ANTICANCER NEW.pptx

natural anticancer drugs in cancer therapy.

1. ANTICANCER DRUGS PRESENTED BY- INDRAJIT SAMANTA M.PHARMA, 1ST YEAR, 1ST SEM, DEPARTMENT OF PHARMACEUTICAL CHEMISTRY, SPER, JAMIA HAMDARD, NEW DELHI- 110062

2. CONTENT:

3. DRUG DISCOVERY FROM NATURAL PRODUCT Natural products have been used for centuries for the treatment of several ailments. Many bioactive compounds have been discovered from plants, animals and microbes, such as natural products and secondary metabolites, developed into drugs to treat diseases. Over 60% of the clinical use of anti-cancer drugs originate from natural products, including plants, marine organisms, microbes, and more than 3,000 species of plants can be used to treat cancer.

4. NATURAL PRODUCTS FOR TREATMENT OF CANCER Active ingredients such as alkaloids, flavonoids, terpenoids, polysaccharide and saponin obtained from natural products have potent biological properties such as anti- tumor , analgesia, anti-inflammatory, immunomodulation, anti-viral, etc. Most natural anti-neoplastic drugs often do not kill tumor cells directly, but regulates the human immune function to achieve this purpose or both. DNA topoisomerase I ( Topo I) is an essential enzyme involved in cell growth. The inhibition of Topo I is an important anti-cancer pathway. A large number of anti-cancer drugs combat cancers through cell cycle arrest, induction of apoptosis and differentiation as well as through inhibition of cell growth and proliferation.

5. WHAT IS CANCER? Cells are the basic units that make up the human body. Cells grow and divide to make new cells as the body needs them. Usually, cells die when they get too old or damaged and new cells growth take their place. Cancer begins when genetic changes occurs. Cells start to grow uncontrollably. These cells may form a mass called a tumor . A tumor can be cancerous or benign. A cancerous tumor is malignant, it can grow and spread to other parts of the body. A benign tumor means the tumor can grow but will not spread. Anything that may cause a normal body cell to develop abnormally, potentially can cause cancer. General categories of cancer-related or causative agents are as follows: chemical or toxic compound exposures, ionizing radiation, some pathogens, and human genetics.

6. NUMBER OF NEW CASES IN 2021 , BOTH SEXES, ALL AGES IN CANCER

7. ANTICANCER DRUG CLASSIFICATION ALKLATING AGENTS- Methyl Hydrazine: Procarbazine Ethylenimine: Thiotepa Nitrosourea: Carmustine, Lomustine Alkyl sulfonate: Busulfan Nitrogen Mustard: Cyclophosphamide, Ifosphamide, Chlorambucil Triazine: Decarbazine, Temozolomide PLATINUM CO-ORDINATION COMPLEX* Cisplatin, Oxaliplatin, Carboplatin ANTIMETABOLITES: Purine Antagonist: 6-mercaptopurine,6-thioguanine Pyrimidine Antagonist: 5-flurouracil, cytarabine Folate Antagonist: Methotrexate, Premetexed

8. ANTICANCER DRUG CLASSIFICATION MICROTUBULE DAMAGING AGENTS: Vinca alkaloids: Vincristine, Vinblastine Taxanes: Paclitaxel, Docetaxel, Estramustine MISCELLANEOUS Hydroxyurea, L-Asparaginase, Arsenic Trioxide. TOPOISOMERASE-1-INHIBITOR:Topotecan, Irinotecan. TOPOISOMERASE-2-INHIBITOR: Etoposide ANTIBIOTICS: Actinomycin D, Doxorubicin, Daunorubicin, Mitomycin C TARGETED DRUGS: Imatinib, Nilotinnib, Sunitinib HORMONAL DRUGS: Prednisolone, Anastrozole, Letrozole

9. CLASSIFICATION OF NATURAL ANTICANCER DRUG

10. MODE OF ACTION OF NATURAL ANTICANCER DRUGS

11. RECENT ADVECES OF NATURAL ANTICANCER AGENTS 1. Natural agents have low toxicity. 2.The MOA of recent natural agents are Acts on DNA bases Intercalation of DNA Inhibit topoisomerases & Protein kinases Induction of Apoptosis (Cell suicide) 3. Many new species are investigated to find out new agents for treatment of cancer. 4.Cell culture techniques are involved to produce new botanical therapeutic agents to treat neoplasms 5. Development of QSAR modelling on anti-cancer agents also produces good therapeutic agents with decreasing toxicity

12. PLANT-DERIVED ANTICANCER AGENTS IN CLINICAL USE First agents that were clinically used are Vinca alkaloids, Vinblastine(VLB) & Vincristine (VCR), isolated from Madagascar periwinkle. Two clinically active agents, cloposide (VM 26) & teniposide (VP 16-213), semi synthetic derivatives of epipodophyllotoxin are used in cancer treatment. The use of various parts of Tbrevifolia and other Taxus species is widely used in caner therapy. Anti-cancer drug amamentarium is the class of clinically-active agents derived from camptothecin, which is isolated from Chinese omamental tree is widely used. Other plant-derived agents in clinical use are homohamingtonine Cephalotaxus harringtonia) and elliptinium, a derivative of ellipticine, isolated from species of several genera of the Apocynaceae family.

13. TAXANES Isolated from the bark of the Western yew tree in 1971, Taxol/Paclitaxel became useful in the treatment of cancer when it was discovered that it possessed the unique ability to promote the formation of microtubules by binding to their B-tubulin subunit and antagonizing their disassembly. However, the amount of paclitaxel in yew bark was small, and extracting it was a complicated and expensive process. Taxol (paclitaxel) and its derivatives are microtubule-stabilizing drugs widely used in the treatment of several types of cancer, including mammary, prostate, ovarian and non small-cell lung carcinoma, as well as AIDS-associated Kaposi's sarcoma and other types of tumour.

14. TAXANES

15. STRUCTURE ACTIVITY RELATIONSHIP OF TAXOL

16. PACLITAXOL A cyclo- decane isolated from the bark of the Pacific yewtree, Taxus brevifolia. It stabilizes microtubules in their polymerized form leading to cell death Abraxane is the latest attempt to improve upon paclitaxel, one of the leading chemotherapy treatments It's brand name is Abraxane, Abraxis Bioscience, Epitaxol , Onxol Paxceed .

17. MECHANISM OF ACTION

18. SIDE EFFECTS OF PACLITAXOL Common side effects include: nausea and vomiting, loss of appetite, change in taste, thinned or brittle hair, Joint pains more than 3days, colour changes in nails, tingling in the hands or toes. More serious side effects such as unusual bruising or bleeding, pain/redness/swelling at the injection site, change in normal bowel habits for more than two days, fever, chills, cough, sore throat, difficulty swallowing, dizziness, shortness of breath, severe exhaustion, skin rash, facial flushing, female infertility by ovarian damage

19. APPLICATION OF PACLITAXOL 1. Development of polyvinylpyrrolidone/paclitaxel self-assemblies for breast cancer.

20. APPLICATION OF PACLITAXOL Paclitaxol used in ovarian cancer.

21. APPLICATION OF PACLITAXOL 2. The Development of Paclitaxel in Pancreatic Cancer

22. APPLICATION OF PACLITAXOL 3. Tumor -specific delivery of a paclitaxel-loading HSA-haemin nanoparticle for cancer treatment

23. APPLICATION OF PACLITAXOL 4. Tannic acid-inspired paclitaxel nanoparticles for enhanced anticancer effects in breast cancer cells.

24. APPLICATION OF PACLITAXOL 5. Nab-paclitaxel for the treatment of triple-negative breast cancer

25. DOCETAXOL Docetaxel is of the chemotherapy drug class; taxane , and is a semi-synthetic analogue of Paclitaxel (Taxol) Due to scarcity of paclitaxel, extensive research was carried out leading to the formulation of docetaxel- an esterified product of 10-deacetyl baccatin III, which is extracted from the renewable and more readily available leaves of the European yew tree.

26. MECHANISM OF ACTION The cytotoxic activity of docetaxel is exerted by promoting and stabilising microtubule assembly, while preventing physiological microtubule depolymerisation/disassembly in the absence of GTP. This leads to a significant decrease in free tubulin, needed for microtubule formation and results in inhibition of mitotic cell division between metaphase and anaphase, preventing further cancer cell progeny. Because microtubules do not disassemble in the presence of docetaxel, they accumulate inside the cell and cause initiation of apoptosis.

27. APPLICATION The main use of docetaxel is the treatment of a variety of cancers after the failure of anthracycline-based chemotherapy. KettoBfacShC21Docetaxel has cytotoxic activity against breast, colorectal, lung, ovarian, prostate, liver, renal, gastric, head and neck cancers, and MELANOMA

28. PODOPHYLLOTOXINS Podophyllum hexandrum Royle of family Berberidaceae is an endangered medicinal plant. Rhizome of P. hexandrum contains several lignans which posses antitumor activity. Podophyllotoxin is the most active cytotoxic natural product. It is used as starting compound for the synthesis of anticancer drug etoposide and teniposide. Podophyllotoxin acts by inhibiting microtubule assembly. These drugs are used for lung cancer, testicular cancer, neuroblastoma, hepatoma and other tumors. Availability of podophyllotoxin from plants is rare because of lack of organized cultivation. The chemical synthesis of podophyllotoxin is complicated.

29. PODOPHYLLOTOXINS The podophyllotoxin molecule includes a number of oxygen containing functional groups: an alcohol, a lactone, three methoxy groups, and an acetal Derivatives of podophyllotoxin are synthesized as properties of the rings and carbon 1 through 4 are diversified. For example, Ring A is not essential to antimitotic activity. Aromatization of ring C leads to loss of activity, Possibly from ring E no longer being placed on the axial position. In addition, the stereochemistry at C-2 and C-3 configures a trans. lactone, which has more activity than the cis counterpart. Chirality at C-1 is also important as it implies an axial position for ring E.

