Read this article to learn about the role of plants as a source of anti-cancer agents.
Since the earliest times naturally occurring substances from plants, animals and minerals provided a source of medicine for man. For a long time man has exploited particularly the plant kingdom, which has proved to be very useful for treating most of our ailments.
During the course of history, experimentation has succeeded in distinguishing those plants which have beneficial effects from those that are toxic or merely non-effective. Throughout the centuries, humans have found through trial and error ways to relieve their pain and sickness.
Every cultural group has responded by developing a medicinal system and making use of natural products to cure various aliments because of the fear of disease and death. These traditions may seem strange and magical, others appear rational and sensible, but all of them attempt to overcome illness, suffering and enhance quality of life.
Plants have adapted to the diverse habitats of the world through their physical and biomedical modifications. For thousands of years plants have been used traditionally as a source of treatment for various ailments throughout the world among all human races.
Plants have always provided an important source of medicines, and were first used in folk medicine. In ancient times in various cultures worldwide people have always been using holistic means of healing. In contrast to the frequent assumptions, the medicines used by traditional healers are surprisingly effective.
Historically the development of many important classes of drugs relied on natural products that have served as templates. Six major fields of study contribute to the studies on natural products. These include: ethno ecology, traditional agriculture, cognitive ethno botany, material culture, traditional photochemistry and paleoethnobotany.
Ethno botany is defined by Cotton (1996) as all the studies, which describe local people’s interaction with the natural environment, as well as all the studies, which concern the mutual relationships between plants and traditional people.
This definition is a very broad description of a large range of subjects such as ethno medicine, ethno taxonomy, ethno ecology etc. Ethno pharmacology on the other hand is known as the scientific evaluation of traditional medicine, which usually excludes spiritual and mythical aspects of plant use.
The ability to correlate the ethno botanical reports with corresponding scientific studies could lead to the improved selection of plants for study in the healthcare system.
Ethno pharmacology provides an alternative approach for the discovery of medicinal compounds. The results obtained by researchers, ethno botanists and scientists often justified the use of plants in folk medicine and is a serious basis for the improvement of the efficacy, safety and quality of the plant remedies used worldwide.
Conventional western medicine accepts folk medicine only when their efficacy is confirmed.
Historically plants have been valuable sources used in the treatment of cancer and many other diseases. Hartwell published a long list of more than 3000 plants that are being used in the treatment of cancer. In many instances the cancer is undefined and is reported on symptoms that apply to the skin or other visible conditions that sometimes correspond to cancerous conditions.
This is a problem because cancer is poorly defined in traditional medicine and folklore. Despite these observations, an essential role have been played by plants as a source of effective anti-cancer agents.
Natural sources derived from plants, marine organisms and micro-organisms account for over 60% of currently used anticancer agents.
Nevertheless, a well reputable armamentarium of valuable chemotherapeutic agents have come from approximately five decades of systemic drug discovery and development, together with several significant achievements in the treatment and management of human cancer.
In reality, chemotherapy effectiveness has endured different confounding factors that include systemic toxicity due to lack of specificity, rapid drug metabolism, and both intrinsic and acquired drug resistance. Furthermore the most unpredictable factor affecting chemotherapy is multidrug resistance since tumour cells are very adaptable.
In the 1950s the search for anti-cancer agents from plants sources started to intensify. It was also during this time when the discovery and development of vinblastine and vincristine (vinca alkaloids), and the isolation of the cytotoxic podophyllotoxins took place.
This led to the intensive plant collection from temperate regions in the 1960s plus the discovery of novel chemo types such as the taxanes and camptothecins, which showed a range of cytotoxic activities.
Revival of plants and other organisms took place when new screening technologies were developed in the 1986, now the focus was on the tropical and subtropical regions of the world. Even though several anticancer agents are now in the preclinical development no new clinical agents from plants have reached the stage of general use.
