A Brief Review of Secondary Plant Metabolites as Anticancer Agents

Thousands of years ago, ancient civilizations in many countries such as China, India and Thailand used plants for medicinal purposes [1-3]. The traditional use of plants has continued into modern times as the World Health Organization (WHO) estimated that 80% of people living in developing countries depend on traditional medicine (mostly herbal medicines) to fulfill their primary health care needs [4]. Moreover, herbal medicines are highly valuable in the international marketplace. In Western Europe, herbal medicine revenue amounted to US $5 billion in 2003-2004. In China, sales of herbal medicine products reached US $14 billion in 2005. In Brazil, herbal medicine revenue reached US $160 million in 2007 [4]. Locally, over 70 plant species are used in Africa to treat both veterinary and human patients [5]. In addition, South Africa has a long history of using plants in traditional healing as it hosts a variety of around 30,000 flowering species [6].

This accounts for almost 10 % of the world’s higher plant species [7]. Thus, plants have been an integral component of the health care system both locally and internationally. There are several advantages to using plants for treat cancer. The complex synergistic interaction of various compounds in plants allows for the designing of herbal formulations that attack cancerous cells without harming normal cells of the body. This is possible as some plants can protect the body against cancer by enhancement of its detoxification functions. Certain plants contain biological response modifiers that can prevent the growth of cancer by modulating the activity of specific hormones and enzymes. Some plants have good immunomodulatory and antioxidant properties which can promote anticancer activity [8,9].

Moreover, a survey documented that over 60% of cancer patients depend on the use of vitamins or herbs as therapy [10]. Therefore, medicinal plants play an important role in the treatment of cancer. Although traditional practices involve the use of complex plant extracts, scientists have focused on purifying and identifying Independently Active Compounds (IACs) from plant extracts. The advantage is that once the structures of the IACs are determined they can be chemically or semi- chemically synthesized. The disadvantage is that some compounds found in plants act in a synergistic manner with other compounds to bring about biological activity.

Plants produce two distinct groups of compounds. The first group consists of the primary metabolites which include sugars (constituents of structural and nutritional elements), amino acids (constituents of structural elements and enzymes), lipids (constituents of membranes and nutritional elements) and nucleotides (constituents of genes). These metabolites are needed for the growth of the plant [11]. The second group consists of the secondary metabolites which include five types of compounds: polyketides, isoprenoids (terpenoids), alkaloids, phenylpropanoids and flavonoids (polyphenols) [12]. They are responsible for metabolic and/or growth regulation, lignification, the colouring of plant parts and protecting the plant against pathogen attack. Secondary metabolites are important constituents as they possess pharmaceutical properties [11,13]. Thus, these compounds are responsible for any possible anticancer activity.

Scientists have discovered many anticancer compounds from plants. A classic example is the discovery of a diterpene known as taxol which was isolated from the Pacific yew tree, Taxus baccata [13]. This research began in 1958 when the National Cancer Institute (NCI) (United States of America) screened 35, 000 plants for anticancer activity. Fortunately, a breakthrough was made in 1963 when Drs M. Wall and M.C. Wani of the Research Triangle Institute (North Carolina) found that the extract from the bark of T. baccata exhibited anticancer activity [14]. Twenty years later human clinical studies began and taxol was shown to be active against ovarian cancer which was incurable during the 80’s. In order to further develop taxol, the NCI issued a contract to Bristol Myers- Squibb in the United States [15]. Nowadays Taxol is semi-chemically synthesized as paclitaxel by using the needles and twigs from yew species which are cultivated under agricultural conditions. This drug has been approved by the Food and Drug Administration (FDA) for treating ovarian, breast, lung and other types of cancers. It is sold under the trade name Taxol [13]. Table 1 shows other plant-derived anticancer compounds that have been commercialized. South Africa has a variety of anticancer plants (Table 2) [13-36].

Table 1: Plant-derived anticancer compounds that have been commercialized.

Table 2: South African plants that have shown to exhibit anticancer activity.

