma), and the production of viral proteins is greatly reduced.

2.3.9 Epothilones:

The epothilones are a class of potential cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, but in early trials epithilones have better efficacy and milder adverse effects than taxanes.⁴⁹

As of September 2008, epothilones A to F have been identified and characterised.⁵⁰ Early studies in cancer cell lines and in human cancer patients indicate superior efficacy to the taxanes. Their mechanism of action is similar, but their chemical structure is simpler. Due to their better water solubility, cremophors (solubilizing agents used for paclitaxel which can affect cardiac function and cause severe hypersensitivity) are not needed.⁵¹ Endotoxin-like properties known from paclitaxel, like activation of macrophages synthesizing inflammatory cytokines and nitric oxide, are not observed for epothilone B.⁵²

Epothilones were originally identified as metabolites produced by the soil-dwelling myxobacterium Sorangium cellulosum.

CONCLUSION:

In this review article an attempt has been made to explain the details of cancer with its impact and increased encroachment on population with number of cases of cancer increasing every year. The cancer various types and operates with set mechanism of attacking new cells and inducing in them carcinogenic activity as a mode of spread. The diagnosis of cancer has been the major concern followed by treatment. The various synthetic drugs like Cisplatin, Carboplatin, Glucarpidase, Docetaxel, Lanreotide and Azacitidine etc. are in clinical use in different phases of cancers of various kinds. These compounds have shown good results in early stages of cancer. In lateral stages of cancer these prove ineffective, these compounds have also shown toxicity and good deal of intolerable side effects as such compounds are seldom potent and permanent anti-cancer agents. The various natural products obtained from medicinal plants and herbs show good and effective anti-cancer activity. Vinblastine inhibited the cell division and cell proliferation of cancer cells, the other plant products in clinical use are Podophyllotoxin Derivatives, Taxanes, Campothecin Derivatives, Homoharringtonine and Favopiridol. These are quite effective against different types of cancers in initial stages. The bacterial metabolite, the epothilones prevent cancer cells from dividing by interfering with tubulin. Obviously, still no synthetic and natural product can be regarded as a complete treatment of the ailment. A good deal of work still has to be done to get a valuable and effective treatment of cancer.

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Received on 01.07.2017 Modified on 06.07.2017

Asian J. Research Chem. 2017; 10(5): 699-707.

DOI: 10.5958/0974-4150.2017.00119.5

Synthetic and Natural Compounds as Anti-Cancer Agents – A Review

1. INTRODUCTION: