Anti-cancer agents from medicinal plants

Cancer is a major public health burden in both developed and developing countries. Plant derived agents are being used for the treatment of cancer. Several anti-cancer agents including taxol, vinblastine, vincristine, the camptothecin derivatives, topotecan and irinotecan, and etoposide derived from epipodophyllotoxin are in clinical use all over the world. A number of promising agents such as flavopiridol, roscovitine, combretastatin A-4, betulinic acid and silvestrol are in clinical or preclinical development. Article Info Received: 29 November 2006 Accepted: 20 December 2006 Available Online: 3 January 2008 DOI: 10.3329/bjp.v1i2.486 Cite this article: Shoeb M. Anti-cancer agents from medicinal plants. Bangladesh J Pharmacol. 2006; 1: 35-41. Anti-cancer agents from medicinal plants

. The World Health Organization estimates that approximately 80% of the world's inhabitants rely on traditional medicine for their primary health care (Farnsworth et al., 1985). Cancer is a major public health burden in both developed and developing countries. It was estimated that there were 10.9 millions new cases, 6.7 million deaths, and 24.6 million persons living with cancer around the world in 2002 (Parkin et al., 2005). Cancer is the second leading cause of death in the United States (Hoyert et al., 2005), where one in four deaths is due to cancer. Plants have long been used in the treatment of cancer (Hartwell, 1982). The National Cancer Institute collected about 35,000 plant samples from 20 countries and has screened around 114,000 extracts for anti-cancer activity (Shoeb, 2005). Of the 92 anti-cancer drugs commercially available prior to 1983 in the US and among world wide approved anti-cancer drugs between 1983 and 1994, 60% are of natural origin (Cragg et al., 1997). In this instance, natural origin is defined as natural products, derivatives of natural products or synthetic pharmaceuticals based on natural product models (Jaspars and Lawton, 1998).

Plant-derived anti-cancer agents in clinical use
The isolation of the vinca alkaloids, vinblastine (1) and vincristine (2) from the Madagascar periwinkle, Catharanthus roseus G. Don. (Apocynaceae) introduced a new era of the use of plant material as anti-cancer agents. They were the first agents to advance into clinical use for the treatment of cancer (Cragg and Newman, 2005). Vinblastine and vincristine are primarily used in combination with other cancer chemotherapeutic drugs for the treatment of a variety of cancers, including leukemias, lymphomas, advanced testicular cancer, breast and lung cancers, and Kaposi's sarcoma (Cragg and Newman, 2005).
The discovery of paclitaxel (TaxolÒ, 3) from the bark of the Pacific Yew, Taxus brevifolia Nutt. (Taxaceae), is another evidence of the success in natural product drug discovery. Various parts of Taxus brevifolia and other Taxus species (e.g., Taxus Canadensis Marshall, Taxus baccata L.) have been used by several Native American Tribes for the treatment of some non-cancerous cases (Cragg and Newman, 2005) while Taxus baccata was reported to use in the Indian ayurvedic medicine for the treatment of cancer. The structure of paclitaxel was elucidated in 1971 and was clinically introduced to the US market in the early 1990s (Wani et al., 1971;Rowinsky et al., 1992). Paclitaxel is significantly active against ovarian cancer, advanced breast cancer, small and non-small cell lung cancer (Rowinsky et al., 1992). Camptothecin (4), isolated from the Chinese ornamental tree Camptotheca acuminate Decne (Nyssaceae), was advanced to clinical trials by NCI in the 1970s but was dropped because of severe bladder toxicity (Potmeisel, 1995). Topotecan (5) and irinotecan (6) are semisynthetic derivatives of camptothecin and are used for the treatment of ovarian and small cell lung cancers, and colorectal cancers, respectively (Creemers et al., 1996;Bertino, 1997). Epipodophyllotoxin is an isomer of podophyllotoxin (7) which was isolated as the active anti-tumor agent from the roots of Podophyllum species, Podophyllum peltatum Linnaeus and Podophyllum emodi Wallich (Berberidaceae) (Stahelin, 1973). Etoposide (8) and teniposide (9) are two semi-synthetic derivatives of epipodophyllotoxin and are used in the treatment of lymphomas and bronchial and testicular cancers (Cragg and Newman, 2005;Harvey, 1997).
Homoharringtonine (10), isolated from the Chinese tree Cephalotaxus harringtonia var. drupacea (Sieb and Zucc.) (Cephalotaxaceae), is another plant-derived agent in clinical use (Itokawa et al., 2005;Powell et al, 1970). A racemic mixture of harringtonine and homoharringtonine has been used successfully in China for the treatment of acute myelogenous leukemia and chronic myelogenous leukemia (Cragg and Newman, 2005;Kantarjian et al., 1996). Elliptinium (11), a derivative of ellipticine, isolated from a Fijian medicinal plant Bleekeria vitensis A.C. Sm., is marketed in France for the treatment of breast cancer (Cragg and Newman, 2005).

Plant-derived anti-cancer agents for future development
Numerous types of bioactive compounds have been isolated from plant sources. Several of them are currently in clinical trials or preclinical trials or   (Pettit et al., 1987). Combretastatin A-4 (14) is active against colon, lung and leukemia cancers and it is expected that this molecule is the most cytotoxic phytomolecule isolated so far (Ohsumi et al., 1998;Pettit et al., 1995).
Two novel alkaloids, schischkinnin (18) and montamine (19) have been isolated from the seeds of Centaurea schischkinii and Centaurea montana 2006). Both of the alkaloids exhibited significant cytotoxicity against human colon cancer cell lines. The unique structural features of 18 and 19 can be exploited as a template for generating compounds with enhanced anti-cancer activity. However, further investigations are necessary for their use as anti-cancer agents.

Conclusion
Natural products discovered from medicinal plants have played an important role in the treatment of cancer. Natural products or natural product derivatives comprised 14 of the top 35 drugs in 2000 based on worldwide sales (Butlet, 2004). Two plant derived natural products, paclitaxel and camptothecin were estimated to account for nearly one-third of the global anti-cancer market or about $3 billion of $9 billion in total annually in 2002 (Oberlines and Kroll, 2004). There are more than 270,000 higher plants existing on this planet. But only a small portion has been explored phytochemically. So, it is anticipated that plants can provide potential bioactive compounds for the development of new 'leads' to combat cancer diseases.