30. SAR OF PODOPHYLLOTOXIN:

31. ETOPOSIDE Etoposide (Demethylepipodophyllotoxinethylideneglucopyranoside, EPE, epipodophyllotoxin). It is usually prescribed in multiple chemotherapy protocols. It is a highly active and widely used antineoplastic agent. It is active against many tumour types and used primarily as part of combination treatment for testicular tumours and leukopenia. This is most active single agent for small cell lung cancer. The product is available as an injectable solution to be administered by infusion or it is administered orally as liquid capsules.

32. MECHANISM OF ACTION Etoposide forms a tertiary complex with DNA and the topoisomerase II enzyme (which aids in DNA unwinding), prevents re-ligation of the DNA strands, and by doing so causes DNA strands to break. Cancer cells rely on this enzyme more than healthy cells, since they divide more rapidly. Therefore, this causes errors in DNA synthesis and promotes apoptosis of the cancer cell. SIDE EFFECT: Major side effects include hair loss, nausea, anorexia, diarrhoea and low leucocyte and platelet counts. Etoposide is known to cause fetal damage and birth defects, so pregnant or nursing women should not use it

33. MECHANISM OF ETOPOSIDE

34. APPLICATIONS Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Advanced Hodgkin's Lymphoma Ewing's Sarcoma, Gestational Trophoblastic Disease, Merkel cell cancer, Multiple Myeloma (MM), Neuroblastoma (NB), Neuroendocrine Tumors, Non-Hodgkin's Lymphoma (NHL), Non-Small Cell Lung Carcinoma (NSCLC), Ovarian Cancer Prostate Cancer , Osteogenic Small Cell Lung Cancer (SCLC) Wilms, Refractory Testicular cancer

35. TENIPOSIDE Teniposide is used for the treatment of lymphomas of acute refractory leukemia and that of brain and bladder tumors. It can be used in single drug therapy for induction ofremission . It is in a class of drugs known as podophyllotoxin derivatives and slows the growth of cancer cells in the body.

36. MECHANISM OF ACTION Teniposide causes dose-dependent single- and double-stranded breaks in DNA and DNA-protein cross-links. The substance has been found to act as an inhibitor of topoisomerase II (an enzyme that aids in DNA unwinding),since it does not intercalate into DNA or bind strongly to DNA. The cytotoxic effects of teniposide are related to the relative number of double-stranded DNA breaks produced in cells, which are a reflection of the stabilization of a topoisomerase II-DNA intermediate

37. MEDICINAL USES Teniposide is used for the treatment of a number of cancer types in children. In the US, it is approved for the second-line therapy of acute lymphocytic leukemia (ALL) in combination with other antineoplastic drugs. In Europe, it is also approved for the treatment of Hodgkin's lymphoma, generalized malignant lymphoma, reticulocyte sarcoma, acute leukaemia, primary brain tumours (glioblastoma, ependymoma, astrocytoma), bladder cancer, neuroblastoma and other solid tumours in children

38. CONCLUSION The actual compound isolated from the plant may not serve as the drug but leads to the development of potential novel agents. Natural agents are proving to be an important source of novel inhibitors & have the potential for development into selective anticancer agents. Taxanes" a 7 letter word which means a lot in the field of cancer treatment, though their mechanism of action is clear to us in numerous cancers but there, still remains several facets of them to be unveiled. All those who contributed in the field of cancer in relation to taxanes are to be endlessly thanked including our patients who have helped researchers, doctors, 2 pharmaceutical companies seen light at the end of the tunnel. But there are still miles to go before curative treatment for cancer patients are delineated; encouragement and faith is thereto continue with those eternal "oncological explorations" which represent a blessing in cancer treatment.

39. REFERENCE Production of podophyllotoxin from Podophyllum hexandrum: a potential natural product for clinically useful anticancer drugs by Archana Giri & M. Lakshmi NarasuSchool of Biotechnology, Jawaharlal Nehru Technological University, Mahavee marg , Hyderabad 500028, IndiaArdalani H. Avan A, Ghayour- Mobarhan M. Podophyllotoxin: a novel potential naturaanticancer agent. Avicenna J Phytomed , 2017; 7 (4): 285-294 Taxanes: Promising Anti-Cancer Drugs Nilufer Jasmine Selimah Fauzee , Zhi Dong, Ya lan Wang. Chowdhury, P., Nagesh, P. K. B., Khan, S., Hafeez, B. B., Chauhan, S. C., Jaggi , M., & Yallapu , M. M. (2018). Development of polyvinylpyrrolidone/paclitaxel self-assemblies for breast cancer. Acta Pharmaceutica Sinica B, 8(4), 602-614. doi:10.1016/j.apsb.2017.10.004Chowdhury, P., Nagesh, P. K. B., Hatami , E., Wagh , S., Dan, N., Tripathi, M. K.,... Yallapu , M. M. (2018). Tannic acid-inspired paclitaxel nanoparticles for enhanced anticancer effects in breast cancer cells. Journal of Colloid and Interface Science. doi:10.1016/j.jcis.2018.09.072