Treatment of cancer

The treatment of cancer can involve surgical intervention, radiation, chemotherapy, targeted therapy and/or other therapies [37]. The objective of any cancer treatment is to remove all cancerous tissue without harming normal tissues. Severe cases of cancer are treated by surgery which allows for the removal of cancerous tissue with less damage to healthy tissues but surgery can also have certain risks (such as bleeding, drug reactions and damage to nearby tissues or organs) and side effects (such as pain and infection) [38,39]. In less severe cases of cancer, radiation or chemotherapy can be used to remove the cancerous tissue but these treatments are limited due to the toxicity imposed on healthy tissues [40].

The side effects of radiation therapy depend on the part of the body that is exposed to the treatment. The following side effects may be experienced: diarrhoea, hair loss, fatigue, mouth and throat changes, nausea, vomiting, sexual changes, fertility changes, skin changes and urinary changes [41]. The side effects of chemotherapeutic drugs may include: anemia, appetite changes, bleeding problems, constipation, diarrhoea, fatigue, hair loss, infection, memory changes, mouth changes, throat changes, nausea, vomiting, nerve changes, pain, sexual changes, fertility changes, skin changes, nail changes, swelling and urination changes [42]. In addition, a major complication that can occur while chemotherapy is administered is multi-drug resistance (MDR). This occurs as a result of

1. The up-regulation of membrane proteins which pump the drugs out of the cell to decrease the intracellular drug concentration,
2. The interruption of the balance between bioactivation and detoxification pathways,
3. Alterations in DNA repair response and
4. Alterations in apoptosis response. Thus, MDR can hinder the success of treating cancers by chemotherapy [43].

On the other hand, some cancers are treated with targeted therapy. This involves the use of monoclonal antibody drugs which target and disrupt molecular pathways that are responsible for promoting tumorigenesis [44]. However, some of these drugs are associated with serious side effects. For example, trastuzumab causes cardiotoxicity in women with metastatic breast cancer [45]. Cetuximab and panitumumab are used for the treatment of refractory metastatic colorectal cancer but these drugs cause a skin rash on the face and upper torso [46]. Rituximab is used to treat non-Hodgkin’s lymphoma but it is associated with serious infections such as the John Cunningham virus which infects the central nervous system [47,48]. Hence due to the side effects caused by the current cancer treatments, there is a need to discover and develop new drugs to effectively and safely treat cancer.

How do anticancer drugs induce apoptosis?

Anticancer drugs are classified according to their mechanism of action. There are four main classes of anticancer drugs: antimetabolites, genotoxic agents, anti-mitotic agents and targeted therapies [49,50] (Table 1). Through their mechanism of action, anticancer drugs can initiate apoptosis by switching on the expression of signal molecules such as Fas and FasL (for initiation of the extrinsic pathway type I and II) or p53 (for initiation of the intrinsic pathway) [51]. For instance, emodin induces topoisomerase II inhibition which causes DNA damage that activates the expression of FasL for initiation of the extrinsic pathway type I [52]. On the other hand, 6-Mercaptopurine incorporates itself into DNA and subsequently activates the expression of p53 for initiation of the intrinsic pathway [53]. Thus, anticancer drugs work in a very intricate manner to facilitate the death of cancer cells (Table 3) [54-60].

Table 3:

Anticancer treatment and therapy have evolved significantly since the 1820s when Dr James Arnott introduced cryotherapy as a mechanism to freeze tumors in breast and uterine cancer patients. Radiotherapy and immunotherapy were the main pillars of treatment for cancers in the late 19th century until the introduction of the chemotherapeutic drug, Mustine in 1942. The introduction of plant metabolites has contributed to the improvements in outcomes related to the treatment of cancer. Advances in phytochemical characterization and understanding the pharmacokinetic properties of plant metabolites are proving effective to increase the survival rate of cancer patients. New discoveries in the identification of novel metabolites from plants and novel targets in cancer cells are of paramount importance to our successful treatment of cancer.

The authors wish to thank the Durban University of Technology and the Department of Higher Education and Training (DoHET) for providing facilities and the National Research Foundation (NRF) for funding.

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