There are many plant-derived anticancer agents which are in clinically use these days. These include the vinca alkaloids/natural alkaloids vinblastine and vincristine that were isolated in minute quantities from Catharanthus roseus G. Don (Fig. 5.3a, b).
Vincristine possesses a formyl group whereas vinblastine has a methyl group and despite these small differences their toxicological properties and spectra of anti-tumour activities differ.
During the search for potential oral hypoglycaemic agents it was found that extracts of C. roseus reduced white blood cell counts and caused bone marrow depression in rats, and afterwards in mice studies these extracts were active against lymphocytic leukemia.
Combinational chemotherapy regimes use vincristine as a key component for the treatment of acute lymphocytic leukemia, a number of children’s solid tumours, acute childhood leukemia, Hodgkin and non-Hodgkin lymphomas as well as multiple myeloma, breast and small-cell lung cancer in adults.
Vinblastine, alternatively, is an essential component of curative chemotherapy regimes used for testes germ cell cancers and advanced Hodgkin disease and it is also frequently used to treat carcinoma of the bladder, breast and Kaposi’s sarcoma through combinational therapy with other anti-cancer drugs.
Vinblastine and vincristine remain in wide spread clinical usage even today. Analogs produced via synthetic modification could possibly have activity against other tumour types, less toxicity and side effects. Several semi-synthetic analogs were made and the most recent are vinorelbine and vindesine (the C-3 amidoanalog of 4-deacetyl vinblastine).
Vindesine when compare with other natural vinca alkaloids has less neurotoxicity, but causes complete remission in acute lymphocytic childhood leukemia and adult non-lymphocytic leukemia.
These semi-synthetic analogs are used in combination with other cancer chemotherapeutic drugs and used against a variety of cancers, breast, lung and highly developed testicular cancers as well as Kaposi’s sarcoma.
Another two semi-synthetic derivatives are etoposide (Fig. 5.4a) teniposide (Pig. 5.4b) of the parent compound epipodophyllotoxin (Fig. 5.4c) (natural product), which is an isomer of podophylotoxin (Fig. 5.4d).
Etoposide and teniposide are clinically used for the treatment of testicular, lymphomas, leukemia’s and bronchial cancers, but their use is limited due to problems such as drug resistance, poor bioavailability and myelosuppression therefore they need further structural modification.
The medicinally used Podophyllum species (Podophyllaceae) from the Indian subcontinent, Podophyllum peltatum Linnaeus (commonly known as the American mandrake or Mayapple), and Podophyllum emodii Wallich, have been used extensively for the treatment of skin cancers and warts throughout history.
In 1880 the major active constituent, ‘podophyllotoxin’ was first isolated and only in the 1950s its correct structure was reported. Podophyllotoxin functions as a mitotic inhibitor by binding reversibly to tubilin and it inhibits microtubule assembly.
Many ligans directly related to podophyllotoxin (podophyllotoxin-like) were reported; several of them were dropped from the clinical trials, due to their unacceptable toxicity and lack of efficacy.
Etoposide and its thiophene analog teniposide are structurally related to podophyllotoxin, but at C-4 they have opposite stereochemistry (a in etoposide and teniposide, a in podophyllotoxin) and different substituents (glycosyl in etoposide and teniposide, OH in podophyllotoxin).
The anti-tumour action of etoposide and its analogs is to inhibit DNA topo II (an essential enzyme) and, then increase DNA cleavage. Etoposides other actions include covalent protein binding by a bio-oxidized E-ring orthoquinone, and metal- and photo-induced cleavage of DNA caused by hydroxyl radicals formed from metal-etoposide complexes.
The taxanes were more recently added to the armamentarium of plant-derived chemotherapeutic agents Paclitaxel (taxol) (Fig. 5.5a) was isolated originally from the bark of Taxus brevifolia Nutt. (Fig. 5.5b), and today paclitaxel, together with several key precursors, are found in the leaves of various Taxus species.
Paclitaxel is used alone or in combination with other cancer drugs primarily for the treatment of ovarian, breast, and non-small cell lung cancer (NSCLC).
Furthermore it showed efficacy against Kaposi sarcoma, potential treatment of multiple sclerosis, psoriasis and rheumatoid arthritis. It has a unique mode of action; it acts as a mitotic inhibitor by promoting the assembly of microtubules and interacts with the polymerized form of αβ-tubulin.
Taxol induces apoptosis in proliferating cells through cell cycle arrest at G2/M. From early on, supply was a major obstacle in the development of paclitaxel since it is present only in minute quantities. It led to the synthesis of ‘Taxotere’, a form of 10-deacetyl-baccatin III which is more readily available. This compound was isolated from the European yew tree.
A major renewable natural source was made available to this important class of drugs through the semi-synthetic conversion of baccatins to paclitaxel, and biologically active paclitaxel related analogs, such as docetaxel. Docetaxel is used in the treatment of breast cancer and NSCLC, and has microtubule-stabilizing properties.
It has also shown efficacy in combination with other cancer drugs such as anthracyclins, prednisone and cisplatin, paclitaxel. Other Taxus species such as Taxus canadensis Marshall, T. baccata L. and other parts of T. brevifolia were used by the Native American tribes for non-cancerous conditions. Only one report for the use of cancer was found for T. baccata in the traditional Asiatic Indian (Ayurvedic) medicine system.
Currently another 23 taxanes are in the preclinical stage, 9 are undergoing Phasel/ll clinical development for new and improved as anti-cancer agents, and several other second generation taxanes were selected for clinical development to improve their solubility and activity against drug resistant tumours.
Taxanes are popular antitumor agents but clinical resistance poses a treat to their successful treatment. Effective conventional chemotherapy treatment of cancer is difficult due to multidrug resistance.
From Camptotheca acuminate Decne (Nyssaceae) ‘camptothecin’ (Fig. 5.6), a natural alkaloid, was isolated. Camptothecin is another important addition to the anti-cancer drug armamentarium of clinically active agents. The National Cancer Institute (NCI) (US), advanced camptothecin (as sodium salt) to clinical trials in the 1970s. It caused severe bladder toxicity and was consequently dropped.
Topotecan (used for treatment of ovarian and small cell lung cancers) and irinotecan (used for treatment of colorectal cancers) (CPT-11; Camptosar) were developed throughout extensive research and structural modification as more effective derivatives of camptothecin.
These compounds together with camptothecin were potent antitumour and DNA topo I inhibitory agents. Both derivatives are amine-hydrochloride salts. Topotecan was made to be 100-fold more water soluble than the parent compound camptothecin, which is poorly water soluble.
Irinotecan was metabolized to be more potent, about 200 to 1000 times more than camptothecin, and in vivo is a phenolic topo I inhibitor.
Several second- and third-generation camptothecins e.g. exatecan and diflomotecan are currently undergoing clinical trials. Five less toxic, water soluble synthetic 7-(acylhydrozono)-formyl camptothecins were found to be more potent than camptothecin in causing protein-linked DNA breaks and DNA topo I inhibition.
‘Homoharringtonine‘ (HHT) (Fig. 5.7a) was isolated from Cephalotaxus harringtonia var. drupacea (Sieb and Zucc.) (Cephalotaxaceae) (Fig. 5.7b). In China, acute myelogenous leukemia and chronic myelogenous leukemia is treated effectively with the use of a harringtonine and HHT racemic mixture.
In patients with chronic myelogenous leukemia (CML) in the late chronic phase complete hematologic remission (CHR) has been reported by homoharringtonine and it is effective against various leukemia.
Elliptinium, a derivative of ellipticine, was isolated from a Fijian medicinal plant Bleekeria vitensis A.C. Sm. (known for anticancer properties) and species of several genera of the Apocynaceae family, is marketed for treatment of breast cancer in France.
These plant derived agents are also clinically in use. By systematically screening plant extracts, clinically active agents with antitumor properties can be isolated, their metabolism can be explained as a result more active molecules might be synthesized.